Chapter 107: Myeloma

Myeloma is a disease characterized by clonal expansion of malignant plasma cells that accumulate in the marrow, leading to anemia and associated cytopenias, hypogammaglobulinemia, osteolytic bone disease, hypercalcemia, and renal dysfunction.¹ Symptoms are a result of tumor mass effects, cytokine release by myeloma cells, marrow stroma or bone cells, or deposition of myeloma proteins into target organs (amyloid light-chain [AL] amyloidosis and light-chain deposition disease [LCDD]). Myeloma is part of a spectrum of diseases called plasma cell dyscrasias that include the following conditions: essential monoclonal gammopathy (MG; also known as monoclonal gammopathy of undetermined significance [MGUS]), smoldering myeloma (Chap. 106); solitary plasmacytoma, located in the bone as isolated lytic lesion or in the soft tissues; macroglobulinemia (Chap. 109); AL amyloidosis and LCDD (Chap. 108); and very rare disorders, such as osteosclerotic myeloma (POEMS [polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes] syndrome), Castleman disease, and heavy chain diseases (α-heavy-chain disease, μ-heavy-chain disease, and γ-heavy chain disease) (Chap. 110). Myeloma derives from cells with plasma cell morphologic features, capable of producing immunoglobulin molecules (Chap. 75), which can be detected in the serum and/or urine by electrophoresis and immunofixation. By definition, plasma cell dyscrasias result from the expansion of monoclonal cells, with resultant monoclonal protein secretion; however, oligoclonal and polyclonal protein abnormalities accompany some conditions, such as Castleman disease.

INCIDENCE AND PREVALENCE

Myeloma represents the second most common hematologic cancer, accounting for 1.4 percent of all cancers and 10 percent of hematologic malignancies, with a prevalence of 83,367 people in 2011.² The American Cancer Society has estimated that 24,050 new myeloma cases were diagnosed in the United States in 2014, of which approximately 11,090 will die. Most of the patients are diagnosed among people ages 65 to 74 years, with a median age at onset of 69 years; only 4 percent of cases occur before age 45 years. Men are affected more frequently than women (1.6:1 ratio) and individuals of African descent have twice the prevalence of myeloma as those of European descent. Conversely, individuals of Japanese and Spanish (Latino) descent have very low prevalence rates.^3–5 Myeloma is always preceded by a condition called MG, as has been demonstrated by long-term followup studies of a cohort of more than 70,000 banked serum samples from healthy subjects and from an independent military cohort.^6,7 MGUS is present in 3.2 to 4.0 percent of the general population,⁸ developing years before the diagnosis of myeloma, at a rate of approximately 1 percent per year (Chap. 106).⁹

GENETIC PREDISPOSITION

The etiology and the mechanisms of myeloma progression are still largely unknown.¹ Several epidemiologic reports have demonstrated an increased risk of myeloma or MG (up to fourfold) in first-degree relatives of individuals affected by plasma cell dyscrasias.¹⁰ Moreover, myeloma is associated with an increased risk of prostate cancer, melanoma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia.¹¹ More than 100 myeloma families have been described from different geographic areas^12–14; in one family, a germline mutation of the CDKN2A (p16) gene together with loss of heterozygosity of the other allele was identified as a rare low-penetrance genetic risk.¹³ Genome-wide association studies have identified six single nucleotide polymorphisms (SNPs) at chromosomes 2p23.3, 3p22.1, 3q26.2, 6p21.33, 7p15.3, 17p11.2, and 22q13.1 that are associated with risk of myeloma. The identified genes (DNMT3A, ULK4, TERC, PSORS1C1, CDCA7L/DNAH1, TNFRSF13B, and CBX7) have never been validated as myeloma-driver genes.^15,16 These same SNPs have also been independently associated with development of MG, with the risk increasing with the number of alleles carried.¹⁷ Moreover, the presence of hyperphosphorylated paratarg-7 (pP-7) carrier status has been reported as an autosomal dominantly inherited risk factor for MG and myeloma in a European population and in MG/myeloma cases in African Americans.^18,19

LIFE STYLE AND OCCUPATIONAL FACTORS

Some epidemiologic studies, including a cohort study of Swedish and Finnish twins and a meta-analysis,^20,21 have shown an association between high body mass index and risk of myeloma.^22,23 Specifically, obese individuals have higher levels of cytokines, such as interleukin (IL)-6 and insulin-like growth factor (IGF-1), which also are produced by adipocytes and are potent growth factor for myeloma cells.²⁴ No consistent associations have been observed with any particular diet, alcohol consumption, or smoking.²⁵ Occupational exposure to pesticides, organic solvents (benzene, petroleum derivatives, styrene) or chronic radiation have been alleged to be associated with myeloma in some studies,^25,26 but refuted by others. Furthermore, the use of thorium dioxide (thorotrast), a contrast medium used in the 1950s for angiography, increases the risk of plasmacytomas up to fourfold.²⁷ Exposure to acute radiation, as in atomic bomb survivors increases the overall rate of MG or myeloma after 15 to 20 years,²⁸ and accelerates MG transformation to myeloma.²⁹ People exposed to fresh wood, wood dust, or working in saw mill factories had an increased risk of myeloma in some studies.^30,31 Finally, associations between myeloma risk and autoimmune diseases (especially rheumatoid arthritis^32,33 or pernicious anemia³⁴) or infections (HIV and hepatitis C^35,36) have been proposed, based on a retrospective study among American male military veterans,^37,38 suggesting an immune-mediated mechanism for malignant transformation. Human herpes virus 8 DNA sequences responsible for Kaposi sarcoma and Castleman disease pathogenesis³⁹ have been reported by some investigators in marrow dendritic cells of myeloma patients, although other studies suggest that this is an epiphenomenon.^40,41

CELL OF ORIGIN

Myeloma cells derive from postgerminal–center marrow plasmablasts/plasma cells (Fig. 107-1). Myeloma cell immunoglobulin heavy chain (IGH) variable genes present somatic mutations in the absence of intraclonal variation or ongoing somatic hypermutation, indicating antigen-contact selection in the germinal center.^42,43 The existence of a myeloma stem cell, that is a precursor with self-renewal capacity, has been proposed for a long time, given myeloma’s low proliferative index and clonogenic efficiency. However, this remains a matter of debate.⁴⁴ Myeloma is a multistep process, always preceded by a MG phase.^6,7 MG cells share several similarities with myeloma, including a similar prevalence of hyperdiploidy and of the three primary IGH rearrangements [t(6;14), t(11;14), and t(14;16)]. However, chromosome 13 deletions, RAS mutations and non–immunoglobulin (Ig)-locus associated MYC translocations are more frequent in myeloma.⁴³ Indeed, the development of myeloma seems to necessitate an immortalizing event, such as a primary IGH translocation, an oncogene activation, or deregulation of a tumor suppressor, to occur in the germinal center during the switch recombination or somatic hypermutation, resulting in uncontrolled expansion of a long-lived plasmablast/plasma cell.⁴² In early stages, myeloma cells are dependent on the growth support provided by bone marrow stromal cells (BMSCs) (intramedullary phase), but can become independent of their medullary environment at late stages (plasma cell leukemia). However, 15 to 70 percent of newly diagnosed myeloma patients, using conventional morphology techniques^45–51 or multiparametric flow cytometry⁵² have circulating clonotypic myeloma cells (circulating tumor cells [CTCs]) in their blood, suggesting the presence of a “metastatic”/dissemination process that disseminates the disease hematogenously.⁵³ Moreover, the presence of CTCs in MG is a risk factor for myeloma progression,^54,55 as well as a poor prognostic factor in newly diagnosed or relapsed/refractory myeloma patients.^56,57 Myeloma CTCs share a similar phenotype to marrow myeloma cells, but are more quiescent, have better in vitro clonogenic capacity and have lower expression of integrin and adhesion molecules (including CD138) making them less dependent on marrow niches.⁵⁸

GENOMIC ALTERATION

Abnormal Karyotype and Common Translocations

Myeloma is a heterogeneous disease with a complex genetic landscape, characterized by several numerical and structural aberrations, including abnormal karyotypes, chromosomal translocations and copy-number changes (Fig. 107-2 and Table 107–1).

Traditionally, myeloma patients have been divided into two subgroups: hyperdiploid cases with more than 46 but less than 76 chromosomes (34 to 60 percent of myeloma); and nonhyperdiploid cases, which include individuals with a hypodiploid (up to 44 to 45 chromosomes), pseudodiploid (44/45 or 46/47 chromosomes with gains or losses), and near-tetraploid karyotype.^59–61 Hyperdiploid patients, normally IgG kappa-type with bone involvement, show gains of odd-numbered chromosomes, including trisomies of chromosomes 15, 9, 5, 19, 3, 11, 7, and 21 (ordered by decreasing frequency), and have a favorable prognosis that can however be affected by the concomitant presence of additional abnormalities such as chr11 or chr1q gains or chr13 loss.^62,63 Fluorescence in situ hybridization (FISH) analysis is employed to detect five major primary IGH translocations in myeloma,⁶⁴ which occur more frequently in nonhyperdiploid patients (85 percent vs. <30 percent).⁶⁵ Primary translocations are caused by errors during normal DNA recombination in isotype class switching of terminally differentiated B cells. Conversely, IGH translocations involving chromosome 8p24 and 11q13 (called secondary translocations) result from errors in somatic hypermutation processes.⁴² All of the translocations induce increased constitutive expression of specific oncogenes by their juxtaposition to immunoglobulin enhancer elements. The most frequent translocation (20 percent of cases) is t(11;14)(q13;q32),^66–68 leading to upregulation of cyclin D1, a crucial promoter of G₁-to-S transition via cyclin-dependent kinase (CDK)-4 or CDK6.^69,70 Rarely, cyclin D2 and cyclin D3 can be rearranged via t(12;14) (<1 percent) or t(6;14) translocations (2 percent of myeloma patients), respectively.⁷¹ Even in the absence of translocations, cyclins D1, D2, and D3 are often upregulated, creating specific patient subgroups with different prognoses.⁷² Specifically, the CD-1 subgroup (cyclin D1-high) responds well to treatment and has an increased frequency of early relapse but also has an excellent long-term survival, while the CD-2 subgroup (cyclin D3-high) exhibits a lymphoplasmacytoid morphology. Translocation t(4;14), a poor prognostic factor, pairs MMSET/WHSC1, a nuclear SET DOMAIN protein with FGFR3 (fibroblast growth factor receptor), an oncogenic tyrosine kinase receptor in 15 percent of patients, often in association with chromosome 13 abnormalities.^73–76 MMSET is an H3K4-, H3K27-, H3K36-, and H4K20-specific histone methyltransferase, that causes global changes in chromatin status, favoring myeloma cellular and clonogenic growth, adhesion, and tumorigenicity,⁷⁵ while FGFR3 promotes myeloma cell proliferation via RAS-MAPK (mitogen-activated protein kinase) and STAT (signal transducer and activator of transcription) pathways.⁷⁷ Additionally, activating FGFR3 mutations, mutually exclusive with RAS mutations, have also been reported in a small fraction of patients.^78,79 MAF translocations, which include t(14;16) overexpressing c-MAF, t(14;20) which deregulates MAFB, and t(8;16) involving MAFA are relatively rare (5 percent, 2 percent, <1 percent of cases, respectively) but associated with poor prognosis.⁸⁰ c-MAF, MAFA, and MAFB are all transcription factors involved in proliferation, responsiveness to IL-6 and BMSC-MM (multiple myeloma) adhesion,⁸¹ promoting cell-adhesion-mediated drug resistance (CAM-DR), via integrin α₇/E-cadherin interactions.⁸² The prevalences of these three primary IGH rearrangements [t(6;14), t(11;14), and t(14;16)] are similar in MG, indicating the need of additional transforming events to precipitate active myeloma.^83–85

Copy Number Alterations in Myeloma

Array comparative genomic hybridization (aCGH) analysis demonstrates numerous copy number alterations (CNAs) in myeloma cells. Deletion of chromosome 13, deletion of chromosome 17p13, and amplification of chromosome 1q21 are genomic aberrations associated with poor prognosis in myeloma patients.^86,87 Deletion of chromosome 13 affects 50 to 60 percent of newly diagnosed myeloma, is more frequent in the nonhyperdiploid group (>70 percent) in comparison to the hyperdiploid group and often cooccurs with t(4;14) or t(14;16) translocations.⁸⁸ Among other genes, RB1 and the miRNA-15a/16–1 cluster are deregulated in this context and may play a role in myeloma pathogenesis. Despite being traditionally associated with a poor prognosis, the adverse impact of isolated chromosome 13 deletion is now controversial,⁸⁹ in view of the good response of such patients to bortezomib-based regimens and the close association of del13 with the t(4;14)(p16;q32) and hypodiploid karyotype.

Deletions of chromosome 17p involving the TP53 locus are rare in newly diagnosed myeloma (5 to 10 percent), more common in relapsed and refractory cases (20 to 40 percent), and inevitably associated with negative prognosis, causing early relapse in patients treated with or without autologous stem cell transplantation. Mutations in TP53 are also often present on the second allele.^90,91 Despite having an unfavorable prognosis, regimens containing bortezomib can increase the median progression-free survival (PFS) and 3 years of patients with TP53 mutations (17 percent to 69 percent [P = 0.028]) in comparison to non–bortezomib-containing regimens, as shown by the HOVON-65/GMMG-HD4 trial.⁹² 1q21 amplification is detected by FISH in approximately 40 percent of newly diagnosed myeloma and in 70 percent of relapsed myeloma, and negatively affects overall survival (OS), with a cumulative effect based on the number of 1q21 locus copies.⁹³ Possible target genes of this lesion are CKS1B, a protein that regulates cyclin-dependent protein kinases, PSMD4, a proteasome subunit modulating response to bortezomib treatment, MCL1 or BCL9.^93–95 Interestingly, a reported jumping translocation of 1q12 (JT1q12) can have a receptor chromosome TP53 genomic locus, causing simultaneous gain of 1q21 and deletion of 17p.⁹⁶ Additionally, deletions of 1p, present in 7 to 40 percent of patients, are linked to reduced PFS and OS despite autologous stem cell transplantation.^97–99 TP73, LAPTM5, CDKN2C, a CDK inhibitor which interacts with CDK4 or CDK6 to regulate G₁/S phase, MTF2, TMED5, and FAM46C are candidate genes of the deletion. FAM46C loss or FAM46C mutations (evident in 15 percent of patients) are especially associated with shortened survival (median OS 25.7 months vs. 51.3 months, P = 0.004).^97,100 The biologic function of FAM46C is uncertain, although some data suggest it is related to mRNA stabilization. Other mutations include MYC rearrangements involving unbalanced translocations and insertions, small duplications, amplifications, and inversions on chromosome 8p24^101–104; homozygous deletions of 11q22 locus resulting in loss of YAP1, BIRC3, and BIRC2 genomic region^105–107; chromosomes 4, 14, and 16 aberrations that disrupt FGFR3, WWOX, and CYLD; deletions or amplifications of chromosome 6; and homozygous deletions of Xp11.2 locus,^62,63 involving UTX, an histone H3 lysine 27 (H3K27) demethylase, which is also mutated in 10 percent myeloma,¹⁰⁰ are also common. The “purpose” of these multiple plasmin inhibitors is to guard against premature plasmin activation and subsequent degradation of fibrinogen, until intravascular fibrin begins to appear.

