Updates in the Treatment of Newly Diagnosed Multiple Myeloma: Combination Therapy with Bortezomib, Pegylated

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1 Updates in the Treatment of Newly Diagnosed Multiple Myeloma: Combination Therapy with Bortezomib, Pegylated Liposomal Doxorubicin, and Dexamethasone The Practicing Oncologist s Perspective Interviews with: Bijay Nair, MD, MPH Myeloma Institute for Research and Therapy University of Arkansas for Medical Sciences Little Rock, Arkansas James R. Berenson, MD Medical and Scientific Director Institute for Myeloma and Bone Cancer Research West Hollywood, California Physician Editor E. Roy Berger, MD, FACP North Shore Prostate Cancer Consultation & Treatment Service North Shore Hematology Oncology Associates East Setauket, New York Publishing Staff President, Intellisphere Oncology Specialty Group Peter Ciszewski Director of Scientific Content Jeff D. Prescott, PharmD, RPh Clinical Projects Manager Kara Guarini, MS Editors Christin Melton Christina Loguidice Assistant Editor Jason M. Broderick Art Director Ray Pelesko A supplement to Office Center at Princeton Meadows Bldg. 300 Plainsboro, NJ (609) For questions or comments, contact: Christin Melton at cmelton@onclive.com Copyright 2010 Intellisphere, LLC. All rights reserved. MARCH 2010 PRIORITY REPORT Updates in the Treatment of Newly Diagnosed Multiple Myeloma: Combination Therapy with Bortezomib, Pegylated Liposomal Doxorubicin, and Dexamethasone Multiple myeloma (MM) is the second most common hematologic malignancy, with an estimated 20,000 new diagnoses in the United States every year. 1 This malignant plasma cell neoplasm is responsible for the death of more than 10,000 people annually. 1 MM is generally considered an incurable disease. In refractory and recurrent MM, salvage therapy has proved disappointing, with progression-free survival (PFS) typically not exceeding 6 months and a median overall survival (OS) of 1 year after relapse. 2-4 These results, however, may become questionable as more patients with MM are dying, but not necessarily because of the disease. 1,5 The recent achievements in managing MM are primarily attributable to a better understanding of its basic pathophysiology and the development of more effective and more tolerable therapies. 6 Newly identified genetic abnormalities revealed that MM has a heterogeneous pathology. This heterogeneity has provided prognostic insight for individual patients, enabling risk factor stratification and therapeutic individualization to achieve optimal outcomes. 7 In patients newly diagnosed with MM, therapeutic choices should provide disease control, reversal of complications, decreased risk of early death, successful stem-cell collection when transplantation is a therapeutic option, and welltolerated treatment with minimal drug toxicity. 1 In recent years, 2 classes of drugs were developed to treat MM and have proven effective in managing newly diagnosed as well as relapsing disease. These include the orally administered thalidomide and its analog lenalidomide (Revlimid), immunomodulatory drugs, and the intravenously administered bortezomib (Velcade), a proteasome inhibitor. Characteristic toxicities of thalidomide (Thalomid) include neuropathy, thrombosis, constipation, and somnolence; lenalidomide is associated with fatigue, thrombosis, leukopenia, and skin rash. Fatigue and painful neuropathy are common with bortezomib. 1

2 PRIORITY REPORT Vincristine, doxorubicin, and dexamethasone combinations have also proven effective, probably due to the high-dose intense steroid schedule. Therefore, modifications to these schedules have been investigated, including substituting doxorubicin with pegylated liposomal doxorubicin (PLD; Doxil), reducing dexamethasone dose frequency, and later adding thalidomide. 8 PLD has a longer half-life than standard doxorubicin and can extravasate through abnormal bone marrow, exposing malignant plasma cells for longer durations at greater drug concentrations while minimizing organ damage. 9 Thus PLD can improve safety without compromising efficacy. 10,11 Combination therapies of bortezomib with doxorubicin or alkylating agents have demonstrated an additive or synergistic effect in treating MM. Initial combination therapy with bortezomib, PLD, and dexamethasone (collectively known as VDD) produced superior overall response (OR) rates of 80% to 100%, complete/near-complete response (CR/nCR) rates of 20% to 30%, and very good partial response (VGPR) rates of 30% to 50%. 5,12-14 In patients with newly diagnosed MM, the addition of lenalidomide to this therapeutic combination (collectively known as RVDD) was highly effective, with a partial response (PR) rate of at least 96% and a VGPR rate of at least 58%. 