Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone. The tumor, its products, and the host response to it result in a number of organ dysfunctions and symptoms, including bone pain or fracture, renal failure, susceptibility to infection, anemia, hypercalcemia, and occasionally clotting abnormalities, neurologic symptoms, and manifestations of hyperviscosity.
The cause of myeloma is not known. Myeloma occurred with increased frequency in those exposed to the radiation of nuclear warheads in World War II after a 20-year latency. Myeloma has been seen more commonly than expected among farmers, wood workers, leather workers, and those exposed to petroleum products. A variety of chromosomal alterations with prognostic significance has been found in patients with myeloma; 13q14 deletions, 17p13 deletions, and translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) predominate, and evidence is strong that errors in switch recombination—the genetic mechanism to change antibody heavy chain isotype—participate in the transformation process. However, no common molecular pathogenetic pathway has yet emerged. The neoplastic event in myeloma may involve cells earlier in B cell differentiation than the plasma cell. Interleukin (IL)-6 may play a role in driving myeloma cell proliferation. It remains difficult to distinguish benign from malignant plasma cells on the basis of morphologic criteria in all but a few cases (Fig. 111-2).
Multiple myeloma (marrow). The cells bear characteristic morphologic features of plasma cells, round or oval cells with an eccentric nucleus composed of coarsely clumped chromatin, a densely basophilic cytoplasm, and a perinuclear clear zone containing the Golgi apparatus. Binucleate and multinucleate malignant plasma cells can be seen.
Estimated 20,180 new cases of myeloma were diagnosed in 2010, and 10,650 people died from the disease in the United States. Myeloma increases in incidence with age. The median age at diagnosis is 70 years; it is uncommon under age 40. Males are more commonly affected than females, and blacks have nearly twice the incidence of whites. Myeloma accounts for ∼1% of all malignancies in whites and 2% in blacks, and 13% of all hematologic cancers in whites and 33% in blacks.
The incidence of myeloma is highest in African Americans and Pacific islanders; intermediate in Europeans and North American whites; and lowest in developing countries including Asia. The higher incidence in more developed countries may result from the combination of a longer life expectancy and more frequent medical surveillance. Incidence of multiple myeloma in other ethnic groups including native Hawaiians, female Hispanics, American Indians from New Mexico, and Alaskan natives is higher relative to U.S. whites in the same geographic area. Chinese and Japanese populations have a lower incidence than whites. Immunoproliferative small intestinal disease with alpha heavy chain disease is most prevalent in the Mediterranean area. Despite these differences in prevalence, the characteristics, response to therapy, and prognosis of myeloma are similar worldwide.
Pathogenesis and Clinical Manifestations (Table 111–1)
Table 111–1 Clinical Features of Multiple Myeloma
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Table 111–1 Clinical Features of Multiple Myeloma
|Clinical Finding||Underlying Cause and Pathogenetic Mechanism|
|Hypercalcemia, osteoporosis, pathologic fractures, lytic bone lesions, bone pain||Tumor expansion, production of osteoclast activating factor by tumor cells, osteoblast inhibitory factors|
|Renal failure||Hypercalcemia, light chain deposition, amyloidosis, urate nephropathy, drug toxicity (nonsteroidal anti-inflammatory agents, bisphosphonates), contrast dye|
|Easy fatigue/anemia||Bone marrow infiltration, production of inhibitory factors, hemolysis, decreased red cell production, decreased erythropoietin levels|
|Recurrent infections||Hypogammaglobulinemia, low CD4 count, decreased neutrophil migration|
|Neurologic symptoms||Hyperviscosity, cryoglobulinemia, amyloid deposits, hypercalcemia, nerve compression, antineuronal antibody, POEMS syndrome, therapy-related toxicity|
|Nausea and vomiting||Renal failure, hypercalcemia|
|Bleeding/clotting disorder||Interference with clotting factors, antibody to clotting factors, amyloid damage of endothelium, platelet dysfunction, antibody coating of platelet, therapy-related hypercoagulable defects|
Multiple myeloma (MM) cells bind via cell-surface adhesion molecules to bone marrow stromal cells (BMSCs) and extracellular matrix (ECM), which triggers MM cell growth, survival, drug resistance, and migration in the bone marrow milieu (Fig. 111-3). These effects are due both to direct MM cell–BMSC binding and to induction of various cytokines, including IL-6, insulin-like growth factor type I (IGF-I), vascular endothelial growth factor (VEGF), and stromal cell–derived growth factor (SDF)-1α. Growth, drug resistance, and migration are mediated via Ras/Raf/mitogen-activated protein kinase, PI3-K/Akt, and protein kinase C signaling cascades, respectively.
