Current Treatment Strategies for Multiple Myeloma

Current Treatment Strategies for Multiple Myeloma Sheeba Thomas, Raymond Alexanian

Abstract In recent years, there have been major advances in the treatment of multiple myeloma. Among previously untreated patients, different combinations of dexamethasone, lenalidomide, thalidomide, and bortezomib have produced overall response rates of 80%-90% with complete response rates of 10%-32%, and remissions are often achieved after only 2 cycles of initiating systemic therapy. Subsequent intensification with high-dose chemotherapy supported by autologous stem cell transplantation has enabled younger patients to achieve partial and complete responses with evidence of prolonged survival. Tandem autologous stem cell transplantation and reduced-intensity allogeneic stem cell transplantation are under investigation in attempts to improve outcomes. For patients unable to pursue consolidation therapy with stem cell transplantation, remissions obtained with induction therapy can often be extended with the use of maintenance systemic therapy. Despite available therapies, relapse of disease is inevitable for nearly all patients, and treatment strategies with novel agents and novel combinations of established agents are under study.

Clinical Lymphoma & Myeloma, Vol. 7, Suppl. 4, S139-S144, 2007 Key words: Allogeneic stem cell transplantation, Proteasome inhibitors, Tandem transplantation

Introduction In recent years, there have been major advances in the treatment of multiple myeloma (MM). These have included the development of new agents, enhanced combinations of standard drugs, more consistent use of intensive therapy supported by autologous stem cell transplantation (ASCT), and better prevention and management of complications. In this review, we discuss treatment strategies by phase of disease (untreated, remission, primary resistant, and relapse) with a focus on programs applied at our center.

Asymptomatic Multiple Myeloma In approximately 15% of patients, the diagnosis of multiple myeloma is made by chance when screening studies reveal an increased serum protein in patients who have no symptoms of myeloma and are being evaluated for another disorder. When anemia is moderate (hemoglobin level < 10.5 g/dL), lytic bone lesions cause pain or are revealed on bone survey, and recurrent infections develop or renal dysfunction is seen, initiation of systemic therapy is indicated. However, most asymptomatic patients do not have such features and should be followed without chemotherapy until there are clearer signs of disease progression. Prognostic factors indicating a shorter time to disease progression Department of Lymphoma/Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston Submitted: Sep 29, 2006; Revised: Jan 8, 2007; Accepted: Jan 18, 2007 Address for correspondence: Raymond Alexanian, MD, Department of Lymphoma/Myeloma, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 429, Houston, TX 77030-4009 Fax: 713-563-5067; e-mail: [email protected]

(TTP) are serum myeloma protein > 3 g/dL or immunoglobulin A myeloma protein type.1 Median times to progression are 17 months with both features, 39 months with one feature, and 95 months with neither feature. The presence of intramedullary defects on magnetic resonance imaging of thoracic and lumbar spine also identifies patients with shorter TTP. Because antimyeloma activity is more likely to be revealed in this early stage of disease compared with later phases of relapsing disease, selected patients at increased risk for disease progression are candidates for first-line, prospective, controlled new agent trials. The distinction of asymptomatic myeloma from monoclonal gammopathy of unknown significance might be difficult in some patients. In 2003, the International Myeloma Working Group characterized asymptomatic myeloma by the presence of a monoclonal component on serum protein electrophoresis > 3 g/dL and/or > 10% marrow plasmacytosis on bone marrow (BM) biopsy, with no evidence of myeloma-related organ or tissue impairment.2 At our center, we have considered a monoclonal component on serum protein electrophoresis > 2.5 g/dL or marrow plasmacytosis > 15% on 2 occasions as diagnostic of asymptomatic myeloma, especially when coupled with reduced levels of uninvolved immunoglobulins. Because most patients with nonthreatening asymptomatic myeloma are followed without chemotherapy in the same manner as those with monoclonal gammopathy of unknown significance, the main value in distinguishing these entities rests on the need for more frequent follow-up of patients with asymptomatic myeloma.