Somatic Mutations and Interclonal Diversity Myeloma evolves in a stepwise process, transforming from MG to smoldering myeloma to overt myeloma, where mutations accumulate, conferring either a growth advantage (driver mutations) or are functionally irrelevant (passenger mutations). So far, more than 300 myeloma patient DNA samples have been sequenced using whole-genome sequencing or whole-exome sequencing approaches.^108–113 Specifically, 11 genes are commonly mutated in myeloma reaching a standard significant threshold.¹¹² Five of them (KRAS, NRAS, FAM46C, DIS3, and TP53) are relatively frequent.^100,108 Approximately 30 to 50 percent of newly diagnosed patients have RAS mutations at codons 12 or 13,^114–117 often in association with t(11;14), but mutually exclusive with t(4;14) that constitutively activates the MAPK pathway via FGFR3 upregulation.^115,118,119 Because RAS mutations are rare in MG, they are considered a possible driver to progression.¹²⁰ Conversely, TP53 mutations are a late event in myeloma,^91,121,122 an independent poor prognostic factor,¹²³ and are associated in one-third of patients with concomitant hemizygous deletion of chromosome 17.^90,124 Mutations in FAM46C and DIS3, genes possibly involved in RNA processing, are present in 10 to 21 percent of patients, often coupled with loss-of-heterozygosity in the remaining allele. Other significant genes are BRAF (4 percent of patients), TRAF3, CYLD, RB1, PRDM1, and ACTG1. TRAF3 and CYLD mutations, together with homozygous deletions in BIRC2/BIRC3, NIK overexpression and mutations in other genes (CARD11 and MYD88) contribute to constitutively activation of the NF-κB pathway.^{100,105,107,112} Genes involved in protein homeostasis, the unfolded protein response, or lymphoid/plasma cell development, such as PRDM1 involved in plasmacytic differentiation, and XBP1, IRF4, LRRK2, SP140, and LTB form a cluster of genes mutated in myeloma. Other recurrent mutated genes are ROBO1, a transmembrane receptor involved in β-catenin and MET signaling; EGR1 transcription factor; FAT3, a transmembrane protein belonging to cadherin superfamily; and histone-modifying genes (MLL, MLL2, MLL3, WHSC1/MMSET, WHSC1L1, and UTX, among others).^100,108,112 Plasma cell leukemia patients possess different aberrancies, including p14^ARF promoter methylation, PTEN loss, RB1 mutations and higher rates of TP53 mutations and deletions.¹²⁵ Finally, a novel intriguing concept is the idea of intratumor heterogeneity in myeloma, where different subclones can emerge and become predominant following different mechanisms of evolution, including linear, branching, parallel or convergent evolution.^108,126 Clonal diversity is indeed a fundamental process akin to Darwinian selection, favoring cancer progression and adaptation to therapy. Next-generation sequencing analyses show that most patients have a subclonal structure at diagnosis, with one predominant clone and several others which can reappear at different stages or following treatment.^108,110,111 Gene-expression profiling of myeloma cells helps categorize patients into distinct subgroups^127,128 and can predict therapeutic responsiveness to specific drugs, although the role of specific genetic signatures in risk stratification is still under debate.¹²⁹

ROLE OF MARROW MICROENVIRONMENT IN MYELOMA

The marrow microenvironment is composed of extracellular matrix (ECM) proteins, such as fibronectin, collagen, laminin and osteopontin; and cells, including hematopoietic stem cells, BMSCs, and endothelial cells, as well as osteoclasts and osteoblasts (Fig. 107-3) (Chap. 5).^130–133 Myeloma cells physically interact with ECM proteins and accessory cells to gain growth, survival, and drug resistance advantages. Among others, CD44, very-late antigen 4 (VLA4), neuronal adhesion molecule (NCAM), intercellular adhesion molecule (ICAM)-1, and syndecan 1 (CD138) mediate the adhesion of myeloma cells to the marrow and ECM, activating signaling pathways, such as nuclear factor-κB (NF-κB), to obtain CAM-DR to conventional chemotherapy.^134,135 In particular, CD138 (syndecan-1) is a transmembrane heparan sulphate bearing proteoglycan, expressed during the plasma cell stage of B-cell maturation, that can bind to type I collagen inducing expression of metalloproteinases, and promoting bone resorption and invasion.¹³⁶ Moreover, CD138 can be shed in the ECM, trapping growth-promoting and proangiogenic cytokines.^137,138 Increased soluble CD138 levels correlate with tumor burden and poor outcomes.¹³⁹ The SDF-1/CXCR4 axis regulates specific homing of myeloma cells to the marrow, but also mobilization or marrow egress, being possibly accountable for the multifocal marrow localization and blood circulation of myeloma cells.^140,141 Moreover, other chemokine receptors, such as CXCR3, CCR1, CCR2, and CCR5 can be expressed by myeloma conferring different migration capabilities to medullary and extramedullary cells.¹⁴² Accessory cells (BMSCs, endothelial cells, osteoclasts, and osteoblasts) secrete factors including IL-6,^143–146 IGF-1,^147–149 vascular endothelial growth factor (VEGF),^150,151 tumor necrosis factor-α (TNF-α),¹⁵² fibroblast growth factor (FGF),¹⁵³ stromal cell-derived factor 1α (SDF-1α),¹⁴¹ and B-cell activating factor (BAFF)¹⁵⁴; all capable of promoting expression of survival factors such as NF-κB.¹⁵⁵ IL-6 and other survival signals also induce phosphatidylinositol 3′-kinase (PI3K)/AKT,^156,157 STAT3 and MAPK signaling (Fig. 107-3).¹³³ BMSCs, myeloma cells and osteoclasts also secrete growth factors and cytokines such as VEGF, basic fibroblast growth factor (bFGF), and IL-8, to promote marrow angiogenesis, which increases delivery of oxygen and nutrients to myeloma cells. Moreover, the same endothelial cells produce growth factors (IL-6 and IGF-1), to favor plasma cell survival^{150,151,158,159} and express deregulated genes important for ECM and bone remodeling, cell adhesion, migration and resistance to apoptosis.¹⁶⁰ The degree of marrow angiogenesis, as assessed by microvessel density (MVD) is higher in active myeloma compared with MG¹⁶¹ and is also related to myeloma proliferation and infiltration, negatively affecting patient prognosis.¹⁶² Also lymphoid and myeloid cells are part of marrow microenvironment and can modulate myeloma survival. Myeloid cells, such as macrophages, mast cells and neutrophils control both pro- and antiinflammatory responses and regulate antigen presentation.¹⁶³ For instance, a specific group of myeloid cells, named myeloid-derived suppressor cells (MDSCs),¹⁶⁴ are highly represented in the marrow of myeloma individuals in comparison to healthy persons, and increase with disease progression, facilitating tumor development, growth, and immune escape, by blocking T-cell (CD8+ T and natural killer [NK] T) antitumor immune responses.¹⁶⁵

BONE METABOLISM

The presence of osteolytic bone lesions, bone pain, increased risk of pathologic fractures and generalized bone loss (or osteoporosis) is a well-defined feature of myeloma.¹⁶⁶ Indeed, as myeloma burden increases, an imbalance between osteoblast and osteoclast activities ensues, with suppression of bone formation by osteoblasts and uncoupled activation of osteoclasts (Fig. 107-4).^167–169 The ligand for receptor activator of NF-κB (RANKL) binds to RANK receptor to stimulate osteoclast differentiation, formation and survival¹⁷⁰; myeloma cells produce RANKL and upregulate RANKL expression in BMSCs and osteoblasts via direct contact interaction, signaling induction^171–173 or production of IL-7. Moreover, they promote suppression of osteoprotegerin (OPG),^174–176 a decoy receptor that normally prevents RANK–RANKL interaction^177,178 via soluble factors, integrin α₄β₁-vascular cell adhesion molecule (VCAM)-1 interaction,¹⁷⁹ production of Dickkopf-1(DKK1),¹⁸⁰ or inactivation by syndecan-mediated internalization into myeloma cells.¹⁸¹ Interestingly, OPG levels are decreased in the serum of myeloma patients and correlate with lytic bone lesion development¹⁸²; a high RANKL-to-OPG ratio is associated with worse prognosis.¹⁸³ Recombinant OPG constructs, soluble RANK, OPG peptidomimetics^{175,178,184,185} and an anti-RANKL antibody, denosumab,^186–189 have been developed to modulate the RANKL/OPG axis and reduce osteoclast activity in myeloma. Macrophage inflammatory protein (MIP)-1α, or chemokine C-C motif ligand, is also produced by myeloma cells and promotes maturation of precursor cells into osteoclasts^190–192; MIP-1α signals via CCR1 and CCR5 on osteoclasts and can further upregulate RANKL in stromal cells.¹⁹⁰ MIP-1α levels are elevated in myeloma patients,^193,194 whereas MIP-1α silencing or blockade of CCR1 reduces bone disease in in vitro or animal models. IL-6,¹⁹⁵ parathyroid hormone-related peptide (PTHrP),^196,197 annexin II,¹⁹⁸ and the ephrinB2/EphB4 axis¹⁹⁹ also promote bone reabsorption. Osteoblast suppression is another major player in myeloma bone disease: WNT signaling antagonists, including DKK1, frizzled related protein-2 (FRP-2),²⁰⁰ and sclerostin (SOST),^201,202 interfere with osteoblast maturation. DKK1 is expressed by myeloma cells and can upregulate RANKL levels in osteoblasts, increasing osteoclast activity.^203–205 DKK1 levels are increased in the serum of myeloma patients,²⁰⁶ and anti-DKK1 antibodies have been tested in animal studies^207–210 and are currently employed in clinical trials. Finally, high levels of Activin A, a member of transforming growth factor-beta (TGF-β) superfamily, IL-3 and IL-7 (via RUNX2/CBFA1 blockade) can inhibit bone formation and promote bone reabsorption.^211–213 Furthermore, the bone niche itself supports myeloma cell survival and prevents TNF-α–mediated apoptosis by producing various molecules.¹⁶⁷ Indeed, bisphosphonates not only block osteoclasts and modulate osteoblasts, but have an effect on tumor burden.²¹⁴ A similar effect is reported with OPG peptidomimetics and RANKL constructs in in vivo xenograft models.²¹⁵ Hence, bisphosphonates, especially zoledronic acid, are currently used in the clinic to reduce bone disease,^216,217 but are also associated with an increase in OS when compared to placebo based on a meta-analysis.²¹⁸ Markers of bone resorption and formation correlate with the extent of osteolytic disease.²¹⁹ Specifically, urine levels of pyridinoline (PYD) and deoxypyridinoline (DPD) crosslinks and serum levels of tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), a resorption marker only produced by activated osteoclasts and of collagen degradation products, including the N-terminal crosslinking telopeptide of type I collagen (NTX), are elevated in myeloma patients compared with healthy controls and can predict early progression of bone disease in myeloma. Conversely, bone formation markers, such as bone alkaline phosphatase (bALP) and osteocalcin (OC), are reduced.²¹⁹

PRECLINICAL MODELS OF MYELOMA

Novel therapies need to be tested in preclinical in vitro/vivo models capable of mimicking the role of human marrow microenvironment. In in vitro settings, myeloma cells are cocultured in liquid or semisolid systems together with different cytokines (IL-6, IGF-1, TNF-α) or with autologous BMSCs from patients. However, these systems do not truly recapitulate the marrow microenvironment^220–222 and in vivo models are necessary. Two main types of myeloma animal models have been exploited to study human myeloma biology and response to treatment: xenogeneic models in immunodeficient and humanized mice or syngeneic tumor models (Fig. 107-5).²²³ The xenogeneic models require subcutaneous injection of tumor myeloma cells in severe combined immune deficiency (SCID) or nonobese diabetic (NOD)/SCID mice, which are immunocompromised. These models lack the complex marrow–myeloma interaction, but can still be used to explore myeloma homing and novel drugs. Conversely, the SCID-hu or the SCID-rab mice models recreate a look-alike microenvironment, able to sustain myeloma cell growth.²²⁴ Specifically, primary myeloma cells or myeloma cell lines are grown in human fetal bone (the SCID-hu model) or rabbit bone (SCID-rab model), later implanted in SCID mice. Myeloma cells grow inside the implanted bones, or disseminate to the outer surface of the implanted bone, if they derive from patients with extramedullary disease. Moreover, these mice have circulating monoclonal immunoglobulins, osteolytic lesions, suppression of bone formation near myeloma foci and angiogenesis.^224,225 Studies propose novel xenogeneic models, where three-dimensional bone-like scaffolds are used instead of human fetal bone or rabbit bone.^226,227 Specifically, these scaffolds are internally coated with murine/human BMSCs or human mesenchymal stromal cells and then implanted in SCID or RAG2–/–γc–/– mice, to recapitulate the autologous marrow microenvironment in vivo. Myeloma cells are then loaded directly inside the scaffold or injected intracardiac to mimic myeloma homing. These models are more suitable for studying the microenvironment and also for drug testing, affording the opportunity to evaluate different stages or type of disease. Syngeneic tumor models include transplantable murine models like 5T33,^228,229 which are mostly representative of aggressive late-stage disease, as well as genetically engineered mouse models, such as the Vk^*MYC mouse,²³⁰ generated from the C57BL/6 mouse strain, which has a high incidence of spontaneous monoclonal gammopathy with aging, after activation-induced cytidine deaminase–dependent MYC activation in germinal center B-cells. This model exhibits high penetrance, clonal malignant plasma cells, which produce isotype class-switched immunoglobulins, a similar histology and immunophenotype to human myeloma, and delayed onset of renal failure, bone lesions, and anemia. The Vk^*MYC mouse model has been used for drug testing, strongly paralleling the drug activity observed in myeloma patients.²³⁰

Table 107–1 summarizes the signs and symptoms associated with myeloma. The International Myeloma Working Group has issued simplified criteria for the classification of myeloma and related disorders.^231,232 Symptomatic myeloma is diagnosed by evidence of organ or tissue impairment (end-organ damage) manifested by anemia, hypercalcemia, lytic bone lesions, renal insufficiency, hyperviscosity, amyloidosis, or recurrent infections, (commonly referred to as the “CRAB” criteria; namely, hypercalcemia, renal failure, anemia, and bone lesions) (Tables 107–2 and 107–3; Fig. 107-6). Presence of these features necessitate immediate treatment for myeloma.

HEMATOLOGIC ABNORMALITIES

Myelomatous involvement of the marrow typically causes anemia, which is present in more than two-thirds of patients with myeloma and relates to the degree of marrow infiltration. The erythropoietin response is insufficient in myeloma, owing to production of cytokines, (IL-1, TNF-β, Fas ligand, MIP-1α, and tumor necrosis factor–related apoptosis-inducing ligand [TRAIL], which produce erythroblast apoptosis),²³⁴ increased serum viscosity, or concomitant renal dysfunction.^235–237 Patients with myeloma have high urinary and serum hepcidin levels that inversely correlate with hemoglobin values.^238,239 IL-6 and bone morphogenetic protein (BMP)-2 mediate hepcidin transcription in the liver via STAT3 signaling,²⁴⁰ which, in turn, blocks iron release from macrophages and inhibits iron absorption from the intestine.^241,242 In contrast to other lymphoproliferative disorders, thrombocytopenia is uncommon at diagnosis, even with extensive marrow infiltration, as IL-6 has thrombopoietic activity.²⁴³ In some patients, thrombocytopenia might occur secondary to treatment or to autoimmune mechanisms (such as those accounting for anemia or factor VIII deficiency^244–246). Specifically, bortezomib causes a cyclic thrombocytopenia, with a different kinetic from cytotoxic drugs, appearing during the first 10 days of each cycle, but with a short recovery time, no cumulative or persistent effects and absence of marrow megakaryocyte toxic damage, as it primarily results from a functional alteration in platelet budding.²⁴⁷ Prolonged exposure to alkylating agents can also promote onset of a concomitant myelodysplastic syndrome. Overt bleeding is a relatively uncommon presenting symptom for myeloma patients²³³; however it occurs more commonly with IgA paraproteins, in the presence of very high concentrations of serum immunoglobins, high serum viscosity, and a prolonged bleeding time, with normal platelet counts, prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time.^248,249 Acquired von Willebrand factor (VWF) deficiency can develop²⁵⁰ as a result of plasma VWF-neutralizing antibodies, antibodies binding to the VWF glycoprotein 1b binding domain, or interfering with VWF binding to collagen,^251,252 or immunoglobulins that nonspecifically coat platelets or bind to fibrin, preventing aggregation. An asymptomatic prolonged thrombin time can also be present,²⁵³ as a result of interference with fibrin clot formation by the monoclonal protein²⁵⁴; in few cases, paraproteins recognizing thrombin and factor VIII have been reported.^253,255 Bleeding may also result from progression of disease, renal insufficiency, infections, therapy-related toxicity, invasive procedures, and anoxia/thrombosis in the capillary circulation. Bleeding is more common in systemic AL amyloidosis (15 to 41 percent of patients at diagnosis),^256–258 because of the deposition of free immunoglobin light chains forming insoluble fibrils in the small vessels or, more rarely, as a result of acquired factor X deficiency, related to absorption of factor X onto AL fibrils in the liver and spleen.^259,260 Amyloid splenic infiltration can cause hyposplenism and thrombocytosis.²⁶⁰ An increased risk of venous thromboembolic events is typical of MG and myeloma patients.^261,262 Hypercoagulable states may result from the pro-inflammatory activity of IL-6, abnormal interactions between myeloma cells, BMSCs and endothelial cells,²⁶³ paraprotein effects on fibrin polymerization and resistance to fibrinolysis, or rarely neutralizing antibodies against protein C, S,^264,265 or lupus anticoagulant²⁶⁶ and acquired protein C resistance.²⁶⁷ IMiDs, such as thalidomide and lenalidomide, have anti-angiogenic properties and are associated with an increased risk of venous thromboembolism (VTE), ranging from 5 percent²⁶⁸ to 18 percent of treated patients,²⁶⁹ especially when combined with high-dose dexamethasone, doxorubicin, or erythropoietic agents.^270–274 Warfarin and low-molecular-weight heparin play a role in primary and secondary VTE prevention,²⁷⁵ but aspirin is normally used in patients treated with IMiDs and steroids, in view of the presence of increased aggregation between platelet and VWF antigens.^276–279