Pathogenesis of multiple myeloma. Multiple myeloma cells interact with bone marrow stromal cells and extracellular matrix proteins via adhesion molecules, triggering adhesion-mediated signaling as well as cytokine production. This triggers cytokine-mediated signaling that provides growth, survival, and antiapoptotic effects as well as development of drug resistance. HSP, heparin sulfate proteoglycan.
Bone pain is the most common symptom in myeloma, affecting nearly 70% of patients. The pain usually involves the back and ribs, and unlike the pain of metastatic carcinoma, which often is worse at night, the pain of myeloma is precipitated by movement. Persistent localized pain in a patient with myeloma usually signifies a pathologic fracture. The bone lesions of myeloma are caused by the proliferation of tumor cells, activation of osteoclasts that destroy bone, and suppression of osteoblasts that form new bone. The increased osteoclast activity is mediated by osteoclast activating factors (OAF) made by the myeloma cells [OAF activity can be mediated by several cytokines, including IL-1, lymphotoxin, VEGF, receptor activator of NF-κB (RANK) ligand, macrophage inhibitory factor (MIP)-1α, and tumor necrosis factor (TNF)]. The bone lesions are lytic in nature and are rarely associated with osteoblastic new bone formation due to their suppression by dickhoff-1 (DKK-1) produced by myeloma cells. Therefore, radioisotopic bone scanning is less useful in diagnosis than is plain radiography. The bony lysis results in substantial mobilization of calcium from bone, and serious acute and chronic complications of hypercalcemia may dominate the clinical picture (see below). Localized bone lesions may expand to the point that mass lesions may be palpated, especially on the skull (Fig. 111-4), clavicles, and sternum, and the collapse of vertebrae may lead to spinal cord compression.
Bony lesions in multiple myeloma. The skull demonstrates the typical "punched out" lesions characteristic of multiple myeloma. The lesion represents a purely osteolytic lesion with little or no osteoblastic activity. (Courtesy of Dr. Geraldine Schechter; with permission.)
The next most common clinical problem in patients with myeloma is susceptibility to bacterial infections. The most common infections are pneumonias and pyelonephritis, and the most frequent pathogens are Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae in the lungs and Escherichia coli and other gram-negative organisms in the urinary tract. In ∼25% of patients, recurrent infections are the presenting features, and >75% of patients will have a serious infection at some time in their course. The susceptibility to infection has several contributing causes. First, patients with myeloma have diffuse hypogammaglobulinemia if the M component is excluded. The hypogammaglobulinemia is related to both decreased production and increased destruction of normal antibodies. Moreover, some patients generate a population of circulating regulatory cells in response to their myeloma that can suppress normal antibody synthesis. In the case of IgG myeloma, normal IgG antibodies are broken down more rapidly than normal because the catabolic rate for IgG antibodies varies directly with the serum concentration. The large M component results in fractional catabolic rates of 8–16% instead of the normal 2%. These patients have very poor antibody responses, especially to polysaccharide antigens such as those on bacterial cell walls. Most measures of T cell function in myeloma are normal, but a subset of CD4+ cells may be decreased. Granulocyte lysozyme content is low, and granulocyte migration is not as rapid as normal in patients with myeloma, probably the result of a tumor product. There are also a variety of abnormalities in complement functions in myeloma patients. All these factors contribute to the immune deficiency of these patients. Some commonly used therapeutic agents, e.g., dexamethasone, suppress immune responses and increase susceptibility to infection.