Primary Chemotherapy Simultaneous with the control of complications (bone pain and/or hypercalcemia), all patients with asymptomatic

Dr Thomas has served as a paid consultant for Millennium Pharmaceuticals. Dr Alexanian has received research support from Celgene and is a member of the Speaker’s Bureau for Millennium Pharmaceuticals and Celgene. This article includes discussion of investigational and/or unlabeled uses of drugs, including the use of lenalidomide, thalidomide, and interferon-α as single agents; bortezomib in combination with dexamethasone, dexamethasone/thalidomide, dexamethasone/doxorubicin, melphalan, thalidomide, or dexamethasone/lenalidomide; thalidomide in combination with melphalan/prednisone; and pegylated liposomal doxorubicin/vincristine/dexamethasone in multiple myeloma.

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Treatment Strategies for Multiple Myeloma Table 1 Bortezomib Combinations for Previously Untreated Multiple Myeloma12-16 Study

Regimen/Schedule

Number of Evaluable Patients

Response Rate (%)

Complete Response (%)

Jagannath et al12

Bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 Dexamethasone 40 mg on the day before and after bortezomib if no PR after cycle 2 or no CR after cycle 4

32

88

6

Oakervee et al13

Bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 Doxorubicin 0, 4.5, 9 mg/m2 on days 1-4 Dexamethasone 40 mg per day; cycle 1: days 1-4, 8-11, and 15-18; cycle 2: days 1-4

21

95

24

Popat et al14

Bortezomib 1 mg/m2 on days 1, 4, 8, and 11 Doxorubicin 9 mg/m2 on days 1-4 Dexamethasone 40 mg per day; cycle 1: days 1-4, 8-11, and 15-18; cycle 2: days 1-4

19

89

11

Wang et al15

Bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 Thalidomide 100-200 mg per day on days 1-28 Dexamethasone 20 mg/m2 on days 1-4, 9-12, and 17-20

38

87

16

60

89

32

Bortezomib 1-1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 Melphalan 9 mg/m2 on days 1-4 Prednisone 60 mg/m2 on days 1-4 Every 6 weeks for 4 cycles, then Mateos et al16

Bortezomib 1-1.3 mg/m2 on days 1, 8, 15, and 22 Melphalan 9 mg/m2 on days 1-4 Prednisone 60 mg/m2 on days 1-4 Every 5 weeks for 5 cycles

myeloma require systemic therapy to reduce plasma cell burden. Optimum therapy should induce a high response rate (RR) with no or few serious side effects. Moreover, in patients who are candidates for ASCT, treatment should not impair capacity to collect autologous BM stem cells. Partial response (PR) to therapy is defined by reduction of serum M protein ≥ 50% and urine Bence Jones protein ≥ 90%, with < 10% plasma cells in BM. Complete response (CR) is defined by negative serum and urine immunofixation with ≤ 5% plasma cells in BM; for patients with Bence Jones protein at initiation of therapy, we have also required normalization of serum-free κλ light chain ratio. However, further validation of the role of free light-chain studies is warranted.3,4 In a phase II dose-finding study, the oral agent thalidomide has shown single-agent activity in newly diagnosed MM with an RR of 72%.5 Based on this trial, a phase III study of thalidomide (200 mg daily) together with high-dose dexamethasone (40 mg/m2 on days 1-4, 9-12, and 17-20, given on a 28-day cycle, provided an RR of 63%, compared with 41% for dexamethasone alone,6 leading the Food and Drug Administration to approve this combination as firstline therapy for MM. Onsets of remission have been rapid (< 2 months) so that the duration of primary therapy before intensification or maintenance can be short. In proportion to dose and duration, thalidomide can cause constipation, fatigue, dry skin, and neuropathy; dexamethasone can cause fluid retention, insomnia, and indigestion. However, with preventive measures and dose adjustments, most side effects are manageable. In the absence of therapeutic-dose anticoagulation, the rate of thrombosis reported when these drugs are given

