KEY WORDS: Multiple myeloma, Autologous transplantation, Induction therapy

Short Course Bortezomib plus Melphalan and Prednisone as Induction Prior to Transplant or as Frontline Therapy for Nontransplant Candidates in Patients with Previously Untreated Multiple Myeloma Cristina Gasparetto, 1 Jon P. Gockerman, 2 Louis F. Diehl, 2 Carlos M. de Castro, 2 Joseph O. Moore, 2 Gwynn D. Long, 1 Mitchell E. Horwitz, 1 George Keogh, 3 John P. Chute, 1 Keith M. Sullivan, 1 Rachel Neuwirth, 4 Patricia H. Davis, 1 Linda M. Sutton, 5 Russell D. Anderson, 5 Nelson J. Chao, 1 David Rizzieri 1 The purpose of this study was to evaluate the efficacy and safety of short-course bortezomib, melphalan, prednisone (VMP) in previously untreated multiple myeloma as frontline therapy for transplant-ineligible patients and induction prior to autologous stem cell transplantation (ASCT). Patients received up to 6 28-day cycles of bortezomib 1.3 mg/m 2, days 1, 4, 8, and 11, plus melphalan 6 mg/m 2 and prednisone 60 mg/m 2,days 1-7. After 2-6 cycles, eligible and consenting patients could proceed to ASCT. Responses were assessed by International Uniform Response Criteria. The primary endpoint was complete response (CR) rate with VMP. Forty-five patients were enrolled. Among 44 evaluable patients, response rate was 95%, including 18% $CR (9% stringent CR), 27% very good partial responses (VGPR), and 50% partial responses (PR). Twenty patients proceeded to ASCT. Stem cell collection was successful in all; median yield was 5.610 6 CD34 1 cells/kg. Posttransplant response rates were 30% $CR (10% stringent CR), 65% VGPR, and 5% PR. After median follow-up of 14.0/14.6 months, median time to progression and progression-free survival were both 19.8/27.9 months in non-asct/asct patients. Seven patients have died; 1-year survival rates were 82%/95% in non- ASCT/ASCT patients. The most common grade 3/4 toxicities were thrombocytopenia (20%), neutropenia (28%), and infection (9%). Peripheral neuropathy grade 2-4 was the most common nonhematopoietic side effect occurring 17 patients (38%), although it was typically reversible, and only 5 patients (11%) discontinued therapy as a result of it. Short-course VMP is highly effective and generally well tolerated, both as initial treatment in non-asct patients and induction prior to ASCT. VMP did not negatively affect stem cell collection. Longer follow-up and prospective phase III trials are required to validate these initial observations. Biol Blood Marrow Transplant 16: 70-77 (2010) Ó 2010 American Society for Blood and Marrow Transplantation KEY WORDS: Multiple myeloma, Autologous transplantation, Induction therapy INTRODUCTION Multiple myeloma (MM) is a B cell lymphoproliferative disorder that accounts for approximately 10% of all hematologic malignancies [1]. High-dose melphalan (Mel) therapy plus autologous stem cell transplant (ASCT) remains 1 of the preferred approaches in previously untreated MM patients aged #65 years, having been shown to result in superior From the 1 Cellular Therapy, Duke University Medical Center, Durham, North Carolina; 2 Oncology Hematology, Duke University Medical Center, Durham, North Carolina; 3 Charleston Hematology Oncology Associates, PA Charleston, South Carolina; 4 Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts; and 5 Duke Oncology Network, Duke University Medical Center, Durham, North Carolina. Previous presentations and publications containing material appearing in this manuscript: Gasparetto C, Gockerman JP, Diehl LF, et al. Bortezomib plus melphalan and prednisone as induction prior to transplant or as frontline therapy for non-transplant candidates in patients with previously untreated multiple myeloma. Blood. 2008;112:abstract 3325. Poster presented at 2008 Annual Meeting of the American Society for Hematology, San Francisco, CA, December 6-9. Gasparetto C, Keogh GP, Gockerman JP, et al. A prospective study of bortezomib in combination with melphalan and prednisone for patients with previously untreated multiple myeloma. Blood. 2005;106:379b (abstract 5181). Financial disclosure: See Acknowledgments on page 76. Correspondence and reprint requests: Cristina Gasparetto, MD, Department of Cellular Therapy, Duke University Medical Center, Durham, NC, 27710 (e-mail: gaspa001@mc.duke.edu). Ó 2010 American Society for Blood and Marrow Transplantation 1083-8791/10/161-0008$36.00/0 doi:10.1016/j.bbmt.2009.08.017 70