IMMUNOGLOBULIN ABNORMALITIES

The majority of myeloma patients produce and secrete a monoclonal immunoglobulin (M-protein or M-spike) that can be detected by protein electrophoresis of the serum (SPEP) and/or of urine (UPEP) after a 24-hour urine collection. The M-protein presents as a single narrow peak, migrating in the γ, or rarely β, region of the densitometer tracing. Myeloma cells can secrete immunoglobulin heavy chains plus light chains, light chains alone, or neither (nonsecretory myeloma). In this last case, cytoplasmic immunoglobulins are detected. Immunofixation analysis identifies the unique and specific immunoglobulin idiotypes.⁴⁷ Monoclonal IgG (usually >3.5 g/dL) is present in approximately 60 percent of myeloma patients, monoclonal IgA (typically >2 g/dL) in 20 percent of patients, monoclonal immunoglobulin light chains alone are detected in 20 percent of patients, while IgD, IgM, and biclonal myeloma are rare (5 percent of cases). A low M-spike concentration is particularly suggestive of IgD myeloma isotype. Light-chain myeloma patients should be followed by UPEP and urine immunofixation and present more often with renal failure or increased creatinine levels. Light-chain proteinuria is frequent especially in IgD myeloma (see Table 107–3). Traditionally, IgA and especially IgD isotypes have been considered prognostically unfavorable.^280,281 Their prognostic value has been confirmed in patients enrolled on Total Therapy 1, 2, and 3 protocols; IgD was of borderline significance, mainly because of its rarity, but was strongly associated with elevated β₂-microglobulin (β₂M) and lactic dehydrogenase (LDH) serum levels, reflecting high tumor burden.²⁸² Suppression of normal, polyclonal serum immunoglobulins resulting in total hypoglobulinemia and an increased risk of infection is present in 70 to 90 percent of patients. The κ light-chain isotype is twice as common as the λ isotype, except in IgD myeloma. The free light chain (FLC) assay (FREELITE assay) is a novel technique used to detect monoclonal FLCs, and provides a FLC κ:λ ratio (Fig. 107-7).²⁸³ The κ:λ ratio is considered abnormal if less than 0.26 (λ-restricted Ig) or more than 1.65 (κ-restricted Ig).²⁸⁴ Because the half-life of FLCs is only 2 to 4 hours, in contrast to the half-life of the entire immunoglobulin, which is 17 to 21 days, the FLC assay can be used to detect early treatment responses and should be evaluated routinely in patients with AL amyloidosis and oligosecretory myeloma.²⁸⁵ A normal FLC ratio is also included in the criteria for stringent complete response (sCR).⁸ The FLC ratio is considered a predictor of the risk of progression from MG or smoldering myeloma to active myeloma^286,287 and it has prognostic value, being related to tumor burden.²⁸⁵ Indeed, high baseline FLC correlates with shorter survival in newly diagnosed myeloma patients despite achievement of complete response.^288,289 A rapid reduction in FLCs after therapy is also linked to inferior overall and event-free survival, suggesting the presence of highly proliferative myeloma cells, particularly sensitive to combination chemotherapy.²⁹⁰

MARROW FINDINGS

A marrow aspirate or biopsy showing plasmacytosis is a key component for the diagnosis of myeloma. The marrow can be evenly infiltrated (diffuse involvement) but more commonly displays considerable site-to-site variability (focal involvement).²⁹¹ The percentage of plasma cells can range from 10 percent to a virtual complete replacement of marrow. Occasionally, the biopsy specimen may contain a normal proportion of plasma cells as a result of the patchy marrow involvement. Myeloma diagnosis is also considered in the presence of less than 10 percent of chain restricted plasma cells if symptoms are reported or after histopathologic confirmation of an intraosseous or extraosseous plasmacytoma. By light microscopy, the morphologic appearance of myeloma plasma cells can be indistinguishable from normal plasma cells, characterized by abundant basophilic cytoplasm and round, eccentrically located nuclei, with “clock-face” or “spoke-wheel” chromatin without nucleoli, or by bizarre plasma cells with giant cellular size, open chromatin, and punched nucleoli (indicating increased transcriptional activity), a high frequency of binucleate or multinucleate cells, and the presence of inclusion globules of condensed or crystallized cytoplasmic immunoglobulin, including Russell bodies (cherry-red refractive round bodies), multiple pale bluish-white, grape-like accumulations (Mott cells or Morula cells), crystalline rods, glycogen-rich IgA (flame cells), or other inclusions. These abnormal cells are characteristic of plasmablastic myeloma,^292,293 a poor prognostic type of myeloma with a high number of mitotic figures (Figs. 107-8,107-9,107-10).²⁹⁴ Myeloma cells are clonal by definition and produce either κ or λ light chains, which are present in the cytoplasm but not on the membrane surface. A κ:λ ratio of greater than 1.65 or less than 0.26 is considered an index of κ or λ monoclonality, distinguishing this condition from reactive plasmacytosis.^295,296 Two-parameter flow cytometry staining for nuclear DNA content by propidium iodide and anti-κ and anti-λ light-chains can also be used to quantitate marrow involvement (Fig. 107-11).²⁹⁷ Myeloma cells are normally CD138+, CD45–, CD38+, and CD19–²⁹⁸, and are CD56+ in 70 percent of patients.^299–301 A few cases are CD20+³⁰² or CD117+ (KIT),³⁰³ but responses to treatment with rituximab or imatinib mesylate are uncommon. If amyloid deposition is suspected, Congo red staining can be performed on the marrow biopsy, showing diffuse involvement or focal perivascular niche localization of amyloid protein. Microvessel density can be assessed by staining for endothelial markers such as CD131 and CD34 in specialized laboratories or during clinical trials.³⁰⁴ Secondary myelodysplastic changes can rarely develop after prolonged treatment in myeloma patients, presenting with pancytopenia in the context of a hypercellular marrow, with characteristic FISH abnormalities (Chap. 87).^305,306 Metaphase cytogenetic studies and interphase FISH analysis should be performed routinely on myeloma cells at diagnosis to evaluate the presence of abnormal karyotypes and poor prognostic chromosomal abnormalities, such as deletion of chromosome 17, gain of chromosome 1q, loss of chromosome 1p, deletion of chromosome 13, and t(4;14) or t(14;16) translocations (Figs. 107-12 and 107-13).^307–310 Genetic analysis should be repeated at relapse only in patients initially classified as genetic standard-risk to rule out emergence of a more aggressive clone.³¹¹ The plasma cell labeling index corresponds to the percentage of plasma cells in the S-phase of the cell cycle and is measured by immunofluorescence staining using an antibody against 5-bromo-2′-deoxyuridine, which is actively incorporated by DNA on marrow plasma cells. Actively cycling myeloma cells represent a small proportion of the total malignant cells, normally 0.5 percent on average,^312–317 with few patients with a labeling index of more than 5 percent.^318,319 This value has been proposed as a myeloma prognostic marker, as patients with a labeling index of more than 0.5 percent at diagnosis have a shorter event-free survival (EFS) and OS.³¹⁸

RENAL DISEASE

Increased creatinine levels (>1.5 to 2.0 mg/dL) occur in 30 to 50 percent of myeloma patients at diagnosis, while overt renal failure requiring hemodialysis affects up to 10 percent of patients.²³³ Renal insufficiency is related to two major causes: myeloma cast nephropathy (also called light-chain cast nephropathy or myeloma kidney) and hypercalcemia.³²⁰ In myeloma cast nephropathy, the tubular absorptive capacity for light chains is overwhelmed, leading to the formation in the distal convoluted tubule (DCT) of the nephron of tubular casts. These tubular casts derive from the binding of precipitated light chains to Tamm-Horsfall mucoprotein (uromodulin) and can obstruct the DCT and parts of the ascending loop of Henle, initiating a giant cell reaction which leads to interstitial inflammation and fibrosis (interstitial nephritis).³²¹ The cast formation rate is strongly related to the urinary free-light chain concentration, which can be estimated by the amount of total proteinuria, based on the 24-hour urine collection or the serum light chain values. Conversely, the urine dipstick may be negative for protein as immunoglobulin light chains are often not detected by this technique. Lambda light chains tend to be more nephrotoxic than the κ type and renal impairment can be present with minimal λ light-chain secretion. Hypercalcemia (calcium >11 mg/dL), the second cause of nephropathy, is present in 15 percent of patients at diagnosis. Hypercalcemia creates volume depletion, natriuresis, and renal vasoconstriction, with an increased risk of prerenal azotemia; moreover, it can lead to intratubular calcium deposition, increasing the toxicity of filtered light chains or cause a reversible form of nephrogenic diabetes insipidus.³²² Light-chain glomerulopathy is caused by the deposition of immunoglobulins either in the form of amyloid or nonamyloid. In AL amyloidosis, light-chain immunoglobulin proteinuria is associated with glomerular damage, resulting into an overt nephrotic syndrome (Chap. 108).³²³ Light chains are converted into insoluble fibrils or granular deposits inside the mesangial cells causing Congo red-positive amyloid accumulation, localized predominantly in the glomeruli. Vascular and tubular amyloid deposits are less common, but can cause narrowing of the vascular lumens or tubular dysfunction such as type 1 (distal) renal tubular acidosis or nephrogenic diabetes insipidus.³²⁴ AL amyloidosis with renal dysfunction is more common in patients with λ light-chains, especially those with λ VI light-chain subgroup.³²⁵ Kappa chains or heavy-chain fragments can form Congo red-negative nonfibrillar deposits with linear involvement of the basement membrane, in a condition called LCDD or, more generally, monoclonal immunoglobulin deposition disease (MIDD). The clinical presentation of LCDD is heralded by development of the nephrotic syndrome followed by renal failure or acquired Fanconi syndrome (more often associated with κ light-chain deposition). In these deposition diseases, the urine dipstick for protein is positive, as a result of the glomerular leakage of albumin.^256,324 Renal enlargement can be caused by AL amyloidosis (Chap. 108) or, less commonly, by renal plasmacytomas.³²⁶ Renal vein thrombosis, hyperviscosity, dehydration, use of nephrotoxic drugs (antibiotics, nonsteroidal antiinflammatory drugs, imaging contrast agents—especially when rapidly infused),³²⁷ hyperuricemia, or type I cryoglobulinemia can all induce or aggravate renal impairment in myeloma patients. Bisphosphonates, in particular, should be infused slowly, at adjusted doses, based on creatinine values. Renal biopsy is usually unnecessary, unless nephrotic syndrome is present. However, if systemic amyloidosis or, less likely, LCDD, is suspected, a subcutaneous fat aspirate or rectal biopsy should be performed first and tested for amyloid deposits.³²⁰ Renal biopsy specimens should be processed fresh-frozen to allow for immunofixation studies, including electron microscopy and Congo red staining for amyloidosis. Supportive care associated with prompt initiation of antimyeloma treatment is the cornerstone of the management of renal impairment in myeloma. To correct hypercalcemia, aggressive hydration, use of calcitonin and a slow infusion of one single dose of a bisphosphonate is applied. Cytoreductive chemotherapy should be started as soon as possible. Rapid removal of light chains by plasma exchange is a controversial technique; the introduction of high cut-off hemodialysis, which employs novel dialysis filters capable of clearing away free-light chains, is showing promising results and improved patient outcomes.^328–330

In general, myeloma renal impairment is reversible in approximately 50 percent of patients. Conversely, amyloid- and LCDD-related renal impairment tends to be stable or progressive. Patients presenting in acute renal failure have a high early mortality, with up to 30 percent dying within the first months. Improvements in renal function rarely occur after 6 months from diagnosis. Renal dysfunction is a negative prognostic factor, results in use of suboptimal therapies, longer hospitalization, and an increased risk of infection. Hence, patients who recover normal kidney function have a better outcome compared to those who do not.^331–333

PAIN

Back or chest bone pain as result of vertebral or rib fractures at sites of osteopenia or from lytic bone lesions is present at the time of diagnosis in approximately 60 percent of patients.²³³ The pain is usually worse with movement and at night. Pathologic fractures of long bones can ensue as well. Kyphosis or reduction of patient’s height is another common feature. Localized pain can also derive from focal plasmacytomas, presenting as expanding masses compressing the spinal cord or nerve roots. Amyloid deposits can provoked painful mass effects, when localizing into nerve sheaths, as in amyloid-associated carpal tunnel syndrome.³³⁴

INFECTIONS

Myeloma patients are at an increased risk for infections that represent a leading cause of morbidity and mortality. Several aspects contribute to infection risk, including immune dysfunction in the innate and adaptive immune systems,³³⁵ extrinsic factors, like type and duration of therapy (e.g., cytotoxic agents, glucocorticoids, lenalidomide, autologous/allogeneic hematopoietic stem cell transplantation), and physical factors, such as age, coexisting comorbidities, hypoventilation secondary to pathologic fractures, indwelling vascular catheters and impaired mucosal integrity. A broad immune dysfunction involving B lymphocytes, T lymphocytes, NK cells, and dendritic cells is noted in myeloma patients.^335–337 Specifically, myeloma cells or BMSCs can produce a series of immunologically molecules, such as TGF-β, IL-10, and IL-6. TGF-β and IL-10 suppress IL-2 autocrine pathways, blocking T-cell antitumoral responses^338–340 and stimulate T-regulatory cell proliferation.³⁴¹ Moreover, these cytokines sustain the immature phenotype of dendritic cells, highly specialized antigen-presenting cells (Chap. 21), reducing their expression of costimulatory molecules (HLA-DR, CD40, and CD80 antigens) and thereby their antigen stimulatory capacity.³⁴² IL-6 also inhibits dendritic cell production from CD34+ progenitor cells.³⁴² Normal CD19+ B lymphocytes at early and late stages are suppressed in myeloma, resulting in hypogammaglobulinemia, inversely correlating with the disease stage.³⁴³ B-cell dysfunction in myeloma can be related to TGF-β effects, lack of stimulatory signals from helper T cells, and altered gene expression. Hypogammaglobulinemia is particularly responsible for a myeloma patients’ susceptibility to encapsulated organisms, such as Streptococcus pneumoniae and Haemophilus influenzae. T-cell subsets are also abnormal, with inversion of the CD4:CD8 ratio³⁴⁴ and T-helper type 2 (Th2) cell–type skewing.³⁴⁵ Moreover, global T-cell receptor (TCR) diversity is reduced, with the presence of oligoclonal expansions of CD4+ and CD8+ T cells and TCR signaling is compromised^344,346,347; χδT cells and NK cells are also aberrant in myeloma. The presence of decreased B cell or T cell counts can negatively impact survival.³⁴⁸ β₂M is the invariant chain of the major histocompatibility (MHC) class 1 molecule, which is shed by myeloma cells. Its levels correlates with tumor burden and are important for patient staging using the International Staging System (ISS)²³² (see section Staging below). β₂M induces IL-6, IL-8, and IL-10 production and activation of STAT3. However, it also has immunosuppressive functions, by reducing surface expression of CD83, HLA-ABC, costimulatory molecules, and adhesion molecules on dendritic cells, impairing stimulatory dendritic-allospecific T-cell responses by inactivation of Raf/MEK/ERK cascade and NF-κB in dendritic cells.³⁴⁹ Vaccines, prophylactic antibiotics or antivirals, and intravenous immunoglobulin are preventative measures apt to decrease infections among myeloma patients. Yearly influenza vaccines and a single pneumococcal vaccine at diagnosis is recommended, as myeloma patients can still mount a suboptimal immunologic response. Antiviral prophylaxis (e.g., acyclovir 400 mg twice daily or valacyclovir 500 mg once daily) is mandatory in patients treated with bortezomib combined with glucocorticoid regimens to prevent herpes zoster. Antibiotic prophylaxis is controversial. A study where patients were randomized on a 1:1:1 basis to receive either a daily quinolone, trimethoprim-sulfamethoxazole, or placebo for the first 2 months of treatment did not show a decreased incidence of serious infection (more severe than grade 3 and/or requiring hospitalization) nor of any infection within the first 2 months of treatment or any improvement in response rate or OS.³⁵⁰ However, antibiotic prophylaxis with ciprofloxacin or trimethoprim-sulfamethoxazole might be still beneficial in selected patients, such as those patients with a history of repeated infections, those receiving more intense regimens or those with persistently low CD4+ counts to prevent Pneumocystis carinii pneumonia or other infections. Intravenous immunoglobulin (IVIG) infusion may be considered in patients with recurrent, serious infections despite antibiotic prophylaxis.