15 Response rates were not affected by cytogenetic status, and RVDD was well tolerated. Phase I/II VDD and RVDD Studies in Patients with Newly Diagnosed Myeloma Results from a single-center, open-label, phase II trial of VDD as initial treatment in patients with newly diagnosed MM (median age, 61 years) were published in the last quarter of Updated results, which included the RVDD regimen, were presented at the American Society of Hematology annual meeting in December The phase II VDD study enrolled 40 patients, and the phase I/II RVDD study enrolled 68 patients (as of December 2009); all patients had newly diagnosed MM that required treatment and had measurable disease and normal cardiac function. 5,15 Patients who previously underwent radiation and/or dexamethasone therapy, as well as those with renal failure and on dialysis were eligible. Exclusion criteria included neutrophil count less than 1000/µL, platelet count less than 30,000/µL, greater than grade 1 peripheral neuropathy, or serious medical or psychiatric illness. 5 Study Design and Treatment 5,15 The primary end point of the VDD study was the CR/ ncr rate after 6 cycles of therapy; secondary end points included OR rate, PFS, and OS. 5 The aim of the RVDD study was to determine the maximum tolerated dose (MTD) of the RVDD regimen and assess its safety and efficacy. 15 Patients received lenalidomide 15 to 25 mg (days 1-14), bortezomib 1.3 mg/m 2 (days 1, 4, 8, 11), dexamethasone 20 mg/10 mg (cycles 1-4/5-8; days of and after bortezomib), and PLD 20 or 30 mg/m 2 (day 4) at 4 dosage levels for up to eight 21-day cycles. In the phase I portion of the RVDD study, patients were assigned to dosage levels 1 through 4, according to the time-to-event continual reassessment method algorithm. Response was assessed using modified European Group for Blood and Marrow Transplantation (EBMT) criteria and the International Uniform Response Criteria (IURC). Patients who achieved at least a PR could proceed to autologous stem-cell transplant (SCT) after at least 4 cycles. After 8 cycles, patients could continue treatment using 21-day maintenance cycles with lenalidomide (days 1-14), bortezomib (days 1 and 8), and dexamethasone (days of and after bortezomib) at the doses tolerated at the end of initial treatment. For efficacy assessment, serum and urine samples were collected at baseline and on day 1 of each treatment cycle and on day 1 of the maintenance treatment cycles. At these time points, M proteins were measured using serum and urine protein electrophoresis and immunofixation. Serum-free light chain assays were also performed. Efficacy assessment was performed according to the modified EBMT criteria. 3,16 Modifications included the addition of ncr rate (defined as the disappearance of M protein upon electrophoresis but the appearance of positive results using immunofixation, with no residual myeloma evident in bone marrow) and VGPR rate (defined by IURC as at least 90% disease reduction). 17 PFS and OS were also defined by IURC. Cytogenetic studies were performed using standard banding methodology and fluorescence in situ hybridization. Efficacy Results 5,15 RVDD. In 57 evaluable patients, at least 96% had a PR, at least 58% had a VGPR, and 30% had a CR/nCR. In 48 patients who completed 4 cycles, at least 98% had a PR, at least 58% had a VGPR, and 29% had a CR/nCR. At the MTD, 100% of patients had a PR. In a subset of 24 patients characterized by genetic deletions [(13q deletion or t(4;14) or t(14;16) or 17p deletion)] response rates were not statistically different; PR, VGPR, and CR/nCR rates were 92%, 67%, and 33%, respectively. Twenty-four patients proceeded to stemcell collection with 7.5 x 10 6 CD34 + cells/kg collected after a median of 4 cycles (range, 3-10 cycles) of RVDD. Stem-cell mobilization and collection was successful in all patients with transplant course reportedly unremark- 2

