Multiple myeloma (MM), although currently incurable, has seen significantly improved response and overall survival (OS) rates with the inclusion of targeted therapy in its treatment schema. MM therapy has evolved greatly over the past several years and, with innovative research and medications, this disease may soon be curable. This article will focus on the novel agents revolutionizing therapy of MM.
Primarily a disease of the elderly, MM is the second most common hematologic malignancy in the United States, second only to non-Hodgkin’s lymphoma.1 The median average age at diagnosis is 62 years for men and 61 years for women, with fewer than 2% of cases occurring in patients younger than 40 years.1 The number of MM cases in 2009 was an estimated 20,580, and the disease is more prevalent in men and blacks.2 Patients receiving standard therapy have a median survival of 3 to 4 years after diagnosis, whereas those who receive an autologous stem cell transplant may survive 5 to 7 years; survival ranges from weeks to >10 years.1
MM is a clonal B-cell disease; malignant plasma cells accumulate in the bone marrow and ultimately cause cytopenias, bone resorption, and monoclonal protein production.3 The clinical picture of MM can range from asymptomatic monoclonal gammopathy of unknown significance (MGUS) to smoldering MM (SMM) and ultimately to symptomatic disease. Patients with MGUS have a 1% per year chance of advancing to MM, and those with SMM have an even higher risk of progression (10% per year for the first 5 years).4 Improved therapy has begged the question of whether to treat MM in these earlier clinical states, but currently therapy is reserved for patients who have symptomatic disease. Typically, treatment is initiated when evidence of at least one of the following criteria are met: hypercalcemia, anemia, renal insufficiency, or bone lesions (CRAB criteria).5
Diagnosis, staging, and prognosis
The MM diagnosis is confirmed by obtaining quantitative serum immunoglobulins, serum and urine protein electrophoresis, and immunofixation or serum immunoglobulin free light chain assay, skeletal survey, and bone marrow biopsy.2 The presence of monoclonal gammopathy on electrophoresis and plasmacytosis (10% plasma cells in the bone marrow) indicates MM. In addition, measuring beta-2-microglobulin levels is standardly performed to assess tumor burden. Of note, fewer than 3% of patients may present with nonsecretory myeloma, and thus may have little to no monoclonal protein in the serum or urine.2
Historically, the Durie-Salmon staging system has been used to categorize MM patients into stage I, II, or III, depending on the level of anemia, hypercalcemia, presence of bone lesions, and levels of monoclonal protein in the serum and urine.2 More recently, the International Staging System (ISS) has been widely employed. The ISS classifies MM using serum values of beta-2-microglobulin and albumin, tests that are easily reproducible and highly prognostic.2 The ISS cannot distinguish MGUS and SMM from active myeloma, however, and cannot be used for therapeutic risk stratification given that beta-2-microglobulin levels may be increased because of either myeloma tumor burden or renal failure.6 The ability of the ISS to determine prognosis will continue to evolve as the effect of the targeted therapies becomes more apparent.
The role of cytogenetics in MM prognosis is becoming ever more important. It is recommended that both conventional cytogenetic testing as well as fluorescence in situ hybridization (FISH) be used to capture the characteristics that place patients in standard- or high-risk categories.6 Conventional cytogenetic studies may reveal chromosomal abnormalities in only one third of patients with MM, whereas FISH may show abnormalities in more than 90%.6 Poor prognosis has been associated with t(4;14), t(14;16), t(14;20), del(17) (p13), or del(13). In contrast, the presence of t(11;14), t(6;14), or hyperdiploidy has conferred a more favorable prognosis. Again, the novel agents used in MM treatment today may change the prognostic ability of these abnormalities. For example, bortezomib has been shown to overcome the poor prognosis garnered by del(13), t(4;14), and del(17)(p13).5 Future study will elucidate how cytogenetics or FISH will affect risk stratification.
Thalidomide, lenalidomide, and bortezomib have significantly changed the landscape of MM therapy. These agents now play a huge role in the treatment of newly diagnosed (both in transplant- eligible and -ineligible patients) and relapsed/refractory disease, and are also being evaluated in the maintenance setting.
Thalidomide. The proposed mechanisms of action for thalidomide include antiangiogenesis effects, inhibition of tumor necrosis factor-alpha, and increased cell-mediated cytotoxicity.7 How ever, its mechanism of action in MM therapy is not fully explained. Thalidomide’s teratogenicity is well known, and thus it is obtained solely through the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) programs.