NEUROPATHY

Local myeloma growth can cause polyneuropathy by spinal cord or peripheral nerve compression, even though polyneuropathy is not a common presenting symptom, unless in the context of perineuronal or perivascular (vasa nervorum) amyloid deposition.²⁵⁶ POEMS syndrome, or osteosclerotic myeloma, is an exception, where complete polyneuropathy is practically always present along with organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes.^351,352 The pathogenesis of POEMS syndrome is largely unknown, but chronic overproduction of proinflammatory cytokines, such as VEGF, plays a major role.

HYPERVISCOSITY

Less than 10 percent of myeloma patients develop signs of hyperviscosity syndrome, a condition that manifests in 10 to 30 percent of patients with Waldenström macroglobulinemia (Chap. 109), because monoclonal IgMs display a higher intrinsic viscosity than other immunoglobulins.^353–355 Cutaneous or mucosal bleeding is very common in hyperviscosity syndrome, together with blurred vision, headache, vertigo, dizziness, nystagmus, deafness, and ataxia. Circulatory problems, affecting cerebral, pulmonary and renal circulation can rarely ensue in the presence of high blood viscosity (see “Hyperviscosity Syndrome” in Chap. 109).³⁵⁶ Relative serum viscosity but not serum immunoglobulin levels correlates with onset and extent of clinical symptoms. Based on the specific physicochemical properties of classes and subclasses of immunoglobulins (Chap. 75), up to one-quarter of patients with IgA myeloma can have blood hyperviscosity as a result of the tendency of IgA to form dimers or polymers.³⁵⁷ Patients with IgG₃ subclass myeloma, whose immunoglobulins have higher propensity to aggregate, can also manifest with hyperviscosity syndrome.³⁵⁸

PLASMA CELL LEUKEMIA AND EXTRAMEDULLARY DISEASE

Plasma cell leukemia (PCL) is diagnosed when more than 2000 myeloma cells/μL are present in the blood or plasmacytosis accounts for greater than 20 percent of the differential white cell count. PCL is rarely manifest at the time of primary presentation and more commonly arises from preexisting myeloma as end-stage disease. In this case, tumor cells have become microenvironment-independent and accumulate in the marrow, but also recirculate in the blood (extramedullary disease).^359–362 However, low levels of circulating plasma cells can be detected in the majority of myeloma patients. By definition, extramedullary disease (EMD) is the presence of a clonal plasmacytic infiltrate outside the marrow. Specifically, it is now considered EMD only if the infiltrate is present at anatomic sites distant from the bone or adjacent soft tissue, hence excluding cases where soft-tissue masses arise in contiguity with the marrow.³⁶³ Indeed, in true EMD, plasma cells have an immature, plasmablastic morphology and have a high proliferative index. According to different clinical trials, 6.0 to 7.5 percent of patients screened with magnetic resonance imaging (MRI) or positron emission tomography–computed tomography (PET-CT) have EMD at the time of diagnosis.^364,365 Extramedullary masses can localize to several organs, including liver, lymph nodes, spleen, kidneys, breasts, pleura, meninges, and cutaneous sites, and are inevitably associated with elevated levels of LDH³⁶⁶ and a poor response to treatment.^367–369 Leptomeningeal myelomatosis with abnormal cerebrospinal fluid findings is rare but can manifest at advanced stage.^370,371 EMD cells are often CD56– or^low, and present t(4;14) and del(17p) more commonly,^372,373 together with TP53 mutations, TP53 nuclear localization,^110,374 or high expression levels of focal adhesion kinase (FAK1).³⁷⁵ Additionally, it has been speculated that high-dose melphalan and modern salvage therapies can artificially increase the incidence of EMD as a result of longer duration of treatment, emergence of dormant cells, and poor penetration of the drugs to sanctuary sites like the central nervous system.³⁷⁶

SPINAL CORD COMPRESSION

Spinal cord compression can result from an extramedullary plasmacytoma or vertebral fracture and present acutely with severe back pain alongside with weakness or paresthesias of the lower extremities, or bladder/bowel incontinence. It should be considered a medical emergency, evaluated with MRI, and promptly treated with a combination of local radiotherapy, decompressive laminectomy, and systemic chemotherapy to avoid permanent deficits. Specifically, local radiotherapy using less than 30 Gy is potentially curative, in the presence of a solitary plasmacytoma; in patients with systemic disease, the DT-PACE regimen, which combines high-dose dexamethasone pulsing, as part of the combination with oral dexamethasone, daily thalidomide, and 4 days of continuous-infusion cisplatin, doxorubicin, cyclophosphamide, and etoposide, can provide effective treatment and should be followed by local radiation in the absence of symptom relief and lack of tumor shrinkage. If a singular vertebral collapse is evident without plasmacytoma, decompressive laminectomy is the treatment of choice.

Minimal evaluation requirements include a complete blood count with differential white cell count; examination of a blood film for the presence of rouleaux and circulating myeloma cells; a comprehensive serum metabolic panel for the detection of hypercalcemia, renal failure, serum β₂M, C-reactive protein, and elevation of LDH (Table 107–4). Myeloma protein studies should include serum protein electrophoresis to quantitate the serum protein electrophoretic pattern in combination with nephelometric quantitation of immunoglobulin levels, serum-free light-chain assay, and a 24-hour urine collection to quantitate 24-hour total urinary protein and determine specific urinary proteins, such as light chains or Bence Jones protein, using urine electrophoresis.

Immunofixation of serum and urine is needed for the immunoglobulin heavy- and light-chain isotype determination. Serum-free light-chain assay is of particular use in the monitoring of patients with a plasma monoclonal immunoglobulin, the diagnosis and monitoring of patients who would otherwise be considered to have nonsecretory myeloma, and patients who only have light-chain proteinuria. Marrow aspiration and biopsy should include genetic studies (FISH and cytogenetics) and flow cytometry. Newer modalities such as mutational profiling and gene expression studies are being undertaken but are not yet standard of care tests. Radiographic examination usually comprises a metastatic bone survey to detect vertebral compression fractures, osteopenia, and impending fractures of long bones and pelvis. MRI and PET-CT are more sensitive than the bone survey, and better capture early bone disease, the extent of bone disease, and EMD. Both MRI and PET-CT findings have important prognostic implications.^209,364 These tests are now being used more frequently specifically in smoldering multiple myeloma (SMM) patients. Assessment of the heart by echocardiogram and electrocardiogram is useful in the right clinical context to detect cardiac amyloidosis and/or LCDD, and, in selected cases, cardiac MRI may be helpful to demonstrate myocardial infiltration. Measurement of brain natriuretic peptide and N-terminal prohormone B-type natriuretic peptide are useful screening tests to detect cardiac dysfunction caused by amyloidosis or LCDD.

STAGING

Multiple attempts have been made to define clinical and laboratory parameters that have prognostic significance in myeloma.^231,377,378 Of the many staging systems, the Salmon-Durie staging system was historically the most commonly used, however, it has been replaced by newer staging systems, which reflect better myeloma biology.³⁷⁹ The Salmon-Durie system relates myeloma cell mass to the extent of bony disease, hemoglobin, and calcium levels, and the monoclonal immunoglobulin levels in serum and urine (Table 107–5). However, measurement of bone disease by skeletal survey in myeloma is observer-dependent and potentially subjective.

The ISS is based on two widely available parameters—serum β₂M and albumin—and recognizes three stages (Table 107–6). Stage I is defined by β₂M less than 3.5 mg/L and albumin 3.5 g or greater/100 mL; stage III is characterized by a β₂M of 5.5 mg or greater/L.²³¹ The intermediate stage II has features of neither stage I nor III. β₂M correlates with tumor mass and impairment in renal function, whereas a low albumin reflects the effect of IL-6 produced by the microenvironment of myeloma cells on the liver.^380–382 The different ISS stages were predictive of outcome in an analysis of more than 11,000 patients receiving either standard therapies or melphalan-based high-dose therapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT; Table 107–7). Although predictive of outcome, several shortcomings of the ISS include lack of accounting for cytogenetics and bone disease in patients.

IMAGING STUDIES

Imaging studies are an essential part of the diagnosis and management of myeloma. The standard of care in the initial staging of newly diagnosed myeloma is a complete skeletal survey, which includes a posteroanterior view of the chest; anteroposterior and lateral views of the cervical spine, thoracic spine, lumbar spine, humeri, femora, and skull; as well as, an anteroposterior view of the pelvis. Approximately 80 percent of patients with myeloma will have radiologic evidence of bone involvement on skeletal survey. Although widely employed, this modality has limitations. Roentgenographically detectable osteolytic lesions require at least 50 to 70 percent loss of bone mass,³⁸⁸ and hence represent advanced bone destruction. Conventional x-rays have limited sensitivity and, consequently, may miss between 10 and 20 percent of early lytic lesions.³⁸⁹ In addition, reproducibility of skeletal survey results is low and dependent on the expertise of the reveiwer.³⁹⁰ Another limitation of plain x-rays is that they cannot be used to assess response to therapy as lytic lesions seldom show evidence of healing.³⁹¹ Although skeletal survey remains the gold standard for the initial evaluation of myeloma, there are limitations to this modality that necessitate the use of additional imaging modalities (Fig. 107-14).³⁹²

MRI is widely used in both newly diagnosed and relapsed myeloma and in the event of suspected cord compression. Whole-body MRI can give complementary information to skeletal survey and is recommended in patients with normal plain radiography, particularly when symptoms are present. Numerous studies demonstrate superior sensitivity of MRI when compared to both skeletal survey^393,394 and whole-body multidetector computed tomography (MDCT).³⁹⁵ MRI also has the ability to discriminate myeloma from normal marrow. Specifically, MRI allows visualization of the medullary cavity and thus direct assessment of the extent of myeloma cell infiltration of the bone.³⁹⁶ In the event of suspected spinal cord compression, MRI is the imaging modality of choice for its ability to provide an assessment of the level and extent of cord compression, the size of the tumor mass, and the extent to which it is compressing the epidural space (Fig. 107-15).³⁹⁷ In the event that MRI is unavailable or contraindicated, urgent CT may be used for the evaluation of a potential cord compression.

PET, particularly in combination with CT, can be used for the detection of active myeloma. Multiple studies demonstrate that PET-CT is able to detect lesions at least 1 cm in diameter using a standard uptake value (SUV) cutoff of 2.5 to indicate the presence of disease.³⁹⁸ The limitation of this technology is that subcentimeter lesions may not be detected.³⁹⁹ In a prospective study comparing PET-CT, MRI, and whole-body x-rays in newly diagnosed myeloma patients, PET-CT was superior to plain films in 46 percent of patients, including 19 percent with negative x-rays. However, PET-CT scans of the spine and pelvis failed to show abnormalities in 30 percent of patients in whom MRI had demonstrated an abnormal pattern of marrow involvement. On the other hand, PET-CT identified myelomatous lesions in areas that were out of the field of view of MRI in 35 percent of patients. The combination of these two modalities proved the most powerful with a detection rate of as high as 92 percent.⁴⁰⁰ In a multivariate analysis, the same group also showed that persistent PET-CT positivity before and after primary therapy and subsequent high-dose therapy, is a predictor of prognosis in patients with symptomatic myeloma (Fig. 107-16).⁴⁰¹ CT, PET-CT, and MRI can be used for the diagnosis and assessment of soft-tissue masses.

If the initial laboratory evaluation indicates the presence of a monoclonal immunoglobulin in serum and/or urine, the finding requires further studies to distinguish among (1) MG; (2) solitary plasmacytoma of bone or soft tissue; (3) indolent myeloma; (4) immunoglobulin deposition diseases, such as primary amyloidosis or LCDD; and (5) symptomatic or progressive myeloma.⁴⁰² Tables  107–1,107–2,107–3,107–4 indicate the findings of symptomatic myeloma. The International Myeloma Working Group has developed new standardized diagnostic criteria that have been widely adopted.⁴⁰³

MANAGEMENT OF NEWLY DIAGNOSED MYELOMA

Myeloma therapy is in a period of dynamic change. The years since 1996 have seen dramatic advances in the treatment of myeloma, beginning with the publication of a randomized trial investigating the use of high-dose melphalan and autologous stem cell transplant in 1996,⁴⁰⁴ followed by the introduction of IMiDs thalidomide,⁴⁰⁵ lenalidomide,⁴⁰⁶ and pomalidomide,⁴⁰⁷ and the proteasome inhibitors bortezomib⁴⁰⁸ and carfilzomib.^409,410 With these new treatments, the 5-year relative survival rate has increased in the Surveillance Epidemiology and End Results (SEER) database from 28.8 percent from the period of 1990 to 1992 to 34.7 percent in years 2002 to 2004 to 40.3 percent in years 2003 to 2007.^411,412 Previously, most of the survival benefit observed was in younger patients, but one analysis showed that patients older than the age of 70 years were deriving benefit as well.^411,412 Table 107–7 lists novel agents and combinations currently used for induction in transplant-eligible patients with newly diagnosed myeloma.

High-Dose Therapy

Every newly diagnosed myeloma patient should be assessed for fitness to undergo auto-HSCT. Although some centers use an age cutoff (usually age 65 years or younger), it is reasonable to take performance status, organ function, and comorbidities into account, rather than age, when deciding whether a patient is eligible. The rationale for the administration of high doses of alkylating agents (melphalan) followed by transplantation of syngeneic, allogeneic, and autologous marrow or blood progenitor cells (PBPCs), is based on the fact that myeloma is uniformly fatal and myeloma cells have demonstrated a dose–response curve to chemotherapy with a high proportion of patients achieving complete responses when higher doses of therapy are given.

High-dose chemoradiotherapy followed by transplantation of either autologous marrow or PBPCs has achieved high (40 percent) complete response (CR) rates, but the median duration of these responses has been only 2 to 3 years. The Intergroupe Francais du Myelome (IFM 90), a national French study, first demonstrated the efficacy of auto-HSCT over conventional chemotherapy in 200 myeloma patients.⁴⁰⁴ Several randomized trials and case-controlled studies have been performed and the results have been variable. For example, the Medical Research Council (MRC) randomized study confirmed a 12-month survival benefit for the transplanted arm.⁴¹⁵ In contrast, the U.S. Intergroup randomized trial was unable to confirm the benefits of transplantation.⁴¹⁶ Despite the use of aggressive approaches like transplantation, few, if any, patients are cured. To improve upon the results of high-dose chemotherapy, the French group has compared single versus double autografts and their data suggest that two sequential transplants may benefit a subset of patients with myeloma who did not achieve a complete remission after the first transplant.⁴¹⁷ This question is also being addressed by the ongoing phase III, multicenter trial of single autologous transplant with or without consolidation therapy versus tandem autologous transplant with lenalidomide maintenance (BMT CTN 0702).

Novel Agents

Beginning in the 1980s, the combination of vincristine, doxorubicin (Adriamycin), and dexamethasone (VAD) was used as the standard induction chemotherapy, but has been replaced by the advent of novel drugs.²⁷¹ Highly active regimens using IMiDs and proteasome inhibitors have replaced VAD. Two studies combined thalidomide with dexamethasone as initial therapy for myeloma and achieved rapid responses in two-thirds of patients, allowing for successful harvesting of blood stem cells for transplantation.^413,414 Thalidomide/dexamethasone has been compared with VAD and with dexamethasone, as initial therapy for patients prior to collection of autologous stem cells and transplantation. In a case-control analysis, Cavo and colleagues showed that thalidomide/dexamethasone achieved higher overall response rates⁴¹⁸ whereas a randomized phase III (Eastern Cooperative Oncology Group [ECOG]) trial showed statistically significantly higher response rates for thalidomide/dexamethasone than dexamethasone-treated patient cohorts.²⁷¹ This study provided the rationale for FDA approval of this regimen for initial treatment of myeloma. Moreover, early studies show 91 percent responses, including 6 percent complete and 32 percent near complete/very good partial responses to lenalidomide combined with dexamethasone.