Renal failure occurs in nearly 25% of myeloma patients, and some renal pathology is noted in more than 50%. Many factors contribute to this. Hypercalcemia is the most common cause of renal failure. Glomerular deposits of amyloid, hyperuricemia, recurrent infections, frequent use of nonsteroidal anti-inflammatory agents for pain control, use of iodinated contrast dye for imaging, bisphosphonate use, and occasional infiltration of the kidney by myeloma cells all may contribute to renal dysfunction. However, tubular damage associated with the excretion of light chains is almost always present. Normally, light chains are filtered, reabsorbed in the tubules, and catabolized. With the increase in the amount of light chains presented to the tubule, the tubular cells become overloaded with these proteins, and tubular damage results either directly from light chain toxic effects or indirectly from the release of intracellular lysosomal enzymes. The earliest manifestation of this tubular damage is the adult Fanconi syndrome (a type 2 proximal renal tubular acidosis), with loss of glucose and amino acids, as well as defects in the ability of the kidney to acidify and concentrate the urine. The proteinuria is not accompanied by hypertension, and the protein is nearly all light chains. Generally, very little albumin is in the urine because glomerular function is usually normal. When the glomeruli are involved, nonselective proteinuria is also observed. Patients with myeloma also have a decreased anion gap [i.e., Na+ – (Cl− + HCO3−)] because the M component is cationic, resulting in retention of chloride. This is often accompanied by hyponatremia that is felt to be artificial (pseudohyponatremia) because each volume of serum has less water as a result of the increased protein. Renal dysfunction due to light chain deposition disease, light chain cast nephropathy, and amyloidosis is partially reversible with effective therapy. Myeloma patients are susceptible to developing acute renal failure if they become dehydrated.
Normocytic and normochromic anemia occurs in ∼80% of myeloma patients. It is usually related to the replacement of normal marrow by expanding tumor cells, to the inhibition of hematopoiesis by factors made by the tumor, and to reduced production of erythropoietin by the kidney. In addition, mild hemolysis may contribute to the anemia. A larger than expected fraction of patients may have megaloblastic anemia due to either folate or vitamin B12 deficiency. Granulocytopenia and thrombocytopenia are very rare except when therapy-induced. Clotting abnormalities may be seen due to the failure of antibody-coated platelets to function properly or to the interaction of the M component with clotting factors I, II, V, VII, or VIII. Deep venous thrombosis is also observed with use of thalidomide or lenalidomide in combination with dexamethasone. Raynaud's phenomenon and impaired circulation may result if the M component forms cryoglobulins, and hyperviscosity syndromes may develop depending on the physical properties of the M component (most common with IgM, IgG3, and IgA paraproteins). Hyperviscosity is defined on the basis of the relative viscosity of serum as compared with water. Normal relative serum viscosity is 1.8 (i.e., serum is normally almost twice as viscous as water). Symptoms of hyperviscosity occur at a level greater than 4 centipoise (cP), which is usually reached at paraprotein concentrations of ∼40 g/L (4 g/dL) for IgM, 50 g/L (5 g/dL) for IgG3, and 70 g/L (7 g/dL) for IgA.
Although neurologic symptoms occur in a minority of patients, they may have many causes. Hypercalcemia may produce lethargy, weakness, depression, and confusion. Hyperviscosity may lead to headache, fatigue, visual disturbances, and retinopathy. Bony damage and collapse may lead to cord compression, radicular pain, and loss of bowel and bladder control. Infiltration of peripheral nerves by amyloid can be a cause of carpal tunnel syndrome and other sensorimotor mono- and polyneuropathies. Neuropathy associated with monoclonal gammopathy of undetermined significance (MGUS) and myeloma is more frequently sensory than motor neuropathy and is associated with IgM more than other isotypes. Sensory neuropathy is also a side effect of thalidomide and bortezomib therapy.
Many of the clinical features of myeloma, e.g., cord compression, pathologic fractures, hyperviscosity, sepsis, and hypercalcemia, can present as medical emergencies. Despite the widespread distribution of plasma cells in the body, tumor expansion is dominantly within bone and bone marrow and, for reasons unknown, rarely causes enlargement of spleen, lymph nodes, or gut-associated lymphatic tissue.