Thalidomide dosing varies, but typically ranges from 200 mg to 400 mg oral daily.7 Lower doses may be used when thalidomide is taken in combination with other chemotherapy or in elderly patients unable to tolerate the side effects. Bedtime is the preferable administration time due to the drug’s potential to cause drowsiness; it should be taken with water at least 1 hour after a meal.8
Thalidomide’s side effects may be dose dependent, and common adverse reactions include somnolence, fatigue, constipation, and rash. In addition, neutropenia, edema, and hypothyroidism are possible. Peripheral neuropathy is also associated with thalidomide, and dose adjustment or discontinuation of the drug may be necessary8 (Table 1). Venous thromboembolism (VTE) is a significant complication of thalidomide treatment, particularly when the drug is used in combination with dexamethasone or other cytotoxic agents. Although a full discussion of VTE in MM is beyond the scope of this article, VTE prophylaxis is an important step in the management of the patient with MM.
Lenalidomide. A more potent analog of thalidomide, lenalidomide was designed to increase efficacy and decrease nonhematologic toxicities compared with thalidomide. Like thalidomide, lenalidomide exerts its activity by inhibiting angiogenesis. It also inhibits adhesion of myeloma cells to bone marrow stromal cells and causes apoptosis of myeloma cells.7
The approved lenalidomide dose is 25 mg orally daily on days 1 to 21 with dexamethasone 40 mg orally on days 1 to 4, 9 to 12, and 17 to 20 of each 28- day cycle for the first four cycles. From the fifth cycle and forward, the lenalidomide dose remains the same, but the dexamethasone dose decreases to 40 mg daily on days 1 to 4 only. This agent is cleared renally, which may necessitate dosage adjustments in patients with renal dysfunction.10 All patients, prescribers, and pharmacists must register with the RevAssist program to obtain this medication.
Unfortunately, VTE is still a major side effect with this agent, and patients should receive VTE prophylaxis if possible. Lenalidomide does not cause the same degree of somnolence, constipation, or peripheral neuropathy as thalidomide. Myelosuppression (neutropenia and thrombocytopenia) is seen with this drug and may lead to dose modification10 (Table 2).
Bortezomib. Bortezomib is a first-inclass proteasome inhibitor that targets the 26S proteasome, ultimately leading to cell death. Bortezomib not only targets the myeloma cell, but also inhibits the binding of the myeloma cell to bone marrow stromal cells.7
Bortezomib is administered as a 3- to 5-second bolus intravenous injection, at a dose ranging from 0.7 mg/m2 to 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21- day cycle. No dosage adjustments are necessary for mild renal impairment (<1.5 upper limit of normal). Patients on dialysis, however, should receive bortezomib after dialysis because dialysis may reduce bortezomib concentrations. Patients with moderate or severe hepatic impairment should be started at a dose of 0.7 mg/m2; the dose may be titrated up or down as necessary. Bortezomib undergoes hepatic metabolism through cytochrome P450 enzymes 3A4, 2C19, and 1A2, and should be used cautiously with concomitant 3A4 inhibitors.11
The most common adverse reactions reported with bortezomib include peripheral neuropathy), gastrointestinal disorders, and thrombocytopenia. Bortezomib-induced peripheral neuropathy is generally manageable and reversible, and often resolves or subsides following dose reduction or after treatment has ended11 (Table 1).
After a diagnosis of stage II or III MM, patients are evaluated as candidates for high-dose therapy and stem cell transplantation based on age and comorbidities. The National Comprehensive Cancer Network (NCCN) has established guidelines to address treatment in the various MM patient populations.2
Transplant-ineligible patients. Until the advent of the immunomodulating agents and proteosome inhibitors, the mainstay of therapy for newly diagnosed patients ineligible for transplant, was melphalan plus prednisone (MP). Several studies have compared MP with MP plus thalidomide (MPT) in elderly patients with newly diagnosed disease who are unable to receive standard induction therapy followed by autologous bone marrow transplant. MPT has produced higher overall response rates (ORR), very good partial response (VGPR), and longer progression-free survival (PFS) than MP.12-14 In addition, Facon and colleagues for Intergroupe Francophone du Myélome (IFM) 99-06 showed improved OS with MPT versus MP (51.6 vs 33.2 months).14 Such results have propelled MPT to become a standard of care in elderly patients with MM and those unable to receive a transplant. As expected, the MPT regimen is associated with increased incidences of thromboembolism, infections, and neurologic toxicity as compared with MP.12-14 Elderly patients are often more sensitive to thalidomide’s toxicities, and the recommended starting dose is 100 mg oral daily.