3 able to date. After a median of 6 months of follow-up, median PFS and OS had not been reached. RVDD was highly active and well tolerated in patients newly diagnosed with MM, and response rates were unaffected by adverse cytogenetic status. The MTD was 25 mg for lenalidomide, 1.3 mg/m 2 for bortezomib, 20 mg for dexamethasone, and 30 mg/m 2 for PLD. Table 1. Response Rates with Therapy Overall response ( PR) 98% 100% a RVDD (n = 48) VDD (n = 40) 85.0% Overall VGPR 58% 57.5% CR and ncr 29% 37.5% Completed cycles 4 6 VDD. Response to therapy was evaluated after 6 cycles. The OR rate was 85%; among those with at least a VGPR (57.5% of patients), the CR/nCR rate was 37.5% and the VGPR rate was 20% (Table 1). A total of 27.5% of patients had a PR. Responses were rapid with a medium time to response (PR or better) of 1 cycle (range, 1-6 cycles) and a medium time to best response of 4 cycles (range, 2-6 cycles). Of the 40 participants, 28 (70%) were able to proceed to stem-cell mobilization and collection. Thirty patients underwent SCT; stem-cell collection was successful in all. A median of 7.5 x 10 6 CD34 + cells/kg were collected after a median of 2.5 days. The CR/nCR rate was 56.6%, and the OR rate was 86.6%. Overall, at least a VGPR was achieved in 76.6% of patients, and a PR was observed in 10%. Although OR rate did not change significantly, CR/nCR rate increased by 20% post-transplantation, and the percentage of patients with at least a VGPR increased by more than 20% (P =.08). Survival analyses revealed that PFS was not achieved after a median follow-up of 23.8 months (range, months). The 1-year PFS rate was 92.5%, with 3 patients experiencing disease progression. Comparable PFS was observed among transplantation patients; 1-year OS was 97.5% based on 1 observed patient death due to disease progression. Projected 2-year PFS and OS rates were 80.1% and 92%, respectively. An exploratory subgroup analysis was performed in 19 patients who had chromosome 13del/13q- and/or hypodiploid phenotype, t(4;14), t(14;16) or 17p. PFS in this subset was not statistically different from that in patients without these genetic mutations. After VDD treatment, a significant difference in 1-year PFS was demonstrated between patients who achieved a VGPR or better (100%) and those who achieved less than a VGPR (82%) (P =.03). At 2 years, the projected CR indicates complete response; ncr, near-complete response; PR, partial response; RVDD, lenalidomide (Revlimid), bortezomib (Velcade), pegylated liposomal doxorubicin (Doxil), and dexamethasone; VDD, bortezomib (Velcade), pegylated liposomal doxorubicin (Doxil), and dexamethasone; VGPR, very good partial response. a At maximum tolerated dose. Table 2. Dosage Levels and DLTs in Phase I of the RVDD Study Dosage Levels DLTs a Level 1 (lenalidomide/pld 15 mg/20 mg/m 2 ) (n = 4) 0 Level 2 (lenalidomide/pld 20 mg /20 mg/m 2 ) (n = 11) 2 Level 3 (lenalidomide/pld 25 mg/20 mg/m 2 ) (n = 21) 3 Level 4 (lenalidomide/pld 25 mg/30 mg/m 2 ) (n = 6) 0 DLTs indicates dose-limiting toxicities; PLD, pegylated liposomal doxorubicin; RVDD, lenalidomide (Revlimid), bortezomib (Velcade), pegylated liposomal doxorubicin (Doxil), and dexamethasone. a Two patients were not evaluable for DLT (1 at level 2 and 1 at level 3) and were replaced, leaving 40 evaluable patients for DLTs. PFS rate was 93% in patients who achieved a VGPR or better as opposed to 63% in patients who achieved less than a VGPR (P =.03). Results were similar in patients who underwent SCT. Safety and Tolerability 5,15 RVDD. At the time of the analysis, 32 of a planned 38 patients had received study medication at the MTD. Patients received a median of 4 therapeutic cycles (range, 1-16 cycles). At least 4 cycles were completed by 48 patients, 11 patients completed all 8 cycles, and 34 patients either completed or discontinued therapy. A total of 7 patients remained on maintenance therapy. Dosage levels and dose-limiting toxicities (DLTs) are listed in Table 2. Of the 5 DLTs, there were 2 cases of grade 3 asymptomatic neutropenia on day 1 of cycle 2, 1 grade 3 elevation of transaminases, 1 grade 3 drug-induced fever, 3

4 PRIORITY REPORT and 1 grade 3 hypophosphatemia. Based on probability estimates of DLTs of 4.7% for level 1, 9.7% for level 2, 13.7% for level 3, and 17.9% for level 4, and a predetermined definition of MTD, dosage level 4 was chosen as the MTD for the phase II part of the study (closest to, but not exceeding, the 20% target rate of DLTs). Overall, toxicities were manageable, with 3% to 18% of patients experiencing grade 3 and 4 toxicities including neutropenia (18%), infections (16%), thrombocytopenia (7%), and deep vein thrombosis (2%). No grade 4 peripheral neuropathy was reported, but 4% of patients reported grade 3 peripheral neuropathy. Grade 1 and 2 palmarplantar erythrodysesthesia was reported in 24%. There were no treatment-related deaths. VDD. There were no occurrences of grade 4 neutropenia or anemia, but there was 1 case of grade 4 thrombocytopenia. Most hematologic toxicities were mild or moderate. Four patients (10%) experienced grade 3 neutropenia. Two patients (5%) experienced thrombocytopenia. Grade 3 anemia was reported in 1 patient. Grade 1 or 2 painful neuropathy was reported in 6 patients (15%). Thromboembolic