The classic triad of myeloma is marrow plasmacytosis (>10%), lytic bone lesions, and a serum and/or urine M component. Bone marrow plasma cells are CD138+ and monoclonal. The most important differential diagnosis in patients with myeloma involves their separation from individuals with MGUS or smoldering multiple myeloma (SMM). MGUS are vastly more common than myeloma, occurring in 1% of the population older than age 50 years and in up to 10% of individuals older than age 75 years. The diagnostic criteria for MGUS, SMM, and myeloma are described in Table 111–2. When bone marrow cells are exposed to radioactive thymidine in order to quantitate dividing cells, patients with MGUS always have a labeling index <1%, whereas patients with myeloma always have a labeling index >1%. Although ∼1% per year of patients with MGUS go on to develop myeloma, all myeloma is preceded by MGUS. Non-IgG subtype, abnormal kappa/lambda free light chain ratio, and serum M protein >15 g/L (1.5 g/dL) are associated with higher incidence of progression of MGUS to myeloma. The features responsible for higher risk of progression from smoldering myeloma to MM are bone marrow plasmacytosis >30%, abnormal kappa/lambda free light chain ratio, and serum M protein >30 g/L (3 g/dL). Typically, patients with MGUS and smoldering myeloma require no therapy. There are two important variants of myeloma, solitary bone plasmacytoma and extramedullary plasmacytoma. These lesions are associated with an M component in <30% of the cases, they may affect younger individuals, and both are associated with median survivals of ≥10 years. Solitary bone plasmacytoma is a single lytic bone lesion without marrow plasmacytosis. Extramedullary plasmacytomas usually involve the submucosal lymphoid tissue of the nasopharynx or paranasal sinuses without marrow plasmacytosis. Both tumors are highly responsive to local radiation therapy. If an M component is present, it should disappear after treatment. Solitary bone plasmacytomas may recur in other bony sites or evolve into myeloma. Extramedullary plasmacytomas rarely recur or progress.
Table 111–2 Diagnostic Criteria for Multiple Myeloma, Myeloma Variants, and Monoclonal Gammopathy of Undetermined Significance
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Table 111–2 Diagnostic Criteria for Multiple Myeloma, Myeloma Variants, and Monoclonal Gammopathy of Undetermined Significance
|Monoclonal Gammopathy of Undetermined Significance (MGUS)|
M protein in serum <30 g/L
Bone marrow clonal plasma cells <10%
No evidence of other B cell proliferative disorders
No myeloma-related organ or tissue impairment (no end organ damage, including bone lesions)a
|Asymptomatic Myeloma (Smoldering Myeloma)|
M protein in serum ≥30 g/L and/or
Bone marrow clonal plasma cells ≥10%
No myeloma-related organ or tissue impairment (no end organ damage, including bone lesions)a or symptoms
|Symptomatic Multiple Myeloma|
M protein in serum and/or urine
Bone marrow (clonal) plasma cellsb or plasmacytoma
Myeloma-related organ or tissue impairment (end organ damage, including bone lesions)
No M protein in serum and/or urine with immunofixation
Bone marrow clonal plasmacytosis ≥10% or plasmacytoma
Myeloma-related organ or tissue impairment (end organ damage, including bone lesions)a
|Solitary Plasmacytoma of Bone|
No M protein in serum and/or urinec
Single area of bone destruction due to clonal plasma cells
Bone marrow not consistent with multiple myeloma
Normal skeletal survey (and MRI of spine and pelvis if done)
No related organ or tissue impairment (no end organ damage other than solitary bone lesion)a
The clinical evaluation of patients with myeloma includes a careful physical examination searching for tender bones and masses. Chest and bone radiographs may reveal lytic lesions or diffuse osteopenia. MRI offers a sensitive means to document extent of bone marrow infiltration and cord or root compression in patients with pain syndromes. A complete blood count with differential may reveal anemia. Erythrocyte sedimentation rate is elevated. Rare patients (∼2%) may have plasma cell leukemia with >2000 plasma cells/μL. This may be seen in disproportionate frequency in IgD (12%) and IgE (25%) myelomas. Serum calcium, urea nitrogen, creatinine, and uric acid levels may be elevated. Protein electrophoresis and measurement of serum immunoglobulins and free light chains are useful for detecting and characterizing M spikes, supplemented by immunoelectrophoresis, which is especially sensitive for identifying low concentrations of M components not detectable by protein electrophoresis. A 24-h urine specimen is necessary to quantitate Bence Jones protein excretion. Serum alkaline phosphatase is usually normal even with extensive bone involvement because of the absence of osteoblastic activity. It is also important to quantitate serum β2-microglobulin (see below).