Based on these promising results, a phase III trial in the United States headed by ECOG investigated the role of lenalidomide and dexamethasone in newly diagnosed myeloma. The study design allowed all patients to stay on-study for the first four cycles only for response assessment, after which patients could go off-study to proceed with stem cell transplantation. Published safety data from this trial found that combining lenalidomide with the low-dose dexamethasone regimen was preferable to the combination with high-dose dexamethasone, with a reduction in grade 3 or higher nonhematologic adverse events at (48 percent vs. 65 percent), including thromboembolism (12 percent vs. 26 percent), and infections (9 percent vs. 16 percent) in the two treatment arms of the trial.³⁸³ The low-dose dexamethasone-containing regimen did lead to an increased occurrence of grade 3 or greater neutropenia (20 percent vs. 12 percent). Importantly, the combination with low-dose dexamethasone had a survival benefit over combination with high-dose dexamethasone, with a 1-year OS of 96 percent and 87 percent, respectively.^383,419 Prophylaxis against clotting with aspirin, Coumadin, or subcutaneous heparin, is needed when patients are treated with lenalidomide therapy.^269,270

One study examined single-agent bortezomib⁴²⁰ and a second tested bortezomib combined with dexamethasone as initial therapy⁴²¹; in both studies, high frequency and extent of response were noted. In the phase I/II trials, the safety and efficacy of the combination of lenalidomide, bortezomib, and dexamethasone (RVD) were demonstrated.³⁸⁶ The benefits of combination therapy with RVD as first-line therapy were documented in two phase II trials—the IFM 2008 trial and the EVOLUTION trial.^422,423 The overall response rate (ORR) after induction in the IFM trial was 97 percent (13 percent sCR, 16 percent CR, and 54 percent very good partial response [VGPR] or better). The EVOLUTION trial was designed to compare RVD with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in a randomized, multicenter setting. The ORR for the RVD arm after primary treatment followed by maintenance with bortezomib for four 6-week cycles was 85 percent (24 percent CR, 51 percent VGPR or better).

Carfilzomib is a second-generation proteosome inhibitor that binds to the proteasome in a highly selective and irreversible fashion. Although the drug was initially approved only for relapsed or refractory myeloma, carfilzomib is now being studied in the upfront setting.⁴⁰⁹ In a dose-escalation study, the combination of carfilzomib, lenalidomide, and dexamethasone (CRD) has been evaluated at carfilzomib doses of 20, 27, and 36 mg/m² given on days 1, 2, 8, 9, 15, and 16 for eight cycles followed by days 1, 2, 15, and 16 with subsequent cycles. Lenalidomide was given at a dose of 25 mg on days 1 to 21 and dexamethasone at 40 mg weekly for cycles one to four, then 20 mg weekly for cycles five to eight, with cycles of 28 days.³⁸⁷ After eight cycles, patients received the regimen every other week for eight cycles. After 24 cycles, maintenance with lenalidomide was recommended off-study. After a median of 12 cycles, 62 percent achieved at least a near CR and 42 percent a sCR. The 24-month PFS was estimated to be 92 percent. The toxicity profile was acceptable and notable for limited peripheral neuropathy.

Doublet, and especially triplet, regimens of novel drugs in combination with dexamethasone can induce complete remission rates comparable to transplantation regimens.^418,424 Examples of modern regimens include doublet combinations of lenalidomide and dexamethasone and bortezomib and dexamethasone, as well as, the triple combination of RVD, CyBorD, and CRD.

Combinations that include alkylating agents should be avoided as damage to normal hematopoietic stem cells can be incurred, which may render it impossible to collect stem cells for auto-HSCT.⁴²⁵ Lenalidomide may also hamper the collection of stem cells, although stem cell mobilization with growth factors and chemotherapy may overcome the myelosuppressive effects of lenalidomide.^426–429 The number of cycles of treatment, especially with lenalidomide-containing regimens is limited to roughly four cycles before stem cell collection, as additional cycles may compromise stem cell harvesting.^426,430

Combination therapy with novel drugs achieves complete remission rates comparable to those obtained with auto-HSCT. This has led to the design of ongoing studies that compare novel agents followed by auto-HSCT with novel agents followed by delayed auto-HSCT following disease relapse. Novel agents seem to be able to overcome some of the cytogenetic adverse prognostic factors such as del 13, t(4;14), and del 17p. However, it is premature to abandon auto-HSCT as the followup of clinical trials with new agents is too short to determine whether increased complete remission rates will translate into durable remissions and EFS and OS. Complete remission rates as a surrogate marker for eventual outcome may prove to be inadequate. NCT01208662 is a phase III, multicenter randomized trial of RVD versus high-dose treatment with stem cell transplantation (SCT) for myeloma patients up to age 65 years, which was designed to address this question of the role of autologous transplantation in the context of novel drugs. It is likely that autologous transplantation will add to the benefits noted with new drugs.

THERAPY FOR THE TRANSPLANTATION-INELIGIBLE PATIENT

The traditional age limit for auto-HSCT has been 65 years, although older patients should be considered for transplantation provided good organ function is present. Physiologic rather than chronologic age is more suitable for determining transplantation eligibility (Chap. 14).

Oral administration of melphalan and prednisone (MP) has been the standard of care for more than 5 decades in elderly myeloma patients. This form of therapy produces objective response in 50 to 60 percent of patients. The shortcomings of MP have stimulated investigators to use many combinations of chemotherapeutic agents. Several different combinations have been tested and two large overviews of more than 10,000 patients have demonstrated that MP had equivalent efficacy and survival to combination chemotherapy.^431,432 Consequently, MP remains a very reasonable treatment strategy for elderly myeloma patients. A number of new approaches promise to be improvements over MP, however. Palumbo and colleagues have incorporated the use of thalidomide in combination with MP in newly diagnosed patients with myeloma who are older than age 65 years.⁴³³ The addition of thalidomide resulted in a 76 percent complete or partial response rate compared to 47 percent in the MP arm. This translated into a doubling of the 2-year EFS to 54 percent from 27 percent. Based on these data, melphalan, prednisone, and thalidomide (MPT) emerged as the standard of care for transplantation-ineligible patients. However, all studies showed an increase in adverse events in the MPT arm, including infections, neuropathy, and thromboembolism, suggesting that thromboprophylaxis and antimicrobial prophylaxis is required.⁴³⁴ Melphalan, prednisone, and lenalidomide (MPR) is another effective regimen in this population. The GIMEMA–Italian Multiple Myeloma Network evaluated 54 patients with this combination. The maximum tolerated dose (MTD) was 0.18 mg/kg melphalan, 2 mg/kg prednisone, and 10 mg lenalidomide. In this study, 81 percent of patients achieved at least a partial response, 47.6 percent a VGPR, and 23.8 percent a CR. One-year OS was 100 percent.⁴³⁵ A subsequent study evaluated the efficacy and safety of induction therapy with MPR followed by lenalidomide maintenance therapy (MPR-R), as compared with MPR or MP without maintenance therapy, in patients with newly diagnosed myeloma who were ineligible for transplantation. At a median followup of 30 months, the median PFS was 31 months for MPR-R versus 14 months for MPR and 13 months for MP. This benefit was observed in patients 65 to 75 years of age, but not in patients older than 75 years. Response rates were superior for the lenalidomide-containing regimen: 77 percent for MPR-R and 68 percent for MPR versus 5 percent with MP.⁴³⁶

Randomized trials of other novel agents, like bortezomib with MP, have proven benefits as well. For example, the VISTA trial compared the regimen of bortezomib, melphalan, and prednisone (VMP) to MP in patients who were not candidates for autologous SCT.⁴³⁷ Overall survival was significantly improved in the VMP group versus MP group, with 3-year OS of 68.5 percent versus 54 percent, respectively.⁴³⁸

The FIRST trial, a randomized, phase III trial, compared continuous lenalidomide with low-dose dexamethasone (Rd) against lenalidomide with low-dose dexamethasone for 18 cycles (Rd18) and MPT for 12 cycles.⁴³⁹ Median PFS for continuous Rd was 25.5 months versus 20.7 for Rd18 and 21.2 for MPT. The OS at 4 years was 59.4 percent for Rd versus 55.7 percent for Rd18 and 51.4 percent for MPT. In the continuous Rd arm, the ORR was 75.1 percent (15.1 percent CR, 28.4 percent VGPR) versus 73.4 in Rd18 (Cr 14.2 percent, VGPR 28.5 percent) and 32.3 percent MPT (CR 9.3 percent, VGPR 18.8 percent). The safety profile with continuous Rd was manageable as hematologic and nonhematologic adverse events were as expected for Rd and MPT. Notably, the incidence of hematologic second primary malignancies was lower with continuous Rd than MPT. In newly diagnosed transplantation-ineligible patients, the FIRST trial established continuous Rd as the new standard of care. There are ongoing trials evaluating three-drug combinations, including bortezomib, lenalidomide, and dexamethasone, at reduced doses and attenuated schedules in this population as well. Table 107–8 provides a summary of clinical trial results for novel agent induction regimen for newly diagnosed transplantation-ineligible patients.

MAINTENANCE THERAPY

Maintenance regimens have been proposed to extend the duration of complete remission following autologous SCT. The increased tolerability and efficacy of newer antimyeloma agents has increased the attractiveness and the applicability of this approach; previous attempts at maintenance therapy with older conventional chemotherapy agents such as melphalan or interferon were not beneficial.⁴⁴³

A meta-analysis of six randomized, controlled trials with 2786 patients, comparing thalidomide maintenance with other regimens after induction chemotherapy, demonstrated that patients receiving thalidomide maintenance had marginally better OS (hazard ratio [HR] 0.83, p = 0.07). The difference was most prominent in groups who received both thalidomide and glucocorticoids (HR 0.70, p = 0.02). Thalidomide improved PFS (HR 0.65, p <0.01) but was associated with a higher thrombotic risk (risk difference 0.024, p <0.05) and increased peripheral neuropathy (risk difference 0.072, p <0.01).⁴⁴⁴

Three randomized trials explored the use of lenalidomide as maintenance therapy, with two of the trials following autologous SCT^445,446 and one trial after 9 months of melphalan-based therapy in patients ineligible for high-dose treatment.⁴³⁶ In all three trials, there was a near doubling in PFS with lenalidomide maintenance; for example, from 27 to 46 months in the Cancer and Leukemia Group B (CALGB) 100104 study.⁴⁴⁶ Furthermore, the CALGB study showed an OS benefit with lenalidomide: 15 percent of the lenalidomide group had died compared to 23 percent in the placebo group (p <0.03) and at 3 years, the OS was 88 percent in the lenalidomide group compared to 80 percent in the placebo group.

A significant concern with maintenance therapy with lenalidomide is the risk of secondary malignancy. The risk of second primary cancers was roughly double in the maintenance group, (7.0 to 7.7 percent) compared to the placebo group (2.6 to 3.0 percent). The secondary cancers observed included both hematologic malignancies, such as acute myelogenous leukemia, and solid tumors. The risk of a secondary hematologic malignancy appears to be greatest when lenalidomide is given in combination with oral melphalan (HR 4.86, p <0.0001).⁴⁴⁷ This increased risk of secondary malignancies and the risk-to-benefit ratio of maintenance therapy should be considered and discussed with the patient when initiating maintenance therapy.

Bortezomib has also been studied as maintenance therapy. In the HOVON-65/GMMG-HD4 study, bortezomib was given every 2 weeks and was associated with increasing the near CR and CR rate from 31 percent to 49 percent.⁴⁴⁸ Table 107–9 summarizes maintenance trials.

CONSOLIDATION THERAPY

The use of a short course of consolidation therapy after autologous SCT increases the CR rate and relapse-free survival. Posttransplantation consolidation using the combination of bortezomib, thalidomide, and dexamethasone made it possible to convert 22 percent of VGPR into full, lasting molecular responses [Polymerase chain reaction, negavtive (PCR–)].⁴⁴⁹ Enhanced rates of CR, ranging between 10 and 30 percent, have been reported with post–autologous SCT use of bortezomib and lenalidomide as single agents.^450,451 In the IFM 2008 pilot study (enrollment completed in December 2009), the usefulness and safety of posttransplantation consolidation with two cycles of the RVD regimen is being tested. Mature results from these trials will help to better define the role of consolidation in therapy for improving clinical outcomes after transplantation.

CONTINUOUS THERAPY

Data in the upfront setting, both in transplantation-eligible and transplantation-ineligible patients, suggest that continuous therapy may result in improved disease control.^452,453 Several clinical trials have demonstrated superiority of maintenance strategies using thalidomide, lenalidomide, and bortezomib in transplantation-eligible patients.

Thus far, the results from lenalidomide trials are perhaps the most convincing. The IFM 2005–02 and CALGB 100104 studies have both demonstrated a doubling of PFS,^445,446 although only the CALGB trial has suggested an OS advantage. Lenalidomide certainly fits the requirements of a maintenance drug for continued use in myeloma, as it is administered orally and is generally well tolerated. The FIRST trial, comparing continuous Rd with Rd for 18 cycles and MPT, demonstrated that continuous treatment with lenalidomide is superior to a finite therapy. Time to progression for the Rd arm was 32.5 months versus 21.9 months for Rd18 and 23.9 months for MPT.⁴³⁹ However, the risk of second primary malignancies, although low, does need to be discussed and balanced in the decision-making process when considering maintenance therapy with this agent.

As far as studies of patients with relapsed/refractory myeloma are concerned, treatment generally continues until disease progression.⁴⁵⁴ However, the development of toxicities is the biggest challenge of continued therapy in this setting. Ultimately, duration of therapy must be balanced with the adverse events encountered by the patient.

As yet, the optimal duration of therapy is myeloma has not been defined. Data suggest that patients should receive continuous antimyeloma therapy as long as patients are benefitting and tolerating therapy without excessive toxicity.

APPROACH TO RELAPSED OR REFRACTORY PATIENTS

A number of options are available for the therapy of relapsing patients. If the relapse occurs more than 6 months after the discontinuation of the initial therapy, patients may be treated with the same primary therapy. Table 107–10 summarizes trials of novel treatment regimens for relapsed or refractory disease.

Proteasome Inhibitors

Two phase II studies, SUMMIT and CREST, demonstrated activity of bortezomib in relapsed or refractory myeloma patients.^408,465 An update of the 202 patients enrolled in the SUMMIT study showed median times to progression and duration of response of 7 and 13 months, respectively.⁴⁶⁶ A similar analysis of the CREST study demonstrated 5-year survivals of 32 and 45 percent in patients treated with 1.0 mg/m² and 1.3 mg/m² of bortezomib, respectively.⁴⁶⁷ The randomized phase III APEX study comparing bortezomib with dexamethasone alone, found a median OS of 30 months in the bortezomib group versus 24 months in the dexamethasone group.^468,455 The addition of dexamethasone to bortezomib monotherapy improved response in 18 to 34 percent of patients.⁴⁶⁹

A next-generation proteasome inhibitor, carfilzomib, was granted accelerated FDA approval as a single agent for the treatment of patients who have received at least two prior lines of therapy based on the results of the phase II of single-agent carfilzomib twice weekly that showed an ORR of 23.7 percent in patients who had had a median of five prior lines of therapy. Median duration of response was 7.8 months and median OS was 15.6 months. The drug was well tolerated. The most common side effects were fatigue, anemia, nausea, and thrombocytopenia, with 12.4 percent reporting treatment-related peripheral neuropathy and cardiac.⁴⁰⁹

Oral proteasome inhibitors, ixazomib and oprozomib, are in clinical trials now and will likely gain approval. Ixazomib, has already demonstrated safety and efficacy in phase I trials in the relapsed, refractory population. Of 60 patients who had received a median of six prior regimens including bortezomib (83 percent), there were 41 evaluable patients. Responses included one VGPR, five partial response (PR), one minimal response (MR), and 15 with stable disease. Only 10 percent of patients had drug-related peripheral neuropathy and none were grade 3 or higher.⁴⁷⁰ In a phase I/II trial, weekly ixazomib was evaluated in combination with standard dose lenalidomide and dexamethasone in patients with newly diagnosed myeloma. Preliminary results from 58 response-evaluable patients demonstrated a 93 percent ORR, with 67 percent of subjects achieving a very good response rate or better, including a CR rate of 24 percent.⁴⁷¹ Based on these results, ixazomib is being evaluated in combination with lenalidomide and dexamethasone in two large, international phase III trials—TOURMALINE MM1 for relapsed, refractory myeloma patients, and TOURMALINE MM2 for newly diagnosed patients. Oprozomib, another oral proteasome inhibitor, is also under investigation for the treatment of myeloma. These drugs could significantly impact the treatment of myeloma, allowing for completely oral treatment regimens and, consequently, completely outpatient care for patients. This could have a measurable quality-of-life benefit for patients, particularly in the elderly population, and may provide a convenient way of incorporating proteasome inhibitor-based maintenance strategies.