Biol Blood Marrow Transplant 16:70-77, 2010 VMP Therapy in Frontline MM Patients Eligible/Ineligible for ASCT 71 response rates and improved outcomes, including prolonged overall survival (OS), compared with conventional chemotherapy alone [2-4]. In preparation for ASCT, patients typically receive induction therapy to reduce their tumor burden. Achievement of a complete (CR) or very good partial response (VGPR) to induction therapy or following transplant has been associated with improved outcomes, including prolonged time to progression (TTP), progression-free survival (PFS), and OS [5]. Higher rates of CR/ VGPR following induction therapy may result in higher rates posttransplant, leading to longer OS [6-8]; therefore, optimizing response to induction therapy remains an important goal. With this aim, a wide variety of induction regimens are being explored. Bortezomib-based regimens are demonstrating substantial activity, with very high rates of CR/VGPR, in patients with previously untreated MM [9], including induction therapy prior to ASCT [6-8]. These clinical findings reflect preclinical investigations in which bortezomib showed synergistic or additive activity in combination with agents commonly used for the treatment of MM, including Mel [10,11], doxorubicin [10,11], dexamethasone [12], and the immunomodulatory agents [13]. Notably, Mitsiades et al. [10,11] demonstrated that bortezomib greatly increased the sensitivity of MM cell lines and patients cells to Mel in vitro, including formerly Mel-resistant cell lines. In phase 1/2 clinical trials, bortezomib plus melphalan resulted in promising activity in relapsed or refractory MM patients [14], and subsequently in a Spanish Myeloma Group trial bortezomib plus melphalan prednisone (VMP) produced an 89% response rate, including 32% CR, in previously untreated MM patients aged $65 years not proceeding to ASCT [15,16]. However, lengthy MP-based therapy is not typically used for transplant-eligible MM patients because prolonged treatment with Mel can adversely affect peripheral blood stem cell collection [17]. In contrast, short-term Mel therapy may not significantly impair stem cell harvesting [18]. Based on the importance of attaining a CR/VGPR prior to ASCT, and the effectiveness of bortezomib in combination with Mel, this phase II study was conducted to evaluate whether a short course of a modified VMP regimen would be effective and tolerable both as frontline therapy in non-asct patients and as induction therapy prior to transplant. PATIENTS AND METHODS Patient Selection Patients aged $18 years with previously untreated (except localized radiotherapy), histologically confirmed MM were eligible. Other inclusion criteria included Eastern Cooperative Oncology Group (ECOG) performance status #3, life expectancy.3 months, and normal organ and marrow function (leukocytes $310 9 /L, absolute neutrophil count [ANC] $1.510 9 /L, platelets $10010 9 /L, serum creatinine #3.5 mg/dl, aspartate aminotransferase [AST]/alanine aminotransferase [ALT] #2.5 upper limit of normal, total bilirubin within normal institutional limits). Patients with severe pancytopenia because of MM bone marrow (BM) involvement and renal insufficiency (serum creatinine.2 mg/dl) because of MM were eligible. Patients were excluded if they were HIV-positive, had history of hepatitis C virus (HCV) infection, or had other uncontrolled intercurrent illness limiting compliance with study requirements. Ineligibility for ASCT was not an exclusion criterion. All patients provided written informed consent. The study was approved by the Cancer Protocol Committee at Duke University Medical Center (DUMC) as well as by the institutional review board at DUMC and the review boards at all participating centers, and was conducted in accordance with International Conference on Harmonization guidelines on Good Clinical Practice and the principles of the Declaration of Helsinki. Study Design This prospective, openrf-label phase II clinical trial was conducted at DUMC, Durham, NC, and 2 centers in the Duke Oncology Network (Johnston Memorial Hospital, Smithfield, NC, and Person Memorial Hospital, Roxboro, NC). Patients were enrolled from August 5, 2004, to August 31, 2007. The primary end points were CR/VGPR rate with VMP and safety, durability of response and ability to collect stem cell postinduction. All patients signed informed consent prior initiation of therapy and the protocol was approved by the local IRB (institutional review board). Patients received up to 6 28-day cycles of i.v. bortezomib 1.3 mg/m 2, days 1, 4, 8, and 11, plus oral Mel 6 mg/m 2 and prednisone 60 mg/m 2, days 1-7. On days of concurrent administration, Mel was administered at least 1 hour prior to bortezomib. Permitted supportive therapy included hematopoietic growth factors after cycle 1, and standard antiemetic agents; bisphosphonates were recommended as standard therapy, and acyclovir was recommended for herpes zoster prophylaxis. Patients discontinued treatment because of disease progression, unacceptable adverse events (AEs), or intercurrent illness preventing further treatment administration, or based on patient/investigator decision. Patients could continue to receive treatment beyond 6 cycles at the discretion of the investigator. Dose reductions were permitted after cycle 1; bortezomib dose reductions were required for greater than grade