The serum M component will be IgG in 53% of patients, IgA in 25%, and IgD in 1%; 20% of patients will have only light chains in serum and urine. Dipsticks for detecting proteinuria are not reliable at identifying light chains, and the heat test for detecting Bence Jones protein is falsely negative in ∼50% of patients with light chain myeloma. Fewer than 1% of patients have no identifiable M component; these patients usually have light chain myeloma in which renal catabolism has made the light chains undetectable in the urine. In most of these patients, light chains can now be detected by serum free light chain assay. IgD myeloma may also present as light chain myeloma. About two-thirds of patients with serum M components also have urinary light chains. The light chain isotype may have an impact on survival. Patients secreting lambda light chains have a significantly shorter overall survival than those secreting kappa light chains. Whether this is due to some genetically important determinant of cell proliferation or because lambda light chains are more likely to cause renal damage and form amyloid than are kappa light chains is unclear. The heavy chain isotype may have an impact on patient management as well. About half of patients with IgM paraproteins develop hyperviscosity compared with only 2–4% of patients with IgA and IgG M components. Among IgG myelomas, it is the IgG3 subclass that has the highest tendency to form both concentration- and temperature-dependent aggregates, leading to hyperviscosity and cold agglutination at lower serum concentrations.
The staging systems for patients with myeloma (Table 111–3) are functional systems for predicting survival and are based on a variety of clinical and laboratory tests, unlike the anatomic staging systems for solid tumors. The Durie-Salmon staging system used previously has been found not to predict prognosis after treatment with high-dose therapy or the novel targeted therapies that have emerged.
Table 111–3 International Staging System
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Table 111–3 International Staging System
|Stage||Median Survival, Months|
|β2M < 3.5, alb ≥ 3.5||I (28%)||62|
|β2M < 3.5, alb < 3.5 or β2M = 3.5–5.5||II (39%)||44|
|β2M > 5.5||III (33%)||29|
Serum β2-microglobulin is the single most powerful predictor of survival and can substitute for staging. β2-Microglobulin is a protein of 11,000 mol wt with homologies to the constant region of immunoglobulins that is the light chain of the class I major histocompatibility antigens (HLA-A, -B, -C) on the surface of every cell. Patients with β2-microglobulin levels <0.004 g/L have a median survival of 43 months and those with levels >0.004 g/L only 12 months. Serum β2-microglobulin and albumin levels are the basis for a three-stage International Staging System (ISS) (Table 111–3). It is also felt that once the diagnosis of myeloma is firm, histologic features of atypia may also exert an influence on prognosis. High labeling index and high levels of lactate dehydrogenase are also associated with poor prognosis.
Other factors that may influence prognosis are the presence and number of cytogenetic abnormalities, hypodiploidy, chromosome 13q and 17p deletion, translocations t(4;14) and t(14;16); circulating plasma cells; performance status; as well as serum levels of soluble IL-6 receptor, C-reactive protein, hepatocyte growth factor, C-terminal cross-linked telopeptide of collagen I, transforming growth factor (TGF)-β, and syndecan-1. Microarray profiling and comparative genomic hybridization have formed the basis for RNA- and DNA-based prognostic staging systems, respectively. The ISS system is the most widely used method of assessing prognosis (Table 111–3).
Treatment: Multiple Myeloma
About 10% of patients with myeloma will have an indolent course (smoldering myeloma) demonstrating only very slow progression of disease over many years. Such patients only require antitumor therapy when the disease becomes symptomatic with development of anemia, hypercalcemia, progressive lytic bone lesions, renal dysfunction, progressive rise in serum myeloma protein levels and/or Bence Jones proteinuria, or recurrent infections. Patients with solitary bone plasmacytomas and extramedullary plasmacytomas may be expected to enjoy prolonged disease-free survival after local radiation therapy to a dose of around 40 Gy. There is a low incidence of occult marrow involvement in patients with solitary bone plasmacytoma. Such patients are usually detected because their serum M component falls slowly or disappears initially only to return after a few months. These patients respond well to systemic therapy.