Immunomodulatory Drugs

Three IMiDs, thalidomide, lenalidomide, and pomalidomide, are FDA approved for the treatment of relapsed or refractory myeloma. Long-term followup of the first thalidomide trial showed that 10 years after initiation of therapy 17 of the original cohort of 169 patients were alive and 10 had an uninterrupted remission.⁴⁷² The combination of thalidomide and dexamethasone was superior to dexamethasone alone in several studies.^473–475 Patients who have had prior thalidomide exposure should probably be treated with one of the other novel agents. Furthermore, cytogenetic abnormalities predict for a poor long-term response to thalidomide.^268,472

Lenalidomide is more potent than its predecessor, thalidomide, and is not associated with sedation, peripheral neuropathy, and severe constipation. In two large, randomized phase III trials, lenalidomide with high-dose dexamethasone produced a superior response and delayed time to progression compared to dexamethasone and placebo.^406,457 The combination of lenalidomide and dexamethasone had activity in both bortezomib-naïve and previously treated patients, in thalidomide-resistant patients, and after prior auto-HSCT. An analysis of the expanded access lenalidomide program, enrolling 1438 patients, showed that the combination of lenalidomide and dexamethasone had an acceptable safety profile, with less than 10 percent of patients experiencing pneumonia or deep vein thrombosis.⁴⁷⁶

Pomalidomide has also demonstrated potent antimyeloma effects. Several studies have evaluated pomalidomide in combination with low-dose dexamethasone in the relapsed population, culminating in the approval of pomalidomide 4 mg orally on days 1 to 21 of 28-day cycles until progression. The phase II, randomized, open-label study compared pomalidomide and low-dose dexamethasone with single-agent pomalidomide in patients with relapsed or refractory myeloma. Median PFS for the combination arm was 4.2 months compared to 2.7 months for monotherapy (HR 0.68, P = 0.003). The ORR was 33 percent with combination therapy versus 18 percent for pomalidomide alone. Median OS was 16.5 months versus 13.6 months, respectively. Refractoriness to lenalidomide and bortezomib did not affect outcomes with pomalidomide and dexamethasone.⁴⁷⁷ In the phase III European study comparing pomalidomide and low-dose dexamethasone with high-dose dexamethasone alone, PFS at the interim analysis was 3.6 months in the combination arm compared to 1.8 months for dexamethasone alone (HR 0.45; P <0.001). The most common side effects seen were myelosuppression and infections.⁴⁷⁸

Histone Deacetylase Inhibitors

Histone deacetylase (HDAC) inhibitors are another class of drugs that have demonstrated activity in relapsed or refractory myeloma when used in combination with bortezomib. The phase III, randomized trial, called Vantage 088, showed the combination of vorinostat and bortezomib was active and well-tolerated. When this combination was compared with bortezomib alone, the ORR for vorinostat and bortezomib was 56.2 percent versus 40.6 percent for bortezomib alone (p <0.0001); similarly, PFS was 7.63 months compared to 6.83 months, respectively (p = 0.01).⁴⁶⁰ Panobinostat has been combined with bortezomib and dexamethasone in a phase II study and compared with bortezomib and dexamethasone alone in the relapsed/refractory population. PFS was 12 months versus 8.1 months (p <0.0001) for patients treated with the triple therapy. ORR was 61 percent versus 55 percent and duration of response of 13.1 months versus 10.9 months. OS data is not yet mature. Common side effects included myelosuppression and diarrhea.⁴⁶¹ ACY-1215, a selective HDAC 6 inhibitor, is another well-tolerated HDAC inhibitor that is being studied in combination with both lenalidomide and bortezomib plus dexamethasone. The ORR in combination with lenalidomide and dexamethasone was 69 percent even though 13 of 16 patients had received prior lenalidomide and three of six were refractory to lenalidomide.⁴⁷⁹ In combination with bortezomib and dexamethasone, the ORR was 60 percent.⁴⁸⁰

Monoclonal Antibodies

Several monoclonal antibodies have demonstrated activity in myeloma, including novel drugs targeting CD38, CS1, and BAFF. Daratumumab, a monoclonal anti-CD38 antibody, was granted Fast Track Designation and Breakthrough Therapy Designation by the FDA based on results of a phase I/II trial that demonstrated single-agent activity in relapsed, refractory myeloma. In the 4 mg or more/kg groups (n = 12), five PRs and three MRs were observed. Median PFS had not been reached by a data cutoff of 3.8 months.⁴⁶² Daratumumab is now being studied in combination with lenalidomide and dexamethasone in relapsed or refractory disease. SAR650984, another anti-CD38 antibody, had an ORR of 30.8 percent as a single agent in the dose-escalation study in relapsed or refractory (RR) patients at the MTD.⁴⁸¹

Elotuzumab, a humanized monoclonal IgG₁ antibody directed against human CS1 (also known as CD2 subset-1, SLAMF7, CRACC, and CD319), a cell-surface antigen glycoprotein that is highly expressed on myeloma cells and normal plasma cells, has also been granted Breakthrough Therapy Designation by the FDA. In a phase I study, no objective responses were seen, although 26.5 percent had stable disease by European Bone Marrow Transplant Group (EBMT) myeloma response criteria.⁴⁸² In combination with lenalidomide and dexamethasone, objective responses were obtained in 82 percent (23 of 28) of treated patients. After a median followup of 16.4 months, the median time to progression was not reached for patients in the 20 mg/kg cohort who were treated until disease progression. An ORR of 92 percent and a median PFS of 33 months was observed after a median followup of 20.8 months at the 10 mg/kg dose which was the dose chosen for the phase III trial.⁴⁶³ Phase I results of elotuzumab in combination with bortezomib and dexamethasone are also favorable. Phase I results demonstrate a PR or better in 48 percent of 27 evaluable patients with relapsed or refractory disease.⁴⁸³

Tabalumab, is a fully human monoclonal antibody designed to have neutralizing activity against both membrane-bound and soluble BAFF, has been combined with bortezomib and dexamethasone. In the phase I/II study, the ORR was 45.8 percent.⁴⁸⁴ A phase II trials of this combination has been completed but results have not yet been reported.

Other Treatments

Bendamustine as a single-agent or in combination with lenalidomide and dexamethasone is another option for patients with relapsed or refractory myeloma. The combination of bendamustine, lenalidomide, and dexamethasone was evaluated in a phase I/II trial. The median PFS was 6.1 months, PR rate 52 percent, and VGPR rate 24 percent.⁴⁶⁴ The MTD of bendamustine was 75 mg/m² as compared with prior studies using 100 mg/m². Toxicity was mainly hematologic arguing in favor of the lower dose, particularly in light of the fact that this population is heavily pretreated.⁴⁸⁵

Other regimens that have been explored include bortezomib and pegylated doxorubicin with or without thalidomide, bortezomib combined with thalidomide and dexamethasone, bendamustine with prednisone and thalidomide, and lenalidomide with doxorubicin and dexamethasone.^{486,456 487–489} There are currently many new drugs in development that target novel pathways. For example, filanesib, a kinesin spindle protein inhibitor, has demonstrated activity in combination with lenalidomide and bortezomib.^490,491 Several other classes of novel drugs are currently under investigation including the bromodomain inhibitors, CDK inhibitors, and inhibitors of the ubiquitin pathway. Data generated from these early studies will provide a better understanding of how these new drugs will be incorporated into the continuum of myeloma care.^492–494

Another area of interest and therapy development is the blockade of interactions between the tumor cells and immune cells. PD-1 and PD-L1 are two targets of interest. PD-1 is a molecule present on T cells that interacts with PD-L1 expressed on tumor cells. There are ongoing clinical trials exploring PD-1 blockade in combination with a dendritic cell/myeloma fusion vaccine in myeloma.⁴⁹⁵

The choice of therapy for relapsed or refractory patients depends on a number of factors, including time since last therapy, prior exposure to novel agents, alone or in combination, and drug-induced comorbidities, for example, neuropathy, renal malfunction, and loss of patient physiologic reserve. In the past decade, there has been a dramatic increase in the number of therapies available to patients with relapsed or refractory myeloma. This is a very dynamic area within oncology and will continue to evolve as more new therapies enter trials and gain approval.

ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

Allogeneic transplantation was seen as an attractive option to treat myeloma because it has the potential to be curative, provides a donor graft that is not contaminated with myeloma stem cells, and may establish a graft-versus-myeloma (GVM) effect that could eradicate any surviving myeloma cells.^496,497 Furthermore, molecular remissions have been observed, which predict for longer survival.^498,499 However, the early experience with myeloablative allogeneic transplantation has not been encouraging as a result of a high mortality, varying from 30 to 50 percent, despite improvements in patient selection and supportive care.^500–507

Studies from Seattle^501,508 and the EBMT⁵⁰⁹ have reported that some patients remain progression-free at long intervals after hematopoietic stem cell transplantation (HSCT). The EBMT has reported that actuarial OS was 32 percent at 4 years, and 28 percent at 7 years for the 72 (44 percent) patients who achieved CR after allografting.^503,504,510 However, overall PFS was 34 percent at 6 years, and few patients remain in continuing CR for more than 4 years post allograft. Favorable pre–marrow transplantation prognostic factors for both response and survival after marrow transplantation were female sex, IgA isotype, low serum β₂M, stage I disease at diagnosis, one line of previous treatment, and being in CR prior to marrow transplantation. Of major concern is the early 40 percent transplant-related mortality (50 percent in males) in the EBMT report,⁵⁰² which has subsequently been reduced to 20 to 30 percent as a consequence of better patient selection, early transplantation, and less pretransplantation treatment.⁵¹⁰ The actuarial probabilities of survival and progression-free survival were 0.50 +/– 0.21 and 0.43 +/– 0.17 at 4.5 years. Adverse prognostic factors included: transplantation more than 1 year after diagnosis; serum β₂M higher than 2.5 mg/dL at time of transplantation; female patients transplanted from male donors; having received more than eight cycles of chemotherapy; and Salmon-Durie stage III disease at presentation (see Table 107–5). Toxicity was substantial, with 35 (44 percent) patients dying of transplant-related causes within 100 days of marrow transplantation.^501,508

Reduced-intensity conditioning regimens were introduced to reduce transplantation-related mortality and extend the age limit for allografting.^{511–515,516} Autografting has been performed prior to nonmyeloablative transplantation by several investigators, demonstrating the feasibility of this approach to cytoreduce tumor and then enhance antimyeloma immunity.^517,518 Bruno and colleagues published a prospective trial of initial autologous SCT followed by mini-allogeneic transplantation versus double autologous transplantation.^519,520 The median OS was 80 months for allografting versus 54 months for double autografting. The CR rate after allografting was 55 percent versus 26 percent after double autograft. In contrast, a randomized trial in high-risk myeloma showed that the combination of autologous SCT followed by dose-reduced allogeneic transplantation (IFM 99–03) was not superior to tandem autotransplant (IFM 99–04).⁵²¹ BMT CTN 0102, also evaluated autologous SCT followed by second autologous versus nonmyeloablative allogeneic SCT. In both standard- and high-risk patients, nonmyeloablative allogeneic HSCT after auto-HSCT was not more effective than tandem auto-HSCT.^522,523 Bjorkstand and colleagues conducted a prospective study of single or tandem autologous SCT versus reduced-intensity allogeneic SCT based on availability of an human leukocyte antigen (HLA)-identical sibling. Long-term followup of 357 patients who received either autologous SCT (single or double) or autologous–allogeneic with HLA-identical sibling matched donor demonstrated that PFS was superior (35 percent versus 18 percent; p = 0.001) at 60 months for those receiving an autologous–allogeneic tandem transplantation. Nonrelapse mortality was 12 percent after autologous–allogeneic versus 3 percent in the autologous group (p <0.001) and the incidence of limited to extensive graft-versus-host disease (GVHD) was 31 percent and 23 percent.⁵²⁴

The use of allogeneic transplantation as salvage therapy, while feasible, is unlikely to be of significant benefit in a heavily pretreated population. The EBMT reported on the outcomes of 229 patients who received reduced-intensity conditioning allogeneic SCT. Transplant-related mortality at 1 year was 22 percent and 3-year OS and PFS were 41 percent and 21 percent, respectively, with 25 percent of patients developing extensive chronic GVHD.⁵²⁵ The best outcomes were seen in patients who received a transplant in remission and early in the course of the disease. Adverse OS was associated with chemoresistant disease, transplantation more than 1 year after diagnosis, and in male patients transplanted with female donors.

In patients whose disease does not respond to or relapses after allogeneic SCT, donor lymphocyte infusion (DLI) can be considered. Molecular remissions are more common after allografting than after autografting,^526–528 and DLI can treat relapsed myeloma post allografting,^497,529,530 indicating a clinically significant GVM effect. In an effort to reduce toxicity and exploit GVM, CD4+ DLI have been used at 6 months post–CD6-depleted marrow allografting so as to enhance GVM and thereby improve outcome.⁵³¹ Although prophylactic DLI induces significant GVM responses after allogeneic marrow transplantation, only 58 percent of patients were able to receive DLI despite T-cell–depleted marrow transplantation.

Allografting should only be undertaken in the context of clinical trials, which aim to reduce chronic GVHD, separate GVM from GVHD, and amplify the GVM effect to improve outcome by ameliorating toxicity and maximizing the antimyeloma effect of immunologic effector cells.⁵³² 

CYTOGENETIC-GUIDED THERAPY OF MYELOMA

In 2016, the International Myeloma Working Group (IMWG) refined the definition of high-risk multiple myeloma based on cytogenetics and suggested treatment approaches for the entities included in the new definition.⁵³³ The IMWG consensus was that cytogenetic abnormalities such as t(4;14), del(17/17p), t(14;16), t(14;20), nonhyperdiploidy, and gain(1q) conferred poor prognosis and that the outcomes of patients possessing these abnormalities varied with the choice of therapy. Based on data available, bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival (PFS), and overall survival in t(4;14) and del(17/17p) myeloma, whereas lenalidomide may be associated with improved PFS in t(4;14) and del(17/17p). Thalidomide does not confer the same benefits as lenalidomide and carfilzomib for patients with t(4;14), t(14;16), t(14;20), del(17/17p), or gain(1q). Double ASCT combined with bortezomib-based treatment partially abrogates poor PFS in patients carrying both t(4;14) and del(17p).

ADJUNCTIVE THERAPIES

Bone Disease

Bone involvement is one of the defining characteristics of myeloma, either as lytic lesions or diffuse osteopenia. Bisphosphonates, such as pamidronate and zoledronic acid, inhibit osteoclast activity and can palliate pain and prevent bone-related complications.^219,534,535 Hypercalcemia is associated with increased bone resorption in myeloma, and bisphosphonates also play a key role in the treatment of hypercalcemia. Zoledronic acid, which is more potent than pamidronate, is superior to pamidronate for the treatment of hypercalcemia.⁵³⁶

The International Myeloma Working Group (IMWG) and the National Comprehensive Cancer Network (NCCN) panels advocate the use of either pamidronate or zoledronic acid monthly for patients with myeloma and lytic bone disease. Both pamidronate and zoledronic acid are considered equally effective in reducing skeletal complications.^537,538 These guidelines recommend the use of pamidronate at 90 mg delivered intravenously for at least 4 hours or zoledronic acid at 4 mg intravenously for 15 minutes every 3 to 4 weeks for patients with myeloma and lytic bone disease.

