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MANAGEMENT OF NEWLY DIAGNOSED MYELOMA
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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.
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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.
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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).
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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.
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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
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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).
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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.
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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.
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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
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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.
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THERAPY FOR THE TRANSPLANTATION-INELIGIBLE PATIENT
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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).
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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
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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
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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.
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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
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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
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Three randomized trials explored the use of lenalidomide as maintenance therapy, with two of the trials following autologous SCT445,446 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.
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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.
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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.
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CONSOLIDATION THERAPY
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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.
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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.
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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.
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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.
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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.
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APPROACH TO RELAPSED OR REFRACTORY PATIENTS
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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.
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Proteasome Inhibitors
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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
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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
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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.
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Immunomodulatory Drugs
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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
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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
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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
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Histone Deacetylase Inhibitors
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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
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Monoclonal Antibodies
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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
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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
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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.
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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
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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
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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
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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.
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ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
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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
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Studies from Seattle501,508 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
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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
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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.
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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.
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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
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CYTOGENETIC-GUIDED THERAPY OF MYELOMA
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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).
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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
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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.
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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
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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
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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.
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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
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Palliative Radiation Therapy
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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.
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EMERGENT COMPLICATIONS OF NEW MYELOMA THERAPY
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Venous Thromboembolism
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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.
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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
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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
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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
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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
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Peripheral Neuropathy
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Bortezomib-553,554 and thalidomide-induced555,556 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.
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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.
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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.
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Osteonecrosis of the Jaw
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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