Patients with symptomatic and/or progressive myeloma require therapeutic intervention. In general, such therapy is of two sorts: systemic therapy to control the progression of myeloma and symptomatic supportive care to prevent serious morbidity from the complications of the disease. Therapy can significantly prolong survival and improve the quality of life for myeloma patients.
The initial standard treatment for newly diagnosed myeloma is dependent on whether or not the patient is a candidate for high-dose chemotherapy with autologous stem cell transplant.
In patients who are transplant candidates, alkylating agents such as melphalan should be avoided since they damage stem cells, leading to decreased ability to collect stem cells for autologous transplant. Newer agents combined with pulsed glucocorticoids have now become standard of care as induction therapy in newly diagnosed patients. Two phase II studies have combined thalidomide with dexamethasone as initial therapy for newly diagnosed multiple myeloma in transplant candidates and reported rapid responses in two-thirds of patients, while allowing for successful harvesting of peripheral blood stem cells for transplantation. A randomized phase III trial showed significantly higher response rates for thalidomide (200 mg PO qhs) plus dexamethasone (40 mg for 4 days every 2 weeks) compared to dexamethasone alone, setting the stage for use of this combination as standard therapy in newly diagnosed patients. Importantly, novel agents bortezomib, a proteasome inhibitor, and lenalidomide, an immunomodulatory derivative of thalidomide, have similarly been combined with dexamethasone and obtained high response rates (>80%) without compromising stem cell collection for transplantation. Their superior toxicity profile with improved efficacy has made them the preferred agents for induction therapy. Efforts to improve the fraction of patients responding and the degree of response have involved adding agents to the treatment program. Combination of lenalidomide, bortezomib, and dexamethasone achieves close to 100% response rate, and other similar three-drug combinations (bortezomib, thalidomide, and dexamethasone or bortezomib, cyclophosphamide, and dexamethasone) achieve >90% response rate. Initial therapy is continued until maximal cytoreduction.
In patients who are not transplant candidates, besides the options available for transplant candidates, therapy consisting of intermittent pulses of an alkylating agent, melphalan with prednisone, has been utilized. The usual doses of melphalan/prednisone (MP) are melphalan, 0.25 mg/kg per day, and prednisone, 1 mg/kg per day for 4 days. Doses may need adjustment due to unpredictable absorption and based on marrow tolerance. However, a number of studies have combined novel agents with MP combination and reported superior response and survival outcome. In patients >65 years old, combining thalidomide with MP (MPT) obtains higher response rates and overall survival compared to MP alone. Similarly, significantly improved response (71 vs 35%) and overall survival (3-year survival 72 vs 59%) were observed with combination of bortezomib with MP compared to MP alone. Lenalidomide added to MP followed by lenalidomide maintenance also prolonged progression-free survival compared to MP alone. These combinations of novel agents with MP also achieve high complete response rates (MPT ∼ 15%; MPV ∼ 30%, MPR ∼ 20%, and MP ∼ 2-4%). Patients responding to therapy generally have a prompt and gratifying reduction in bone pain, hypercalcemia, and anemia and often have fewer infections. Improvement in the serum M component may lag behind the symptomatic improvement. The fall in M component depends on the rate of tumor kill and the fractional catabolic rate of immunoglobulin, which in turn depends on the serum concentration (for IgG). Light chain excretion, with a functional half-life of ∼6 h, may fall within the first week of treatment. Since urine light chain levels may relate to renal tubular function, they are not a reliable measure of tumor cell kill; however, improvements in serum free light chain measurement are often seen sooner. Although patients may not achieve complete remission, clinical responses may last long periods of time. The important feature of the level of the M protein is not how far or how fast it falls but the rate of its increase after therapy.