In addition to playing an important supportive role, bisphosphonates may have a direct antitumor effect. The MRC Myeloma IX trial compared zoledronic acid to oral clodronic acid and found that zoledronic acid reduced mortality by 16 percent and increased median OS from 44.5 months to 50 months.⁵³⁹ The benefit of zoledronic acid on skeletal morbidity was also seen in patients without bone lesions at baseline.⁵⁴⁰

A key concern with bisphosphonates, especially zoledronic acid, is the risk of osteonecrosis of the jaw (ONJ).⁵⁴¹ In the MRC Myeloma IX trial, the rate of ONJ was 4 percent.⁵³⁹ Attention to dental hygiene and minimizing invasive procedures may reduce the risk of ONJ.⁵⁴²

Denosumab is a monoclonal antibody to RANK ligand that also inhibits osteoclasts; it showed promising activity in myeloma in a phase II trial.¹⁸⁸ Although denosumab was superior to zoledronic acid in patients with solid tumors and bone metastases, denosumab was inferior in a subset analysis of myeloma patients in a phase III trial.¹⁸⁷ However, interpretation is limited based on the small numbers in the trial. A larger phase III study (NCT01345019) focusing on patients with myeloma is ongoing.

Vertebroplasty (injection of methyl methacrylate or bone cement) and kyphoplasty (use of an inflatable balloon followed by instillation of bone cement) are percutaneous procedures for treating compression fractures, and have also been used in the setting of myeloma.^543,544

Palliative Radiation Therapy

Radiation also plays a key role for palliation of painful bony lesions in myeloma. An estimated 38 percent of patients are expected to receive radiation over the course of their illness.⁵⁴⁵ The primary indication for the use of radiation therapy is palliation of bone pain. Other indications include impending fracture, cord compression, or relief of symptoms associated with a mass (i.e., cranial nerve palsies, cosmesis or organ or joint dysfunction). Doses of 20 to 35 Gy can be used, but it is essential to consider ability to retreat when designing treatment fields, particularly of the spine. Doses of 20 Gy, delivered in either 5 or 10 fractions, typically provide adequate symptom relief.

EMERGENT COMPLICATIONS OF NEW MYELOMA THERAPY

Venous Thromboembolism

Patients with myeloma are at an increased risk for deep vein thrombosis and pulmonary embolism, particularly when known risk factors are present (history of VTE, immobilization, dehydration, other factors).⁴³⁴ Genetic predispositions include high levels of homocysteine and deficiencies of antithrombin, protein C, and protein S, as well as mutations that predispose to thrombosis, such as the factor V Leiden allele and/or the prothrombin gene G20210A allele. Genetic abnormalities should be suspected with repeated episodes of VTE. The incidence of VTE is highest during the first 3 to 4 months following diagnosis and occurs in approximately 3 to 4 percent of patients receiving either dexamethasone alone or MP, but is much higher when newer agents are combined with dexamethasone and melphalan.^271,440,546 A number of procoagulant abnormalities have been described in myeloma, including endothelial damage, paraprotein interference with fibrin structure, elevated von Willebrand multimers, elevated factor VIII, decreased protein S, and acquired activated protein C resistance.^547,548 A SNP analysis discovered 18 polymorphisms associated with thalidomide-induced VTE. These polymorphisms were involved in pathways important for drug transport or metabolism, DNA repair, and cytokine pathways.⁵⁴⁹ The precise mechanisms causing VTE in myeloma patients absent a known genetic predisposition remain elusive, but the type of therapy plays an important role.

The incidence of VTE with single-agent thalidomide is approximately 2 to 4 percent in newly diagnosed and in relapsed patients, comparable to that observed with dexamethasone alone or MP, implying that thalidomide alone does not increase the risk of VTE. However, the risk for VTE increases significantly when thalidomide is combined with dexamethasone, melphalan, doxorubicin, or cyclophosphamide, or with multiagent chemotherapy.^274,434 The MPT combination causes VTE in 12 to 20 percent of patients who do not receive anticoagulant prophylaxis, whereas the incidence of VTE with thalidomide and dexamethasone in newly diagnosed patients is 14 to 26 percent.^{271,413,433,440} Most VTEs occur within the first 60 days of therapy, coinciding with maximum cytoreduction. In the Total Therapy 2 study, 22 percent of patients developed a VTE, 95 percent of which occurred in the first 12 months of therapy.⁵⁵⁰ Oral regimens principally promote deep vein thrombosis or pulmonary embolism, whereas infusional regimens can give rise to central line–related thrombosis in approximately 50 percent of patients.⁵⁴⁹

Single-agent lenalidomide does not appear to increase VTE, at least not in the setting of myeloma relapse, but is associated with a marked increase in VTE risk when lenalidomide is combined with dexamethasone.⁴⁸⁹ Three risk factors for lenalidomide-associated VTE are higher dexamethasone doses, administration of erythropoietin, and concomitant administration of other agents. When combined with cyclophosphamide, the incidence of lenalidomide-induced VTE was 14 percent.⁵⁵¹ Bortezomib did not seem to increase the risk of VTE, at least not in patients with relapsed or refractory disease.²⁷²

Prevention of VTE is based on the assessment for known risk factors for VTE: (1) myeloma-related (hyperviscosity, newly diagnosed status); (2) therapy-related (high-dose dexamethasone [≥480 mg/month], doxorubicin, multiagent chemotherapy); (3) individual factors (age, history of VTE, inherited thrombophilia, obesity, immobilization, central venous line, infections, surgery, administration of erythropoietin); and (4) factors related to comorbidities (acute infection, diabetes mellitus, cardiac or renal dysfunction). Therapy-related risk factors weigh highest in the risk equation for VTE. The following thromboprophylaxis is recommended: (1) acetylsalicylic acid (aspirin) in either a standard dose of 325 mg/day or in a low dose of 81 mg/day for patients with one or no risk factors or (2) low-molecular-weight heparin (LMWH) once a day, or full-dose warfarin for patients if two or more risk factors or therapy-related risks are present. The recommended duration of prophylaxis in general is 6 to 12 months.⁴³⁴

Therapy for VTE should begin with standard therapeutic doses of LMWH. Oral anticoagulation may be considered as a followup. If oral anticoagulation is deemed inappropriate in a given patient, LMWH should be continued as long as the patient is receiving antineoplastic therapy. The optimal duration of therapy is unknown but one study reported a recurrence of VTE of 10 percent in patients who had discontinued anticoagulant therapy,⁵⁵² suggesting that long-term prophylaxis may be indicated in some patients. A survival benefit for patients who were anticoagulated for a VTE may suggest an additional effect of anticoagulants on the myelomatous process.⁵⁵⁰

Peripheral Neuropathy

Bortezomib-^553,554 and thalidomide-induced^555,556 peripheral neuropathy should be distinguished from other causes such as paraneoplastic neuropathies, antecedent chemotherapy with neurotoxic agents (vincristine or cisplatin), diabetes mellitus, and AL amyloidosis. Patients with AL amyloidosis of the peripheral nerves are especially sensitive to neurotoxic agents. Clinical findings include bilateral tingling, and numbness in the toes and/or fingers and/or pain ascending in the extremities when neurotoxic drug therapy is continued. Symptoms are typically in a glove-and-stocking distribution. Neurologic examination should evaluate sensory loss, deep tendon reflexes, and distal weakness, especially in the lower extremities. If significant weakness or asymmetry of signs is present, a neurologic consultation must be obtained along with electromyography and nerve conduction studies.

Bortezomib inhibits NF-κB activation, blocking the transcription of nerve growth factor–mediated neuron survival. Other proposed mechanisms for bortezomib-induced neuropathy include mitochondria and endoplasmic reticulum damage because of activation of the mitochondrial-based apoptotic pathway.^553,557,558 Second-generation, more selective proteasome inhibitors such as carfilzomib have a reduced neurotoxicity.⁵⁵⁹ Grade 3 or 4 bortezomib-induced neurotoxicity occurs in approximately 20 percent of newly diagnosed patients and in 30 percent of patients with relapsing disease.^421,560,561 A 50 percent dose reduction should be made for bortezomib-induced grade 2 neuropathy while grade 3 or 4 neuropathy requires drug discontinuation. Improvement or resolution of symptoms has been reported in 3 months, whereas in other patients maximum improvement may take 2 years.^{408,560,562,563} Subcutaneous dosing of bortezomib appears to be similarly effective to intravenous administration and has a significantly improved safety profile. When compared head-to-head, 38 percent of patients receiving bortezomib subcutaneously reported any grade of neuropathy compared to 53 percent when given IV (p = 0.044). By grade, 24 percent versus 41 percent (p = 0.012) had grade 2 or worse, and 6 percent versus 16 percent (p = 0.026) had grade 3 or worse when comparing subcutaneous with intravenous administration, respectively.⁵⁶⁴ Subcutaneous administration is now the preferred route of administration based on these findings.

Daily thalidomide dose, dose intensity, cumulative dose 400 mg or greater, and duration of therapy are all implicated in the pathogenesis of thalidomide-induced neuropathy, which occurs in up to 75 percent of patients.^{555,556,565 566–570} Dose reduction or cessation of therapy with the option of switching to lenalidomide will usually improve neuropathy, although resolution or improvement of neuropathy can take considerable time as thalidomide appears to induce an axonal-length-dependent neuropathy.⁵⁷¹ Symptomatic treatment for thalidomide- and bortezomib-induced neuropathy usually comprises gabapentin, pregabalin, or tricyclic antidepressants.

Osteonecrosis of the Jaw

ONJ is a severe “bone” disease, associated with bisphosphonate therapy that affects the jaws and typically presents as infection with necrotic bone in the mandible or maxilla. ONJ is characterized by the presence of exposed bone in the maxillofacial region that does not heal within 8 weeks. Although asymptomatic at times, ONJ usually presents as pain and/or numbness in the affected area, soft-tissue swelling, drainage, and tooth mobility. The exact cause of ONJ is not known and is likely to be multifactorial. The risk of developing ONJ increases with duration of bisphosphonate exposure and is 5 to 15 percent at 4 years.^572–574 A further predisposing factor for ONJ is invasive dental procedures such as extractions.^575,576 Approximately 50 percent of affected patients had dental work prior to developing ONJ.⁵⁷⁶ A genome-wide SNP analysis has shown that a polymorphism in the cytochrome P450–2C polypeptide is associated with an increased risk of developing ONJ on bisphosphonate therapy, although the mechanism underlying this genetic predisposition to ONJ has as yet not been elucidated.^577,578 To prevent ONJ, patients should be referred for dental evaluation prior to commencing intravenous bisphosphonates and should be advised to maintain excellent oral hygiene and avoid dental procedures while receiving these agents.⁵⁴² Antibiotic prophylaxis before dental procedures may reduce the incidence of ONJ in patients receiving bisphosphonate therapy.⁵⁷⁹ Management is usually conservative (discontinuation of bisphosphonates, limited debridement, antibiotic therapy, and topical mouth rinses).⁵⁸⁰ Surgical resection of necrotic bone should be reserved for refractory cases. In a series of 97 patients, healing of ONJ was observed in 75 percent of patients. Patients who develop spontaneous ONJ have a significantly higher risk of nonhealing ONJ or recurrence.⁵⁷⁵

MONITORING DISEASE MARKERS FOR DOCUMENTATION OF RESPONSE AND RELAPSE

The previously widely used criteria for assessing response developed by the EBMT Registry, also referred to as the EBMT criteria, have been supplanted by the International Uniform Response Criteria proposed by the IMWG (Table 107–11).^8,581 The IMWG response criteria incorporate the serum-free light-chain assay to allow for assessment of patients previously thought to have hyposecretory or nonsecretory disease. Stricter definitions of complete remission resulted in the inclusion of a category of stringent complete remission in which monoclonal plasma cells are not detectable in the marrow by immunohistochemistry or immunofluorescence and the free light-chain ratio is normal. The previously used near complete remission (only positivity by serum monoclonal immunoglobulin immunofixation) is now included in the new category of “very good partial response” and the previously used minor response category is eliminated.

Survival end points include PFS, EFS, and disease-free survival. PFS is the time from start of therapy to myeloma progression or death and includes all patients. It is being used as a surrogate for OS. In the case of EFS, precise definition of what constitutes an event is required (e.g., significant drug toxicity, death, etc.). Stable disease is no longer used as a measure of treatment efficacy, but rather time to progression, which is measured from the start of therapy and, importantly, includes all patients entered into clinical studies. Duration of a response is calculated from the onset of response and only counts the subgroup of responding patients. Long-term followup is recommended to fully evaluate the impact of novel treatment. Other limitations of the new criteria are that response is determined only by monoclonal immunoglobulin and marrow evaluation. Dynamic changes in skeletal events readily identified by modern imaging techniques such as MRI and PET-CT are excluded from response assessments.

Sequencing-based platforms, quantitative polymerase chain reaction, and multiparametric flow cytometry are now being employed to detect minimal residual disease (MRD) in patients attaining at least a VGPR after primary therapy which may be of significant prognostic value. Martinez-Lopez and colleagues reported the results of sequencing-based marrow evaluations on 133 patients in VGPR or better following primary therapy. In patients achieving a CR, the TTP was 131 months for MRD-negative patients compared to 35 months for MRD-positive patients. When stratified by level of MRD, the respective TTP medians were 27 months for MRD 10^–3 or greater, 48 months for MRD 10^–3 to 10^–5, and 80 months for MRD less than 10^–5 (p = 0.003 to 0.0001).⁵⁸² Although not currently a standard of care, MRD assessment may play an important role in evaluating disease response in the future.

Disease features can change over the course of the disease. Not infrequently, clonal evolution occurs with successive relapses, resulting in the loss of previously secreted intact immunoglobulin and a switch to secretion of light-chains only (“Bence Jones escape”) or entire loss of immunoglobulin-secretory capacity, often associated with extramedullary spread, best signified by increased LDH levels and lesions found on PET-CT examination. Occasionally, unexplained anemia or pancytopenia accompanies the disappearance of myeloma protein markers, necessitating prompt marrow examination to detect fulminant relapse.

Many induction regimens currently affect tumor cytoreduction rapidly, so that monoclonal immunoglobulin reduction of 50 percent or more is apparent within a few months of therapy. Thus, at least monthly myeloma protein evaluations should be performed during induction. After two to four induction cycles and prior to high-dose melphalan-based auto-HSCT, the disease is restaged, to include marrow examination with cytogenetics and MRI and/or PET-CT of indicator lesions in order to assess whether intramedullary or EMD has been reduced. Disease monitoring should be performed at least every month for the first year and at a minimum every other month thereafter. Marrow biopsy, including cytogenetic examinations, should be performed at the time of progression or change in therapy. Imaging should be performed annually or in the presence of new symptoms.

PROGNOSIS

The prognosis of myeloma is determined by three factors: (1) the host, (2) tumor biology and disease burden, and (3) the type of therapy applied. Host parameters, such as comorbidities, advanced age, frailty, and poor performance status, negatively impact overall outcome and increase treatment-related morbidity and mortality. With the advent of new drugs, used in combination or incorporated into high-dose melphalan-based auto-HSCT approaches, some poor prognostic factors can be overcome (see “Management of Newly Diagnosed Myeloma” above).

Advances in cytogenetics, gene-expression profiling, and imaging (MRI and PET-CT) have greatly increased our understanding of tumor biology and burden. Furthermore, such variables are more powerful prognostic indicators than standard prognostic variables.

Numerous individual parameters have been examined for their value as prognostic features. Higher labeling indices, serum IL-6 receptor levels, increased RAS mutations, more aggressive disease, and shortened survival has been reported in patients with plasmablastic morphology.²⁹² Serum β₂M represents the light chain of the MHC complex of the cell membrane. Increased serum β₂M results from secretion by tumors with a high growth fraction and rapid cell turnover rates. In patients with myeloma and normal renal function, rising serum β₂M predicts for progression.³⁰¹ The labeling index (LI), a measure of DNA synthesis by myeloma cells, predicts for survival. It is usually low (<1 percent) at diagnosis, higher at relapse, and lower in MG and indolent myeloma.⁵⁸³

Serum IL-6 levels appear to correlate both with stage of disease and survival.^584,585 IL-6 stimulates hepatocytes to produce acute phase proteins, such as C-reactive protein (CRP); CRP, therefore, may reflect the IL-6 level and proliferative status of marrow plasma cells. Indeed, CRP levels are significantly lower in patients with MG than in those with MM, and survival can be correlated with serum CRP level.⁵⁸⁶ High serum levels of soluble IL-6 receptor (sIL-6R), hepatocyte growth factor,⁵⁸⁷ and syndecan-1,⁵⁸⁸ as well as low serum levels of hyaluronate,⁵⁸⁹ are independent prognostic factors predicting poor outcome.