72 C. Gasparetto et al. Biol Blood Marrow Transplant 16:70-77, 2010 2 bortezomib-related peripheral neuropathy using established dose modifications [19]. Mel and prednisone were withheld for any grade $3 nonhematologic or grade 4 hematologic toxicity, and reinitiated without dose reduction upon resolution. All patients were to receive a minimum of 2 cycles of therapy up to a maximum of 6 cycles. Patients who achieved a CR/VGPR proceeded to ASCT at the point this was first documented (between cycles 2 and 6). All patients were mobilized with growth factors, although 2 had the addition of cyclophosphamide. The conditioning regimen was Mel 200 mg/m 2 (140 mg/m 2 if aged.65 years). Assessments Hematology and serum chemistry were assessed at baseline, in weeks 1 and 2 of each cycle, and at the end of treatment. Performance status was determined at baseline, the start of each cycle, and the end of treatment. Blood and urine samples for M-protein measurement were collected, and bone marrow aspirate and biopsy performed, at baseline, every 2 cycles during induction, and upon completion of treatment. Response was assessed every 2 cycles and post-asct. Although this was a prospective study, to grade efficacy we applied the more stringent recently published International Uniform Response Criteria [20]. Patients who proceeded to ASCT were followed every 3 months for the first year and every 3 to 6 months thereafter. AEs were monitored throughout induction and graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Statistical Analysis A sample size of 45 was required to detect a CR rate of 20% with VMP compared with 5% in historical controls receiving MP, assuming a 5 0.073 (1 sided) and 96% power. PFS and OS were defined as time from first dose until progression or death, or until last follow-up or death, respectively. TTP, PFS, and OS distributions were estimated using the Kaplan- Meier method. Descriptive statistics are presented separately for non-asct and ASCT patients as a post hoc subgroup analysis. RESULTS Patient Characteristics Forty-five patients were enrolled, of whom 20 proceeded to ASCT. Patients baseline demographics and disease characteristics are listed in Table 1, overall, and by ASCT status. Overall, 60% of patients were male, median age was 63 years, 37% had International Staging System [21] (ISS) Stage III disease, 22% had ECOG performance status.1, and 70% had $40% plasma cells in their BM; the MM subtype was IgG in 67%, IgA in 16%, and kappa or lambda light chain in 9% each. Cytogenetic and fluorescein in situ hybridization (FISH) analyses were performed in 37 patients (Table 1). Among non-asct versus ASCT patients, median age was higher (66 versus 54 years), and proportions of patients with albumin \3 g/dl, b 2 -microglobulin $3.5 mg/l, ISS Stage III disease, ECOG performance status.1, and BM plasma cell infiltration $40% appeared somewhat higher; in Table 1. Baseline Patient Demographics and Disease Characteristics Overall and According to Transplant Status Total N545 Non-ASCT Patients N525 ASCT Patients N520 Median age, years (range) 63 (33-75) 66 (43-75) 54 (33-74) Male, n (%) 27 (60) 15 (60) 12 (60) Albumin <3 g/dl, n (%) 5 (11) 4 (16) 1 (5) b 2 -microglobulin $3.5 mg/l, n/n (%) 21/38 (55) 12/19 (63) 9/19 (47) ISS stage, n (%) n538 n518 n520 I/II 24 (63) 10 (56) 14 (70) III 14 (37) 8 (44) 6 (30) Creatinine >2.5 mg/dl, n (%) 2 (4) 1 (4) 1 (5) ECOG PS >1 10 (22) 9 (36) 1 (5) Bone marrow plasma cell 30/43 (70) 19/24 (79) 11/19 (58) infiltration $40%, n/n (%) MM isotype, n (%) IgG 30 (67) 18 (72) 12 (60) IgA 7 (16) 2 (8) 5 (25) Light chain Kappa 4 (9) 3 (12) 1 (5) Lambda 4 (9) 2 (8) 2 (10) Cytogenetic abnormalities, n (%) n537 n521 n516 del(13) 10 (27) 7 (33) 3 (19) del(17 p) 5 (13) 3 (14) 2 (13) t(11;14) 7 (19) 5 (24) 2 (13) Hyperdiploidy 2 (5) 1 (5) 1 (6) Hypodiploidy 1 (3) 1 (5) ASCT indicates autologous stem cell transplantation; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System.