Randomized studies comparing standard-dose therapy to high-dose melphalan therapy (HDT) with hematopoietic stem cell support have shown that HDT can achieve high overall response rates and prolonged progression-free and overall survival; however, few, if any, patients are cured. Although complete responses are rare (<5%) with standard-dose chemotherapy, HDT achieves 25–40% complete responses. In randomized studies, HDT produced better median event-free survival in four of five studies, higher complete response rate in four of five trials, and better overall survival in three of five studies. A randomized study failed to show any significant difference in overall survival between early transplant after induction therapy versus delayed transplant at relapse. These data allow an option to delay transplant, especially with the availability of more agents and combinations. Two successive HDTs (tandem transplants) are more effective than single HDT in the subset of patients who do not achieve a complete or very good partial response to the first transplant. Allogeneic transplants may also produce high response rates, but treatment-related mortality may be as high as 40%. Nonmyeloablative allogeneic transplantation is now under evaluation to reduce toxicity, while permitting an immune graft-vs-myeloma effect.
Oral prednisone maintenance therapy was effective in a single trial after standard-dose chemotherapy. Maintenance therapy prolongs remissions following standard-dose regimens as well as HDT. Thalidomide administered post-HDT prolongs relapse-free survival. Phase III studies have demonstrated improved outcome in patients receiving lenalidomide compared to placebo as maintenance therapy after HDT, and another phase III study showed prolonged progression-free survival after MP lenalidomide and lenalidomide maintenance therapy in nontransplant candidates.
Relapsed myeloma can be treated with novel agents including lenalidomide and/or bortezomib. These agents target not only the tumor cell but also the tumor cell–bone marrow interaction and the bone marrow milieu. These agents in combination with dexamethasone can achieve up to 60% partial responses and 10–15% complete responses in patients with relapsed disease. The combination of bortezomib and liposomal doxorubicin is active in relapsed myeloma. Thalidomide, if not used as initial therapy, can achieve responses in refractory cases. High-dose melphalan and stem cell transplant, if not used earlier, also have activity in patients with refractory disease.
The median overall survival of patients with myeloma is 7–8 years, with subsets of younger patients surviving more than 10 years. The major causes of death are progressive myeloma, renal failure, sepsis, or therapy-related myelodysplasia. Nearly a quarter of patients die of myocardial infarction, chronic lung disease, diabetes, or stroke—all intercurrent illnesses related more to the age of the patient group than to the tumor.
Supportive care directed at the anticipated complications of the disease may be as important as primary antitumor therapy. The hypercalcemia generally responds well to bisphosphonates, glucocorticoid therapy, hydration, and natriuresis. Calcitonin may add to the inhibitory effects of glucocorticoids on bone resorption. Bisphosphonates (e.g., pamidronate 90 mg or zoledronate 4 mg once a month) reduce osteoclastic bone resorption and preserve performance status and quality of life, decrease bone-related complications, and may also have antitumor effects. Osteonecrosis of the jaw and renal dysfunction can occur in a minority of cases. Treatments aimed at strengthening the skeleton, such as fluorides, calcium, and vitamin D, with or without androgens, have been suggested but are not of proven efficacy. Iatrogenic worsening of renal function may be prevented by maintaining a high fluid intake to prevent dehydration and to help excrete light chains and calcium. In the event of acute renal failure, plasmapheresis is ∼10 times more effective at clearing light chains than peritoneal dialysis; however, its role in reversing renal failure remains controversial. Importantly, reducing the protein load by effective antitumor therapy with agents such as bortezomib may result in functional improvement. Urinary tract infections should be watched for and treated early. Plasmapheresis may be the treatment of choice for hyperviscosity syndromes. Although the pneumococcus is a dreaded pathogen in myeloma patients, pneumococcal polysaccharide vaccines may not elicit an antibody response. Prophylactic administration of IV γ globulin preparations is used in the setting of recurrent serious infections. Chronic oral antibiotic prophylaxis is probably not warranted. Patients developing neurologic symptoms in the lower extremities, severe localized back pain, or problems with bowel and bladder control may need emergency MRI and radiation therapy for cord compression. Most bone lesions respond to analgesics and chemotherapy, but certain painful lesions may respond most promptly to localized radiation. The anemia associated with myeloma may respond to erythropoietin along with hematinics (iron, folate, cobalamin). The pathogenesis of the anemia should be established and specific therapy instituted, where possible.