The percentage of circulating plasma cells in the blood and their labeling indices are independent prognostic factors for survival in myeloma after both conventional and high-dose therapy.^294,590 Circulating endothelial cells also correlate with disease course and response to thalidomide.⁵⁹¹ Finally, circulating proteasome levels are an independent prognostic factor for survival.⁵⁹²

Many of these factors are interrelated and, therefore, of limited independent value. Using multivariate analysis, several groups have found that the best combination of variables to predict outcome was serum β₂M, reflecting both the tumor burden and the renal function; and the proliferative activity of plasma cells, evaluated by the LI or number of tumor cells in S-phase. Age and performance status also improves the prognostic assessment.^593,594

Cytogenetic findings associated with poor outcome include hypodiploidy and deletion 17p13, the locus of the tumor-suppressor gene TP53.^{308,309,372,595} Gains of chromosome 1q arm and loss of 1p occur in tandem duplications and jumping translocations of chromosome 1, and signify more aggressive and more advanced myeloma.^596–598 Combining hypodiploidy and high β₂M has also been used to identify patient populations with a poor outcome.^595,599 In contrast, hyperdiploidy, which accounts for almost half of the patients with abnormal cytogenetics and involves nonrandom gains of chromosomes 3, 5, 7, 9, 11, 15, 19, and 21, is associated with chemosensitive disease and better OS. Translocation t(11;14) also confers a better outcome.¹⁰¹ Chromosome 13 deletions are present in more than 50 percent of patients with myeloma and are associated with poor prognosis; however, these deletions are also associated with MG,^83,89,307 and their role in transformation to myeloma is undefined at present. Chromosome 13 deletion is not prognostic for response to bortezomib, highlighting the importance of prognostic factors for particular therapies.⁶⁰⁰

Interphase FISH does not depend on cycling cells and increases the detection of abnormal cells to 80 to 90 percent.⁶⁰¹ Interphase FISH can also detect cytogenetically silent translocations, for example, t(4;14), t(14;16), and t(14;20), and can be performed on stored material. The above data suggest that analysis of metaphase cytogenetic abnormalities and FISH can identify patients who do not do well with auto-HSCT or standard therapies. Individual prognostication remains highly variable despite the application of these more sophisticated cytogenetic techniques. The Total Therapy 2 patient data set revealed that standard prognostic variables and metaphase cytogenetic had limited ability to account for outcome variability with hazard ratios not exceeding 2.0.^64,602,603

Gene-expression profiling on newly diagnosed patients has allowed for the interpretation of outcome in the context of whole human genomic data. Gene-expression profiling not only has the ability to define disease pathogenesis, but also to identify both novel prognostic factors and potential therapeutic targets.^604,605 Using tumor cells from 532 newly diagnosed patients, Shaughnessy and colleagues defined a 70-gene model and a 17-gene subset that have the ability to identify high-risk disease.⁶⁰⁶ In a study by the IFM, gene-expression profiles were generated for 250 newly diagnosed patients. The 15 most stable genes were used to construct a survival model. The 15-gene model demonstrated an improved ability to predict survival in newly diagnosed patients with myeloma treated with high-dose therapy. Specifically, this work demonstrated that high-risk patients have a 6.8-fold hazard ratio (95 percent confidence interval, 3.92 to 11.73; P <0.001) of death compared with low-risk patients. IFM 15-gene and University of Arkansas for Medical Sciences (UAMS) 17-gene models, when applied to their respective data sets, are powerful prognostic tools that can enhance the ISS for the identification of high-risk disease. The HOVON group developed a 92 gene signature which predicts for differential outcome.⁶⁰⁷ These gene signatures are, however, not yet generalizable, as they have not been studied prospectively. Moreover, an analysis of signatures defined in Arkansas, IFM, Millennium, and HOVON studies shows that these signatures are not broadly useful in myeloma.¹²⁹

These gene-expression profiling studies also identify mechanisms of sensitivity versus resistance to conventional and novel myeloma therapies.^608,609 For example, gene-expression profiling of patient tumor samples showed genes upregulated in patients responding to bortezomib compared to patients who did not respond. Hsp27 upregulation correlated with intrinsic or acquired bortezomib resistance (Chap. 109). Preclinical studies showed that p38^MAPK inhibition downregulated Hsp27 expression and restored Velcade sensitivity in resistant myeloma cell lines and patient samples,⁶¹⁰ providing the basis for a trial combining these two agents.

Gene-expression profiling data should have an important impact on the interpretation of future clinical trials. Validated prognostic models from gene microarray data are now used for improved prognostication and will ultimately be used to assist in selecting therapy for individual patients.

Myeloma is a very complex disease at the genomic level. Parallel sequencing of paired and normal samples from 203 myeloma patients were performed and mutations were most frequently observed in KRAS, NRAS, BRAF, FAM46C, TP53, and DIS3.¹¹² The tumors demonstrated significant heterogeneity. Mutations were often present in subclonal populations and multiple mutations within the same pathway were observed within the same patient. Results of whole-exome sequencing, copy-number profiling, and cytogenetics of myeloma samples, including serial samples in 15 patients, demonstrated complex clonal evolution over time.¹⁰⁸ Moreover, clonal and subclonal heterogeneity within the same patient without the predominant clone did not necessarily translate into mRNA. These and other studies demonstrate the complexity of the myeloma genome underscoring a need for rapid identification of possible druggable oncogenic mutations to customize therapy for myeloma patients. Genomic analysis technology that can facilitate this understanding may prove valuable in the further development of effective targeted therapies. Future strategies of treatment may include the combination of targeted therapies with existing proteosome inhibitors and IMiDs. In addition, identification of mutations may provide important prognostic information. For example, SP140 mutations were associated with increased risk of relapse suggesting that this gene may have prognostic features in myeloma.

IGM MYELOMA

A rare diagnostic dilemma concerns the existence of an IgM myeloma entity that is distinct from Waldenström macroglobulinemia (histopathologic diagnosis, immunocytoma).^611,612 Upon examination, plasma cells, rather than the lymphoplasmacytic infiltrate, are seen to dominate the marrow of myeloma, whereas mastocytosis is a hallmark of immunocytoma. DNA aneuploidy and the presence of lytic bone lesions support a diagnosis of myeloma. Myeloma, also of the IgM isotype, is resistant to purine analogues, which are effective in Waldenström macroglobulinemia.^613,614

SOLITARY PLASMACYTOMA

Plasmacytomas are collections of monoclonal plasma cells originating either in bone (solitary osseous plasmacytoma [SOP]) or in soft tissue (extramedullary plasmacytoma [EMP]). They comprise less than 10 percent of plasma cell dyscrasias. Indications of systemic disease such as marrow plasmacytosis, anemia, renal insufficiency, or multiple lytic or soft-tissue lesions must be excluded before the diagnosis of either SOP or EMP can be made. MRI can be useful to show additional marrow abnormalities consistent with myeloma.⁶¹⁵ The median age of diagnosis of either SOP or EMP is approximately 50 years, nearly 10 years younger than that for myeloma.^616–618 Although patients with SOP and EMP can both progress to myeloma, persons with SOP progress in the majority of cases, in contrast to EMP, where only 50 percent eventually develop myeloma. The median survival of 86.4 months and 100.8 months for patients with SOP and EMP, respectively, is similar; however, PFS is markedly different, 16 percent for SOP patients versus 71 percent for EMP patients. The persistence of stable monoclonal Ig in the serum and/or urine after primary treatment of plasmacytoma does not necessitate additional therapy, as it does not influence survival or disease-free survival.⁶¹⁶ In contrast, rising monoclonal Ig levels in a patient with a history of either SOP or EMP should trigger a workup for either recurrent plasmacytoma or myeloma. It has been suggested, as is true for myeloma, that serum β₂M has prognostic value in patients with SOP. For example, 17 of 19 patients with elevated serum β₂M had transformation to myeloma and shorter survival (31 months) as compared with those with normal serum β₂M levels.⁶¹⁹

Local therapy, primarily radiotherapy, with surgery as needed for structural anatomic support is the standard treatment for SOP and EMP.^616–618 Patients with soft-tissue solitary plasmacytomas can often be cured with appropriate local radiation (dose of at least 4.5 Gy). By contrast, this local treatment approach fails in the majority of patients with solitary plasmacytomas of bone.⁶²³ The development of myeloma in such patients probably reflects multifocal systemic disease present at the outset and hitherto not detectable by standard radiographic imaging but readily by applying MRI⁶²⁴ and PET-CT.⁶²⁵

The benefit of chemotherapy, either alone or in combination with radiotherapy and surgery, as primary therapy for SOP or EMP has not been proven. Moreover, the benefit of adjuvant chemotherapy, given to prevent recurrent disease and/or progression to myeloma, is also undefined. Disappearance of protein after involved-field radiotherapy predicts for long-term disease-free survival and possible cure.⁶²³

AMYLOID LIGHT-CHAIN AMYLOIDOSIS

When clinical features of congestive heart failure, nephrotic syndrome, malabsorption, coagulopathy, skin rash (oral mucosal rash, “raccoon’s eyes”) or neuropathy are present, a careful search for primary amyloidosis should be carried out (Chap. 108). LCDD may also have a similar clinical presentation. The primary difference between AL amyloidosis and LCDD is the difference in structure of the deposited protein; in AL amyloidosis it is fibrillar versus granular in LCDD. LCDD is usually associated with the κ light-chain subtype, whereas AL amyloidosis is associated with the λ light-chain subtype of myeloma.

Primary AL amyloidosis and immunoglobulin deposition diseases are best characterized functionally as MG with clinical manifestations because of normal tissue infiltration by these processes, although they can also accompany overt myeloma. Further workup following suspicion on clinical presentation depends on the organ of concern. Cardiac amyloidosis may be associated with low voltage on an electrocardiogram, arrhythmias, increased interventricular septal thickness greater than 12 mm, diastolic dysfunction or speckling on echocardiogram, and elevation of markers, such as B-type natriuretic peptide, N-terminal pro–B-type natriuretic protein, and cardiac troponin T.^620,621 Involvement of the gastrointestinal tract may present with decreased albumin and prealbumin. Renal involvement may present as nonspecific proteinuria with high total protein on 24-hour collection and low monoclonal immunoglobulin. Carpal tunnel syndrome and peripheral neuropathy may be a manifestation of amyloid, and nerve conduction studies may help in this diagnosis. Orthostatic hypotension also should alert to the possibility of systemic amyloidosis as a result of amyloid deposition in vasa nervorum of the autonomic nervous system or in adrenal glands resulting in hypoadrenalism. Occasionally, primary amyloidosis presents as tumors either mostly consisting of amyloid or mixed with plasmacytoma. Typically, MRI signals can distinguish plasmacytomas, which show hypointensity on T1-weighted images and hyperintensity on short tau inversion recovery (STIR)–weighted images, whereas amyloidoma-type lesions remain hypointense.

Appropriate biopsy techniques should be applied to clarify the presence and extent of accompanying amyloidosis or, similarly, LCDD in these patients. The diagnosis of AL amyloid (Chap. 108) often can be made by fine-needle aspiration of subcutaneous fat or by biopsy of the rectal mucosa,⁶²² although biopsy of accessible clinically involved tissue is preferable. AL amyloid also may be detectable on marrow biopsy.²⁵² Staining the tissue with Congo red may reveal perivascular amyloid with its classical apple-green birefringence when viewed under polarized light.⁶²⁶ Thioflavin T is also a useful stain, producing intense yellow green fluorescence in AL amyloidosis. LCDD require immunofluorescence analysis of unfixed tissue; formalin fixation should be avoided whenever it is suspected.

Even though the tumor load is very low, patients with AL amyloidosis and immunoglobulin deposition disease suffer from the consequences of myeloma secretory products, even at relatively modest amounts, resulting in damage to kidneys, heart, gastrointestinal tract, liver, spleen, and peripheral and autonomic nerves. All current treatment targets the monoclonal plasma cell population and advances have paralleled the advances in treatment of myeloma. Whereas standard melphalan-prednisone has been only marginally effective, high-dose dexamethasone pulsing plus interferon, effecting more rapid and profound responses in myeloma, has also shown encouraging results in AL amyloidosis.⁶²⁷ Similarly, positive results have been obtained with dexamethasone plus melphalan.⁶²⁸ The Boston University group has pioneered the use of high-dose melphalan with auto-HSCT (see Fig. 107-16),⁶²⁹ which is an effective regimen in carefully selected patients. In a study of 312 patients, high-dose melphalan (100 to 200 mg/m²) with auto-HSCT resulted in a median survival of 4.6 years with a treatment-related mortality of 13 percent.⁶³⁰ There was also significant improvement in organ function. The role of allogeneic transplantation in AL amyloidosis is unclear.

Incorporation of the newer agents, such as the IMiDs and proteasome inhibitors, has shown promising results in the treatment of patients with AL amyloidosis in combination with other agents such as melphalan, dexamethasone, and cyclophosphamide. In phase II trials of lenalidomide in combination with dexamethasone 29 percent achieved a CR and 38 percent achieved a PR with an OR RF of 67 percent. Lenalidomide was given at a dose reduction of 15 mg/day because of poor tolerability at standard dose of 25 mg/day.⁶³¹ The safety and efficacy of the combination of pomalidomide and dexamethasone was also evaluated in a phase II clinical trial. Of 33 patients, the ORR was 48 percent. The time to response was 1.9 months and the median overall and PFS rates were 28 and 14 months, respectively. The most common side effects were fatigue and neutropenia.⁶³²

Bortezomib has also demonstrated efficacy and tolerability in the treatment of AL amyloidosis. In a phase II trial of 40 patients not achieving a CR after autologous SCT, 21 patients were treated with bortezomib and dexamethasone. Of the 12 evaluable patients at 1-year post–autologous SCT, ORR was 92 percent—67 percent achieved a CR and 50 percent had organ responses.⁶³³ When used in combination with cyclophosphamide (CyBorD), high response rates are reported. Venner and colleagues evaluated the combination in 43 treatment-naïve patients. The overall hematologic response rate was 81.4 percent with CRs in 39.5 percent; 30 percent of patients reported peripheral neuropathy. This is likely attributable to the fact that dosing on this regimen was biweekly and the route of bortezomib administration was intravenous.⁶³⁴

Cardiac amyloid remains the most challenging clinical condition and is currently addressed with repeated cycles of dose-reduced melphalan (70 to 100 mg/m²) and stem cell support to avoid cardiac catastrophes possibly linked to arrhythmias, caused by fluid overload or cytokines.⁶³⁵ There is a prevailing misconception that high-dose dexamethasone pulsing, alone or with added thalidomide, even at low doses, is safer and better tolerated than appropriately dosed melphalan with stem cell support. Owing to its hematopoietic stem cell–compromising properties, melphalan, even at 50 to 70 mg/m², is still best administered in the context of autologous stem cell support.

SMOLDERING MYELOMA

Patients with smoldering myeloma have historically been followed without therapy.^636–638 At this time, there is no role for treating smoldering myeloma patients. Patients should be followed at close intervals of every 3 to 6 months and clinical trials should be offered where available.

At a median followup of 40 months in a small, randomized, prospective study of 125 patients with high-risk smoldering myeloma, treated with either lenalidomide and dexamethasone or observation,⁶³⁹ TTP was not reached by the intervention arm compared to 21 months in the observation arm (p <0.001), and the 3-year OS was 94 percent versus 30 percent (p = 0.03). Despite these favorable finding, the high-risk criteria employed by this study are not those commonly used in practice. High-risk in this study was defined as having at least 10 percent marrow infiltration with plasma cells, a M-protein of 3 g/dL or greater, or a urinary Bence Jones protein level of more than 1 g/24 hours. Based on these criteria, some patients with active myeloma were classified as having high-risk smoldering myeloma, which may have contributed to the differences in the outcomes between the two arms of the trial. The IMWG has advised that those smoldering myeloma patients who have greater than 60 percent marrow plasma cells,⁶⁴⁰ κ:λ FLC ratios greater than 100,⁶⁴¹ and two lesions on MRI or PET-CT imaging may benefit from therapy.^642–644 Further investigation of treatment in high-risk myeloma is warranted before changing the treatment paradigm in this population.