events comprised grade 3 or 4 deep vein thrombosis in 2 patients (5%) and pulmonary embolus in 2 patients (5%). These events occurred early in therapy when tumor burdens are higher. A protocol amendment was introduced that required thromboembolic prophylaxis; thereafter, no additional thromboembolic events were observed, suggesting that prophylaxis is necessary. Grade 3 pneumonia occurred in 1 patient. Three patients developed grade 3 or 4 muscle weakness. Two patients experienced grade 3 or 4 mood alterations that were attributed to dexamethasone. Gastrointestinal symptoms were common (ie, 70% of patients had grade 1 or 2 constipation) but manageable and generally mild. Grade 1 and 2 hand-foot syndrome (HFS) was experienced by 75% of patients; only 1 patient reported grade 3 HFS. Elevated serum glucose and infections (both grade 3) occurred in 12.5% and 7.5% of patients, respectively. No patients experienced a significant decline in heart function. All grade 2 and higher toxicities either resolved or improved to grade 1, including peripheral neuropathies. No differences in tolerability of the VDD regimen were observed in the elderly; however, a formal statistical analysis was not possible. No deaths were attributed to the study drug regimen. Conclusions Results suggest, at least preliminarily, that while VDD is among the most active regimens for initial therapy in newly diagnosed MM, the addition of lenalidomide to the combination may constitute an even more active regimen. 15 Further clinical research is required to make this determination. Both regimens, however, provide evidence that when a VGPR is achieved with initial therapy, improved outcomes are also achieved. Recently, the IURC recognized achieving a VGPR with initial therapy as an important benchmark, and a number of studies have demonstrated that in the post-transplantation setting, it is prognostic for PFS and OS. 13,18,19 Results from these trials demonstrate the high level of activity associated with combination therapies in newly diagnosed MM. Both the VDD and RVDD regimens were well tolerated, with limited grade 3 or 4 adverse events. It is likely that the substitution of PLD for standard doxorubicin played a role in the tolerability of these regimens. Further study is needed to elucidate the relationship between initial therapeutic choice, achievement of an initial VGPR or better, and CR on long-term outcomes. References 1. Kumar SK, Mikhael JR, Buadi FK, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (msmart) consensus guidelines. Mayo Clin Proc. 2009;84: Palumbo A, Gay F, Bringhen S, et al. Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma. Ann Oncol. 2008;19: Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348: Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341: Jakubowiak AJ, Kendall T, Al-Zoubi A, et al. Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol. 2009;27: Fonseca R. Many and multiple myeloma(s). Leukemia. 2003;17: Stewart AK, Bergsagel PL, Greipp PR, et al. A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy. Leukemia. 2007;21: Hussein MA. Modifications to therapy for multiple myeloma: pegylated liposomal doxorubicin in combination 4

5 with vincristine, reduced-dose dexamethasone, and thalidomide. Oncologist. 2003;8(suppl 3): Offidani M, Corvatta L, Marconi M, et al. Low-dose thalidomide with pegylated liposomal doxorubicin and high-dose dexamethasone for relapsed/refractory multiple myeloma: a prospective, multicenter, phase II study. Haematologica. 2006;91: Hussein MA, Baz R, Srkalovic G, et al. Phase 2 study of pegylated liposomal doxorubicin, vincristine, decreasedfrequency dexamethasone, and thalidomide in newly diagnosed and relapsed-refractory multiple myeloma. Mayo Clin Proc. 2006;81: Rifkin RM, Gregory SA, Mohrbacher A, Hussein MA. Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: a phase III multicenter randomized trial. Cancer. 2006;106: Oakervee HE, Popat R, Curry N, et al. PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol. 2005;129: Barlogie B, Anaissie E, van Rhee F, et al. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol. 2007;138: Offidani M, Corvatta L, Piersantelli MN, et al. Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma. Blood. 2006;108: Jakubowiak AJ, Reece DE, Hofmeister CC, et al. Lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed multiple myeloma: updated results of phase I/II MMRC trial. Presented at: 51st American Society of Hematology (ASH) Annual Meeting, New Orleans, LA. December 6, Abstract Blade J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998;102: Durie BG, Harousseau JL, Miguel JS, et al. International Uniform Response Criteria for multiple myeloma. Leukemia. 2006;20: Rajkumar SV, Buadi F. Multiple myeloma: new staging systems for diagnosis, prognosis and response evaluation. Best Pract Res Clin Haematol. 2007;20: van de Velde HJ, Liu X, Chen G, Cakana A, Deraedt W, Bayssas M. Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma. Haematologica. 2007;92:

6 PRIORITY REPORT The Practicing Oncologist s Perspective Interviews with Bijay Nair, MD, MPH Myeloma Institute for Research and Therapy University of Arkansas for Medical Sciences Little Rock, Arkansas James R. Berenson, MD Medical and Scientific Director Institute for Myeloma and Bone Cancer Research West Hollywood, California What is your philosophy in treating a newly diagnosed patient with MM? Dr. Nair: In a clinically fit patient, my strategy is to use a combination of currently available active agents upfront in the context of tandem autologous transplants, followed by a maintenance program to achieve a high rate and duration of complete remission, which in turn translates into better event-free survival and OS. We routinely perform gene array on random marrow samples in all newly diagnosed patients with myeloma. Based on this, we can categorize patients into low-risk (5-year OS of about 80%) and high-risk (median OS of 2 years) groups. As we learn more about the molecular mechanisms behind the disease, we can tailor our treatment to the specific molecular pathology within an individual patient. Currently, our institution is evaluating a more dose-dense and less dose-intense approach in a phase II trial in high-risk patients. In patients who relapse or are refractory to these approaches, I offer clinical trials with newer agents. Dr. Berenson: There is no typical patient any more; they are all different. In order to decide what drugs we are going to use, we need to take 3 things into consideration. One consideration is the characteristics of the myeloma itself (ie, cytogenetics). The second factor is how a patient feels, and their lifestyle and work style. For example, if fine motor skills are important for their job, I don t want to administer a drug that may produce neuropathy. The third thing to consider is whether the patient has any comorbid conditions, as this will determine which drugs should be avoided. What has been your experience with the use of doxorubicin? Specifically in treating MM? What are some of its limitations? Dr. Nair: At the University of Arkansas, we have used doxorubicin during induction for about 20 years: as part of VAD [Vincristine-Adriamycin- Dexamethasone] in Total Therapy 1 protocol, as part of DPACE/DTPACE [Dexamethasone-Cisplatin- Doxorubicin-Cyclophosphamide-Etoposide/D- Thalidomide-PACE] in TT2, and VTDPACE [Velcade-TDPACE] in TT3 and now TT4/TT5. Here we use it as a continuous infusion (approximately 10 mg/m 2 daily) over 4 days. Most people have tolerated this regimen well. Major toxicity has been hematologic, with significant cytopenias, requiring transfusions, as well as increased risk of infections. We have not seen problems with cardiac toxicity at the above doses with these regimens. Dr. Berenson: Although doxorubicin was believed to be a drug that you should use once every 3 to 4 weeks and at a big dose, we began looking at different schedules in our severe combined immunodeficient mice that harbored our own patients myelomas. Metronomic low-dose doxorubicin was not only more effective but also much better tolerated than in our animal models. Subsequently, in the relapse setting, we are giving doxorubicin on the 4 days of bortezomib therapy (days 1, 4, 8, and 11) with dexamethasone, and did a study that showed very good responses. We just completed a front-line trial and had an extremely high 6

7 response rate (results will be reported at ASCO). Not only did we observe a high response rate, compared with recently published results with the same drug combination, we used less doxorubicin (5 mg/m 2 on days 1, 4, 8, and 11) and had fewer cases of handfoot syndrome. What are your thoughts on the use of combination therapies for MM? Fewer drugs, higher doses versus additional drugs at lower doses? Dr. Nair: Combining active agents is the right strategy in myeloma, since there are multiple pathways involved, and any single agent is unlikely to effectively suppress the involved clone. But this cannot be done in place of autologous stem-cell transplant using melphalan, which is a proven and highly effective approach. I recommend an approach that incorporates a combination of novel agents along with autologous stem-cell transplant. Dr. Berenson: I am not a big believer in more is better