together has been 15%-17%, a high frequency for which there has been no clear explanation. Therefore, we believe that some form of anticoagulation, such as low molecular weight heparin or warfarin in therapeutic dose, is essential for all patients who receive the combination. When given alone, thalidomide has been associated with a low frequency of deep vein thrombosis (< 5%), so that anticoagulation is unnecessary.7 Bortezomib is a proteasome inhibitor that is effective against MM, mantle cell lymphoma, and certain low-grade lymphomas.8-12 Controlled studies have shown single-agent RRs of 38% in patients with relapsing myeloma, and a longer survival than that observed with high-dose dexamethasone.11 When combined with other active agents in the treatment of newly diagnosed patients, RRs have ranged from 87% to 95%, with CR rates from 6% to 32% (Table 1).12-16 Noteworthy side effects of bortezomib include an increased risk of peripheral neuropathy and reactivation of varicella zoster. We have advised prophylaxis with such drugs as valacyclovir or acyclovir for patients who receive bortezomib. Lenalidomide is a potent thalidomide analogue that is effective against myeloma cells in vitro and has a lower incidence of fatigue, constipation, and neuropathy when compared with thalidomide.17 In the relapsed setting, singleagent lenalidomide has provided RRs of 18%; in combination with high-dose dexamethasone, the RR was 59% compared with 21% with high-dose dexamethasone alone.17,18 Among previously untreated patients, the RR has been 91%, but with a low frequency of CR (6%).19 Concomitant use of erythropoietin with lenalidomide and high-dose dexamethasone can increase the risk of thrombosis.20

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Sheeba Thomas, Raymond Alexanian Based on their independent activity, the combination lenalidomide/ bortezomib/dexamethasone has an excellent prospect for high overall and CR rates, with fewer complications. This regimen is in the early phases of clinical trial investigation.21-23 A recent study compared the combination of MPT (melphalan/ prednisone/thalidomide) with MP (melphalan/prednisone) in patients aged 65-85 years.24 The addition of thalidomide improved the RR (76% vs. 47%) and 2-year event-free survival (54% vs. 27%). Longer follow-up is necessary to assess any impact on survival. A subsequent study (French Intergroup of Myeloma [IFM] 99-06) compared MP, MPT, and melphalan 100 mg/m2 supported by ASCT in patients aged 65-75 years. Progression-free survival (PFS) and overall survival (OS) were significantly prolonged in patients treated with MPT compared with MP. However, no significant differences in PFS or OS were noted between the MP and melphalan 100 mg/m2 arms.25 These studies suggest that MPT might provide an advantage for older patients (aged > 70 years) who might be ineligible for intensive therapy. However, it is yet unclear if MPT is superior to ASCT with melphalan 200 mg/m2, because a reduced-intensity conditioning regimen was used in IFM 99-06. Whether a limited program of bortezomib/lenalidomide/dexamethasone is equivalent to MPT is also not clear. In previously untreated patients, dexamethasone alone has been associated with an RR of 41%.6 The addition of vincristine and doxorubicin to dexamethasone (VAD) improved RRs to 61%-67%; however, a central venous catheter is required, myelosuppression is more severe, and vincristine is associated with significant treatment-emergent neuropathy.26,27 Rates of response, PFS, and OS are similar between VAD and the combination of vincristine/liposomal doxorubicin/dexamethasone (DVd).28 However, DVd has been associated with a lower incidence of severe neutropenia, neutropenic fever, and sepsis, with no need for central venous access or growth-factor support. Recent retrospective analysis has shown superior RRs for thalidomide/ dexamethasone compared with VAD (76% vs. 52%), suggesting that primary therapy with VAD is rarely justified.29