Biol Blood Marrow Transplant 16:70-77, 2010 VMP Therapy in Frontline MM Patients Eligible/Ineligible for ASCT 73 addition, rates of chromosome 13 deletion and t(11;14) appeared slightly higher in non-asct patients. Treatment Exposure Patients received a median of 4 cycles of VMP (range: 1-6 in non-asct patients; range: 2-6 in ASCT patients). Ninteen patients discontinued VMP prior to completing 6 cycles for reasons other than proceeding to transplant; these included AEs in 11 patients, disease progression in 5 (no response in 2, early response followed by relapse in 3), and withdrawal of consent in 3. Only 1 patient failed to complete the first cycle, because of development of grade 3 pneumonia and subsequent early withdrawal of informed consent prior to receiving thalidomide-dexamethasone. Consequently, only 44 patients were evaluable for response, all of whom received 2 cycles of therapy. The 24 evaluable non-asct patients did not receive any additional therapy until relapse or progression; of these, 22 elected not to proceed to transplant or were removed from the study by the referring physician, and 2 developed toxicity during VMP (chest pain, and myocardial infarction, respectively, both with a history of coronary artery disease, resulting in withdrawal of consent), which rendered them ineligible for ASCT according to institutional guidelines. Response to VMP Best responses to VMP overall and by treatment cycle in which they were achieved are shown in Table 2. Responses were seen in 42 of 44 (95%) evaluable patients, and included 18% CR or better (9% stringent CR [scr], 9% CR), 27% VGPR, and 50% PR. The 2 patients who failed to respond to therapy completed only the first cycle and 2 cycles of therapy, respectively. Responses to VMP were rapid; best response was achieved after cycle 2 in 10 patients, cycle 4 in 25 patients, and cycle 6 in 7 patients. Best responses to VMP by ASCT status are shown in Table 3. Among 24 evaluable patients who did not Table 2. Best Response to VMP, Overall and by Treatment Cycle Cycle by Which Best Response Achieved proceed to transplant, overall response rate was 92%, which included 25% $CR (8% scr, 17% CR), 17% VGPR (42% $VGPR), and 50% PR. All 20 ASCT patients achieved a response prior to transplant, including 2 (10%) scr, 8 (40%) VGPR, and 10 (50%) PR. Stem Cell Harvest and ASCT Following VMP induction, 1 patient received an additional cycle of therapy with bortezomib plus liposomal doxorubicin prior to ASCT, and 1 patient developed grade 3 peripheral neuropathy after 4 cycles of VMP and received 2 cycles of lenalidomide plus lowdose dexamethasone prior to transplant. All 20 ASCT patients met stem cell collection requirements (.210 6 CD34 1 cells/kg), and 14 (70%) achieved yields of (.510 6 CD34 1 cells/kg). Median yield was 5.610 6 CD34 1 cells/kg (range: 2.3-12.210 6 cells/kg), collected in a median of 2 aphaeresis (range: 1-4). Of the 20 ASCT patients, 18 received Mel 200 mg/m 2 as conditioning and 2 patients aged.65 years received Mel 140 mg/m 2. Median day of neutrophils recovery (.50010 9 /L) following stem cell reinfusion was day 11, with a median of 5 days of severe neutropenia. Median day of platelet recovery (.20,00010 9 /L) following stem cell reinfusion was day 13. Posttransplant response rates were 30% $CR (10% scr, 20% CR), 65% VGPR, and 5% PR. This represented an improvement in equal to or more than VGPR rate from 50% pretransplant to 95% post-asct. Response improved from completion of VMP to post-asct in 11 patients; 7 improved from PR to VGPR, 2 from PR to CR, and 2 from VGPR to CR. Outcomes After median follow-up of 14.0 months (range: 7.4-47.7) in non-asct patients and 14.6 months (range: 8.2-42.9) in ASCT patients, median TTP and PFS Table 3. Best Response to VMP by Transplant Status, and Best Response