but more specific is better. We need to get a lot smarter on how we combine drugs, and not just give the maximum doses of 3 drugs. If drugs are really synergized and work better when they are given together, then maybe we should think about giving less. If one drug causes neuropathy (eg, bortezomib) and the other causes bone marrow suppression (eg, lenalidomide), then maybe you can reduce the dose of both and have less neuropathy and less bone marrow suppression. In the long term, this is much more important to me than being able to say you had a CR. Are you familiar with the research presented at ASH in December [Jakubowiak et al. Revlimid, Velcade, and Dexamethasone, and Doxil (RVDD) in newly diagnosed MM]? What are your thoughts on how this can be used by practicing oncologists? Dr. Nair: Yes, the study by Jakubowiak et al illustrates the tolerability and effectiveness of a 4-drug chemotherapy regimen in patients with newly diagnosed myeloma. Major toxicity appears to have been hematologic. To put it in the context of experience from our institution, we have used a 7-drug regimen (VTDPACE) for over 7 years and found it to be well tolerated and highly effective in producing an initial response in myeloma, and it is also an effective regimen for stem-cell collection. The major limitation with our regimen has been the degree of hematologic toxicities requiring daily monitoring of labs and other resources that may be available only in a transplant center. RVDD incorporates some of the active agents in this regimen in a manner that can be adopted by community oncologists. Dr. Berenson: Yes. Multiple drug combinations are being used. I am involved in proposing a study to look at whether it really is superior to give 3 drugs together, not just in terms of response, but in terms of longevity, versus starting out with single agents and adding drugs. What characteristics would identify a patient appropriate for the RVDD regimen? Dr. Nair: I would feel comfortable using this regimen in a patient who is a potential candidate for autologous stem-cell transplant in the future. My main reservation is in regard to the use of lenalidomide prior to collection of stem cells. In the study by Jakubowiak et al, however, it did not appear to impair the stem-cell collection process. I would consider the possibility of using thalidomide in its place. For nontransplant candidates, this regimen may be too toxic, and I would consider a 2- or 3-drug combination instead. Dr. Berenson: You must consider the patient as well as the side effects of treatment. We are conducting a relapse trial with an RVDD regimen (Revlimid 10 mg for 14 days on a 28-day cycle). We have observed extremely good activity with lower doses, and it is a very well-tolerated regimen. Combining active agents is the right strategy in myeloma, since there are multiple pathways involved, and any single agent is unlikely to effectively suppress the involved clone. Bijay Nair, MD, MPH 7

8 PRIORITY REPORT What are the other current trends in treating MM? Dr. Nair: Regarding the induction regimen for newly diagnosed patients, VRD [Velcade, Revlimid, and Dexamethasone] and VTD [Velcade, Thalidomide, and Dexamethasone] are both highly effective upfront regimens. Addition of doxorubicin/pegylated liposomal doxorubicin, as well as cyclophosphamide, to this regimen can be done safely with excellent results. In the context of autologous stem-cell transplant, there have been attempts to use bortezomib as part of a conditioning regimen along with melphalan. We are also seeing an emerging role of maintenance therapy. Dr. Berenson: There is a trend to stay away from highdose therapy, which really makes the bone marrow unable to take other therapies. Myeloma today is like a marathon, and running 10-minute miles and finishing the 26-mile race is a much better way to approach treating it rather than running 5-minute miles and dropping out at mile 5. It is important to realize that there are many new options for treating this incurable The goal is to give a patient the longest life possible, with the least impact from the disease and side effects of treatment. James Berenson, MD disease, but if we give too much therapy to patients we may create situations in which patients have been made too ill to tolerate new and potentially effective alternative therapies to replace the ones that are no longer working. There will also be much more emphasis on keeping patients in remission longer. The goal is to give a patient the longest life possible, with the least impact from the disease and side effects of treatment. Copyright 2010 Intellisphere, LLC. All rights reserved.