Intensive Therapy After Primary Chemotherapy In order to achieve maximum reduction of plasma cell burden, thereby extending remission and survival times, intensive therapy has developed as the second phase of treatment for approximately 50% of patients with MM at this time. Techniques have evolved so that autologous stem cells are harvested by leukapheresis with granulocyte colony-stimulating factor. Chemotherapy with high-dose melphalan is then given, followed by reinfusion of collected stem cells. Such treatment is followed by a marked degree of myelosuppression for approximately 10 days, with a high risk of infection and bleeding and the need for daily monitoring in a hospital or outpatient setting. Approximately two thirds of patients with myeloma qualify for this procedure, with ineligibility based on impaired performance, other medical problems, patient refusal, or inadequate insurance. Medicare covers patients aged ≤ 76 years, provided there is PR of myeloma.

In a study comparing conventional chemotherapy with or without intensive chemotherapy supported by ASCT, rates of CR were higher with intensive therapy than with standard therapy (22% vs. 5%), with median survival prolongation of 1 year.30 In a second study, the rate of CR again favored intensive therapy compared with conventional chemotherapy (44% vs. 8%), and median survival was prolonged by 1 year (54 months vs. 42 months).31 In the experience of most experts, progressive reduction of myeloma based on standard criteria of response has correlated with longer survival. We recently evaluated the data of 748 consecutive patients aged < 65 years who were treated with various dexamethasone-based combinations over the past 20 years. Of these, 397 patients also received intensive therapy with a high-dose, melphalan-based regimen supported by autologous stem cells within 1 year of initial chemotherapy. Intensive therapy induced PR or CR in 65% of patients with disease resistant to primary chemotherapy and led to CR in 34% of patients treated while in PR. Among all 748 patients, median survival times were approximately 2 years for the 28% of patients with persistent resistant disease, 5 years for the 51% with PR, and 12 years for the 21% of patients with CR as the best outcome (Figure 1). Intensive therapy had been given to 22% of patients with persistent resistance, to 57% of patients who had exhibited a PR, and to 82% of patients who were in CR. The median survival of patients with disappearance of myeloma protein on standard electrophoresis but with persistent abnormality on immunofixation (near CR or very good PR) was similar to that of patients in PR. Such patients should be considered in PR rather than CR in future analyses. Among 32 patients intensified while in CR, median survival was not prolonged in comparison with comparable patients in CR after only chemotherapy (Figure 2). Thus, the relative benefit of intensive therapy decreased progressively in patients treated for resistant disease, for PR, and for CR.32,33 This conclusion was consistent with the report on tandem transplantation by Attal et al, who observed no survival gain for patients intensified after > 90% reduction of the myeloma.34

Tandem Transplantation Tandem ASCT refers to the procedure of having a second program of intensive therapy supported by autologous stem cells soon after recovery from the first. Because CR represents a surrogate marker of long survival, the primary goal of tandem transplantation has been to improve the rates of CR. In one study, 399 previously untreated patients aged < 60 years were assigned at random to receive a single or double transplantation. A complete or very good PR was exhibited by 42% of patients in the single-transplantation group and by 50% of patients in the tandem-transplantation group. The probability of surviving event free for 7 years after diagnosis was 11% in the single-transplantation group and 43% in the double-transplantation group, with 7-year OS rates of 21% and 42%, respectively. The benefit of a second transplantation was more pronounced among patients who did not exhibit a CR or near CR (or very good PR) within 3 months after the first procedure. A second study of 441 patients found that, although second intensification improved CR rate, event-free survival, PFS, and TTP, there was no improvement of survival when compared with single intensification (55 months vs. 50 months).35

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Treatment Strategies for Multiple Myeloma Figure 1 Overall Survival of 748 Patients Aged < 65 Years Treated with Dexamethasone-Based Induction Chemotherapy

Figure 2 Overall Survival of Patients in Complete Remission After Induction Chemotherapy Versus Induction Chemotherapy Followed by Autologous Stem Cell Transplantation 100