post-asct in Patients Proceeding to Transplant ASCT Patients, N520 Response rate, n (%)* Best Response to VMP N 5 44 2 4 6 Response rate, n (%) Non-ASCT patients, N524 Pretransplant Posttransplant $CR 8 (18) 1 4 3 scr 4 (9) 1 3 CR 4 (9) 1 3 VGPR 12 (27) 1 8 3 PR 22 (50) 8 13 1 Overall ($PR) 42 (95) 10 25 7 NR 2 (5) 2 CR indicates complete response; PR, partial response; NR, no response; scr, stringent CR; VMP, short-course bortezomib, melphalan, prednisone; VGPR, very good partial response. *Response was evaluated according to the IMWG Criteria [20]. $CR 6 (25) 2 (10) 6 (30) scr 2 (8) 2 (10) 2 (10) CR 4 (17) 4 (20) VGPR 4 (17) 8 (40) 13 (65) PR 12 (50) 10 (50) 1 (5) Overall ($PR) 22 (92) 20 (100) 20 (100) NR 2 (8) ASCT indicates autologous stem cell transplant; CR, complete response; PR, partial response; NR, no response; VMP, short-course bortezomib, melphalan, prednisone; scr, stringent CR; VGPR, very good partial response.

74 C. Gasparetto et al. Biol Blood Marrow Transplant 16:70-77, 2010 were identical in both groups, at 19.8 months (95% confidence interval [CI]: 14.3, not estimable [NE]) in non-asct and 27.9 months (95% CI: 14.6, NE) in ASCT patients (Figure 1A and B). Seven patients have died, 5 in the non-asct and 2 in the ASCT group; 1-year survival rates were 82% (95% CI: 59, 93) in the non-asct and 95% (95% CI: 69, 99) in the ASCT group, respectively. Safety The most common AEs reported during VMP therapy in all 45 patients are shown in Table 4. Peripheral neuropathy grade 2-4 was the most common nonhematopoietic side effect occurring 17 patients (38%), although it was typically reversible and only 5 patients (11%) discontinued therapy as a result of it. The most common nonneurologic grade 3/4 AEs were thrombocytopenia (8, 18%), neutropenia (7, 16%), and infection (5, 11%). Deep-vein thrombosis was reported in 1 (2%) patient. Additionally, 1 patient with a history of severe peripheral vascular disease experienced worsening symptoms while receiving therapy, but with no evidence of occlusion; no intervention was necessary. Eight (18%) patients discontinued treatment because of AEs, including peripheral neuropathy in 5 (11%), severe orthostatic hypotension, sustained grade.3 pancytopenia, and pneumonia each in 1 (2%) patient. Bortezomib dose reductions were required in 7 (16%) patients because of peripheral neuropathy, including 1 patient in cycle 2, 2 in cycle 3, and 4 in cycle 4. Seven patients have died, 6 from disease progression plus the patient who discontinued because of pneumonia. DISCUSSION The results of our phase II study indicate that short-course VMP represents a highly effective induction therapy prior to ASCT for previously untreated MM patients. The rate of equal to or more than CR, the primary end point of the study, was 18%, including 9% scr, whereas overall, 45% of patients achieved equal to or more than VGPR to VMP. Among patients who proceeded to transplant, the notable responses to VMP induction translated into very high post-asct response rates, including 30% equal to or more than CR and 95% equal to or more than VGPR, which appear to compare favorably with other studies of bortezomib-based induction regimens [6-8]. Because achievement of CR/VGPR is associated with improved long-term outcomes [5], the high response rates seen in our study are important, and the preliminary outcome data reported herein appear promising in both ASCT and non-asct patients. However, longer follow-up beyond the current median of approximately 14 months is required. As this was not a randomized study, strong conclusions cannot be drawn from comparisons of outcomes among ASCT and non-asct patients. Randomized phase III studies, with lengthy follow-up, comparing VMP alone with VMP induction plus ASCT would be required to determine whether