Likewise, the combination of MP plus bortezomib (VMP) has also demonstrated positive results in newly diagnosed transplant-ineligible patients. In the phase 3 international VISTA trial, San Miguel and colleagues compared standard MP with VMP in transplant-ineligible patients with MM.15 Results of this study demonstrated significant improvement in ORR, time to progression (TTP), and OS with VMP compared with MP. A recent update of this study by Mateos and colleagues confirmed this survival advantage. At a median follow-up of 3 years, 69% of patients in the VMP group were alive, compared with 54% in the MP group.16 Per ipheral neuropathy, gastrointestinal side effects, and herpes zoster infection were more commonly reported in the VMP arm. VMP, like MPT, is considered a standard of care in the elderly population.
Lenalidomide is also a valuable drug in the transplant-ineligible population. In a study by Zonder and associates, lenalidomide plus high-dose dexa methasone (LD) had a higher complete response (CR) rate and 1-year PFS when compared with dexamethasone alone.17 The combination of lenalidomide plus low-dose dexa methasone (Ld) showed an OS advantage when compared with LD.18 Toxicities were fewer in the Ld arm,18 and thus Ld is considered a viable option in patients who cannot receive a transplant.
Transplant-eligible patients. Primary induction therapy options for transplant- eligible patients include bortez - omib/dexamethasone (VD), bortez - omib/doxorubicin/dexamethasone (PAD), bortezomib/thalidomide/dexamethasone (VTD), and lenalidomide/ dexamthasone; all regimens are NCCN category I recommendations.2
Rajkumar and colleagues studied Ld (40 mg on days 1, 8, 15, and 22) versus LD (40 mg on days 1-4, 9-12, and 17- 20) in a large randomized phase 3 trial.The results showed significantly better PFS and OS at 1 and 2 years with Ld than with LD.18
The IFM performed a large randomized trial comparing VD induction versus vincristine/doxorubicin/dexamethasone (VAD), and found that the VD arm showed improved ORR and duration of response. Data on PFS and OS are still needed, however.19
Likewise, VTD, when given before transplantation, led to a VGPR in 61% of patients compared with 30% of those given thalidomide/dexamethasone (TD) (P <.001). In addition, 33% of patients receiving VTD achieved near-complete response or CR versus 12% in the TD arm (P <.001).20 Of interest, VTD overcame the adverse cytogenetics on response (del), whereas TD did not.20
Lastly, Sonneveld and colleagues performed a phase 3 trial comparing PAD with VAD. Three hundred patients with newly diagnosed stage II or III disease were randomized to receive PAD or VAD. In the PAD arm, 41% of patients achieved at least a VGPR, whereas only 17% of patients in the VAD arm achieved this result (P = .001). After transplant, 15% of the PAD group re ached CR, versus 4% in the VAD group (P = .05). Partial respose (PR) or better was seen after transplant in 92% and 77% of patients, respectively.21
Relapsed and relapsed/refractory. The three NCCN category I regimens that are indicated for salvage therapy in the relapsed and relapsed/refractory patient population include bortezomib alone, bortezomib plus liposomal doxorubicin, and LD.2
Bortezomib was superior to high-dose dexamethasone in a phase 3 clinical trial conducted by Richardson and colleagues for the APEX Investigators. Bortezomib showed an ORR of 38% compared with 18% for the dexamethasone arm (P <.001). In addition, CR was seen in 6% of patients in the bortezomib group, with only 1% in the dexamethasone arm achieving the same result (P <.001). Median TTP and 1-year survival rate favored the bortezomib arm (P <.001 and P = .003, respectively).22
The combination of bortezomib and liposomal doxorubicin has also gained NCCN category I status as a result of a phase 3 trial in which bortezomib was compared with bortezomib plus liposomal doxorubicin.23 Patients were bortezomib-naïve with recurrent disease. Median TTP was 6.5 months in the bortezomib alone arm, and increased to 9.3 months in the combination group (P = .000004). Survival rate at 15 months was also superior in the combination group (76% vs 65%; P = .03), although response rates were similar between the groups. The bortezomib plus liposomal doxorubicin group did, however, experience more grade 3 and 4 toxicities, such as neutropenia, thrombocytopenia, diarrhea, and hand-foot syndrome.23
Lenalidomide has also proved effective in the relapsed and refractory MM patient population. LD was compared with dexamethasone in two trials, which showed a significantly increased median TTP in their combination arms (11 vs 4.7 months, respectively). Median OS in both studies, at approximately 30 months, was also higher in the combination group.24,25
Other regimens that may be considered in the relapsed and relapsed/ refractory population include VD, dexamethasone alone, dexamethasone/ thalidomide/cisplatin/doxorubicin/ cyclophosphamide/etoposide (DTPACE), and TD; all are NCCN category IIA recommendations.2
[Tables summarizing induction trials for newly diagnosed patients who are ineligible or eligible for transplant and for relapsed/refractory MM are available at www.TheOncologyNurse.com or by writing to firstname.lastname@example.org.]