80 60

Living Patients (%)

Living Patients (%)

100

CR (156)

40 PR (383)

20 NR (209)

0

5

10

Primary treatment alone (28)

80

NR to CR (18)

60 CR to CR (32)

40

PR to CR (78)

20

15

Years of Treatment

0

5

10

15

Years of Treatment Markedly different survival from initial chemotherapy for groups of patients with different outcomes after primary chemotherapy with or without early intensive therapy (P < 0.01). Parentheses indicate number of patients. Abbreviation: NR = no response

At our center, only 10% of patients with residual myeloma protein after their first intensive therapy exhibited CR after a second treatment. The potential gain from tandem intensification appears limited to a small fraction of patients, such as the 10%-15% of patients who are converted to CR or who exhibit a longer duration of PR.

Reduced-Intensity Allogeneic Stem Cell Transplantation Although myeloablative conditioning supported by ASCT is effective in converting many patients from PR to CR, high rates of transplantation-related mortality have been an obstacle to its use.36 Accordingly, the role of less intensive, nonmyeloablative regimens has been considered promising. At our institution, 22 patients received a reduced-intensity conditioning regimen with fludarabine and melphalan, supported by unmanipulated grafts from human lymphocyte antigen matched sibling donors (n = 13) or matched unrelated donors (n = 9). Seven patients exhibited CR, and 6 were alive after a median follow-up of 15 months. Overall survival and PFS were 30% and 19% after 2 years. Nonrelapse mortality was high at 19% within 3 months and 40% after 1 year.37 The role of reduced-intensity ASCT remains under study, such as earlier in the disease course. Currently, a multicenter trial is comparing tandem transplantation-supported treatment using autologous blood stem cells for the first intensification followed by matched donor cells for the second, with tandem intensification supported by autologous blood stem cells with both procedures. This trial seems appropriate for patients at high risk for resistance or early relapse, such as younger patients with advanced disease or deletion of chromosome 13 on cytogenetic analysis.

Maintenance Therapy After maximum reduction of myeloma with induction and consolidation therapies, the primary goal is to maintain remission for as long as possible, while preserving disease sensitivity to later attempts at re-control. Among the approximately 20% of patients

Similar survival for groups of patients who exhibited CR after initial chemotherapy or after intensive therapy had been given for disease in NR, PR, or CR (P = 0.19). The median survival of all patients was 12 years. Parentheses indicate number of patients. Abbreviation: NR = no response

with disease in CR, the median duration of remission is 3 years, and no chemotherapy appears necessary. For the 40% of patients in PR after primary therapy, the projected duration of disease stability is short without treatment, so that some form of cytostatic therapy is warranted. Because our experience has shown that drugs used as maintenance are less likely to be effective in a salvage combination, we have favored interferon (IFN)-α in a dose of 1.5-3 mU twice a week or thalidomide alone.38 Current analysis indicates that IFN-α as maintenance does not improve median survival, but the modest cytoreductive effect and occasional long remissions support its value for selected patients.39 Interferon-α is contraindicated in patients with a history of depression. Other common side effects of IFN-α include fevers, chills, arthralgias, and myalgias. Maintenance therapy with thalidomide improved event-free survival (52% vs. 36%) and 4-year probability of survival (87% vs. 77%) when compared with observation alone.40 A multicenter phase II study by the National Cancer Institute of Canada observed that maintenance therapy with thalidomide at doses > 200 mg was poorly tolerated, so that most centers have limited the dose to 50-100 mg daily.41 With disease recurrence, combination of an alkylating agent and glucocorticoid given intermittently might sustain stability for many months. The role of new drugs such as lenalidomide and bortezomib in long-term maintenance requires study, although currently we favor the use of these drugs in salvage combinations.