Myelosuppression. Although thalidomide, lenalidomide, and bortezomib have greatly improved MM therapy, they all have the potential to cause some degree of myelosuppression; dosage adjustments for neutropenia and/or thrombocytopenia may be necessary7,8,10,11,26 (Table 2). Neutropenia (all grades) is seen in 28% of patients taking lenalidomide, and limited data in lenalidomide trials suggest growth factor support may be helpful for these patients through the neutropenic period.27 Bortezomib-related neutropenia is predictable and usually self-limiting, thus dosage reductions are not recommended until the patient is experiencing grade 4 neutropenia.11 Likewise, severe neutropenia is not widely seen with thalidomide use, and doses are typically reduced solely for grade 4 neutropenia.8
Bortezomib-related thrombocytopenia is usually transient and returns to baseline in the rest period between treatment cycles. If a patient does develop grade 4 toxicity, current recommendations include holding the bortezomib dose until the platelet count recovers and then decreasing the dose by 25%.11 Likewise, lenalidomide’s package insert calls for dose reduction by 5-mg increments when the platelet count falls to less than 30 109/L.10
Peripheral neuropathy. Peripheral neuropathy is another potential toxicity associated with bortezomib and thalidomide use. Bortezomib-related peripheral neuropathy appears to occur at a dose threshold, and incidence peaks around cycle five of therapy. Fortunately, the neuropathy is often reversible upon drug discontinuation. In the case of thalidomide, peripheral neuropathy may be cumulative and therefore is frequently irreversible.9 Dosage reduction or cessation of therapy in severe cases may be warranted; Table 1 lists potential dose alterations. Pharmacologic interventions such as tricyclic antidepressants, gabapentin, pregabalin, duloxetine, and lidocaine patches have been used with some success in the treatment of peripheral neuropathy, and may be used along with dosage adjustments to allow continuation of therapy if at all possible.9
Venous thromboembolism. VTE is a serious complication of lenalidomide and thalidomide therapy. Factors that contribute to VTE include hyperviscosity, previous VTE, dexamethasone and other chemotherapy use in MM therapy, immobility, other comorbid conditions (cardiac disease, diabetes mellitus, renal dysfunction, blood clotting disorder), presence of a central catheter, surgery, and the use of erythropoiesis-stimulating agents.28 Thus, VTE prophylaxis is a major component of care for MM patients. Aspirin, low-molecular-weight heparins (LMWHs), and warfarin have all been used for VTE prophylaxis in this patient population, but strong data illustrating which agent is most effective in the MM patient are lacking. Palumbo and colleagues, with the IFM, suggest that patients with zero or one of the risk factors should receive aspirin as prophylaxis, whereas those with two or more factors should use LMWH or fulldose warfarin.28 Patient-specific characteristics, degree of thrombocytopenia, renal im pairment, and contraindications to anticoagulation must be considered when choosing a method for VTE prophylaxis.28
Skeletal lesions. Bone disease is very common in patients with MM, and, as mentioned previously, is one of the markers of active disease.29 Affected patients may have significant pain, and the American Society of Clinical Oncology has created guidelines for the prevention and management of MM-related bone disease. It is recommended that intravenous bisphosphonates such as pamidronate and zoledronic acid be administered on a monthly basis to patients with lytic bone destruction or spine compression fractures. Pamidronate is dosed at 90 mg over 2 to 6 hours; the dose of zoledronic acid is 4 mg over 15 minutes. Although there are no formal recommendations on pamidronate dosing in the setting of renal dysfunction, it is often recommended that the dose be decreased to 60 mg monthly. In patients with a creatinine clearance of less than 30 mL/min, zoledronic acid should not be given. The starting dose for zoledronic acid for patients with a clearance greater than 30 mL/min ranges from 3 mg to 4 mg, depending on the degree of renal impairment.29
A rare but serious complication of intravenous bisphosphonate therapy is osteonecrosis of the jaw. In an effort to reduce the incidence or severity of the condition, it is recommended that all MM patients receive a comprehensive dental examination as well as any preventive dental procedures before initiating bisphosphonate therapy. Oral infections should be promptly treated, and major dental work should be avoided if at all possible while patients are receiving active bisphosphonate therapy.29
MM is a disease whose treatment is in process. Novel therapeutic agents such as thalidomide, lenalidomide, and bortezomib have dramatically improved response and survival rates in patients with this disease, but more research is certainly needed to cure this cancer. !