Relapsing Myeloma In clinical trials, the effects of treatments should be evaluated separately for patients with primary resistant disease and for those with relapsing disease. The latter category can be further stratified into those relapsing with or without previous maintenance therapy. This section focuses on treatments for patients with relapsing disease. Patients with progressive myeloma in the absence of maintenance therapy, such as after CR induced by intensive therapy, are good candidates for new agent trials. Such patients also

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Sheeba Thomas, Raymond Alexanian Table 2 Bortezomib Combinations for Resistant, Relapsing Multiple Myeloma42-44 Study Berenson et al42

Richardson et al43

Regimen/Schedule

Number Evaluable

Response Rate (%)

Complete Response (%)

Bortezomib 0.7-1 mg/m2 on days 1, 4, 8, and 11 Melphalan 0.025-0.25 mg/kg per day on days 1-4 every 4 weeks for 8 cycles

34

68

6

Bortezomib 1-1.3 mg/m2 on days 1, 4, 8, and 11 Lenalidomide 5, 10, 15, 20 mg per day on days 1-14 Dexamethasone 20 mg per day on days 1, 2, 4, 5, 8, 9, 11, and 12 every 3 weeks

21

67

5

85

55

–

Group A Bortezomib 1 mg/m2 on days 1, 4, 8, and 11 Thalidomide 50, 100, 150, 200 mg per day or Zangari et al44

Group B Bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 Thalidomide 50, 100, 150, 200 mg per day Dexamethasone 20 mg per day on days 1, 2, 4, 5, 8, 9, 11, and 12 if < PR by cycle 3 Every 3 weeks for 8 cycles

have a high likelihood of regaining control with a program that combines components of the originally effective chemotherapy. This includes regimens of intermittent dexamethasone, thalidomide, alkylating agents, and combinations of drugs that have been used individually. When disease is again controlled, maintenance therapy should be continued for the long term, such as with daily thalidomide alone. Of more concern are patients with disease relapsing despite combinations of effective agents. For these patients, programs have been developed that apply new drugs such as bortezomib and/or lenalidomide in rational combinations. The APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial is one such study that compared the use of bortezomib/high-dose dexamethasone with high-dose dexamethasone alone in patients with relapsed/refractory myeloma. The rate of overall response with bortezomib/dexamethasone was 38% compared with 18% with dexamethasone alone, and 1-year OS rates were 80% and 66%, respectively.11 Table 2 summarizes results that show higher RRs for several bortezomib-based combinations for relapsed/refractory MM, indicating that rational combinations are more useful in this setting than single-agent therapy.42-44 The combination of lenalidomide and high-dose dexamethasone has been compared with high-dose dexamethasone in 2 phase III multicenter studies of patients with progressive disease. Pooled analysis of these studies showed superior rates of overall response (59% and 22%) and TTP (48 weeks vs. 20 weeks) for patients receiving lenalidomide/dexamethasone.45 The shorter TTP with lenalidomide/dexamethasone among patients exposed previously to thalidomide suggests some degree of crossresistance for thalidomide and lenalidomide.46 A higher rate of thrombotic events in patients receiving lenalidomide after previous thalidomide also suggests some degree of additive toxicity.

New Agents All patients with disease in resistant relapse are candidates for new agent trials. Only in this manner have effective drugs, such as dexamethasone, thalidomide, lenalidomide, and bortezomib, been

identified. Many drugs are now in different stages of phase I/II study. Promising agents based on in vitro trials include mitogenactivated protein kinase inhibitors, RAS and RAF inhibitors, heat-shock protein–90 inhibitors, vascular endothelial growth factor inhibitors, and histone deacetylase inhibitors.47-52 When an effective drug has been identified without unacceptable toxicity, further trials in rational combinations should follow as rapidly as possible. Application of such drugs as part of combinations for newly diagnosed patients should then be considered.

Acknowledgements We are grateful to Kay Delasalle for the data analyses and to Bonnie Baum and Rose Guevara for their assistance in typing this paper.

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S144 • Clinical Lymphoma & Myeloma Vol 7 Suppl 4 April 2007