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13. Palumbo A, Bringhen S, Liberati AM, et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008;112:3107-3114.
14. Facon T, Mary JY, Hulin C, et al; for the Intergroupe Francophone du Myélome. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007;370:1209-1218.
15. San Miguel JF, Schlag R, Khuageva NK, et al; for the VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917.
16. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28:2259-2266.
17. Zonder JA, Crowley J, Hussein MA, et al. Superiority of lenalidomide (len) plus highdose dexamethasone (HD) compared to HD alone as treatment of newly-diagnosed multiple myeloma (NDMM): results of the randomized, double-blinded, placebo-controlled SWOG trial S0232. Blood (ASH Annual Meeting Abstracts). 2007;110:Abstract 77.
18. Rajkumar SV, Jacobus S, Callander N, et al. Randomized trial of lenalidomide plus highdose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed myeloma (E4A03), a trial coordinated by the Eastern Cooperative Oncology Group: analysis of response, survival, and outcome. J Clin Oncol. 2008;26(May 20 suppl):Abstract 8504.
19. Harousseau JL, Mathiot C, Attal M, et al. Velcade/dexamethasone (Vel/D) versus VAD as induction treatment prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM): updated results of the IFM 2005/01 trial. Blood (ASH Annual Meeting Abstracts). 2007;110:Abstract 450.
20. Cavo M, Tacchetti P, Patriarca F, et al. Superior complete response rate and progression-free survival after autologous transplantation with up-front Velcade-thalidomide-dexamethasone compared with thalidomide-dexamethasone in newly diagnosed multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2008;112: Abstract 158.
21. Sonneveld P, van der Holt B, Schmidt-Wolf IGH, et al. First analysis of HOVON-65/ GMMG-HD4 randomized phase III trial comparing bortezomib, adriamycine, dexamethasone (PAD) vs VAD as induction treatment prior to high dose melphalan (HDM) in patients with newly diagnosed multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2008;112: Abstract 653.
22. Richardson PG, Sonneveld P, Schuster MW, et al; for the Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487-2498.
23. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25:3892-3901.
24. Dimopoulos M, Spencer A, Attal M, et al; for the Multiple Myeloma (010) Study In vestigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007; 357:2123-2132.
25. Weber DM, Chen C, Niesvizky R, et al; for the Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133-2142.
26. Kettle JK, Finnkbiner KL, Klenke SE, et al. Initial therapy in multiple myeloma: investigating the new treatment paradigm. J Oncol Pharm Pract. 2009;15:131-141.
27. Mateos MV, Garcia-Sanz R, Colado E, et al. Should prophylactic granulocyte-colony stimulating factor be used in multiple myeloma patients developing neutropenia under lenalidomidebased therapy? Br J Haematol. 2008;140:324-326.
28. Palumbo A, Rajkumar SV, Dimopoulos MA, et al; for the International Myeloma Working Group. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423.
29. Kyle RA, Yee GC, Somerfield MR, et al; for the American Society of Clinical Oncology. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2007;25:2464-2472.