consolidation with ASCT provides additional benefit in terms of longterm outcomes. Indeed, because many centers no longer have an upper age limit for ASCT eligibility, and transplant-related mortality has been reduced to \2%, it may be reasonable to consider comparing VMP plus ASCT with other induction-plus-transplant strategies as well as with nontransplant multiagent approaches such as lenalidomide plus dexamethasone and other combinations. An important consideration in these studies will be to carefully monitor patients during long-term follow-up, because any advantages in terms of outcomes may become evident only after an extended period of time. VMP therapy was well tolerated by the majority of patients; toxicities were predictable and generally manageable, and did not include any unexpected AEs. The safety profile was in line with previous experience with this regimen [15,16,22] and with bortezomib [23] and MP [22,24,25]. Although only 20 of 45 patients proceeded to ASCT, this was primarily because of patient and physician choice regarding treatment options and was not related to excessive toxicity with VMP. Although Mel-based therapy is typically avoided prior to transplant because prolonged exposure to Mel can adversely affect stem cell collection [17], we observed no difficulties in collecting stem cells from VMP-treated patients, nor any delays in engraftment following transplant. This was presumably because VMP was given for only a relatively short time prior to stem cell collection; however, the possibility that VMP induction could result in stem cell collection problems in a minority of patients cannot be excluded based on results from this relatively small study. Our results with short-course VMP in non-asct patients suggest that this regimen may be worth further investigation in the transplant-ineligible population. At 24 weeks, the planned duration of VMP treatment in the present study was shorter than in the VISTA phase III (54 weeks) [22,26] and previous phase I/II (49 weeks) [15,16] studies, which used more intense dosing of bortezomib for the first 24 weeks (twice weekly for 2 of every 3 weeks), and similar to that in a recently reported Spanish Myeloma Group phase III study of reduced-intensity VMP in transplant-ineligible elderly MM patients (31 weeks; 6 weeks of bortezomib twice weekly for 2 of every 3 weeks, then 25 weeks of weekly bortezomib for 4 of every 5 weeks) [27]. Our overall response rate among all 45 patients of 95% appears favorable in relation to the response rates of 71% [22,26], 89% [15,16],

Biol Blood Marrow Transplant 16:70-77, 2010 VMP Therapy in Frontline MM Patients Eligible/Ineligible for ASCT 75 Figure 1. (A) Time to progression, (B) progression-free survival, and (C) overall survival among all patients receiving VMP, according to transplant status.

76 C. Gasparetto et al. Biol Blood Marrow Transplant 16:70-77, 2010 Table 4. Most Common Adverse Events in Patients Receiving VMP (N545) Adverse event Grade 2 Grade 3/4 Peripheral neuropathy 9 (20) 10 (22) Thrombocytopenia 4 (9) 8 (18) Neutropenia 5 (11) 7 (16) Infection 4 (9) 5* (11) Gastrointestinal 5 (11) 2 (4) Deep vein thrombosis 0 1 (2) Orthostatic hypotension 0 1 (2) Fatigue 6 (13) 0 Skin rash 2 (4) 0 *One death. and 81% [28] in the above 3 studies, respectively, although our CR rate (18%) and that in the study of reduced-intensity VMP (22%) [27] appear lower than in VISTA (30%) [22,26] and the phase I/II study (32%) [15,16]. As in these other studies [15,16.22,26,27] responses to VMP in the present study were rapid, with 83% of responders achieving their best response by the end of cycle 4. The higher CR rates in the VISTA and phase I/II studies may be because of prolonged courses of VMP improving quality of response in a proportion of patients [15,28]. However, prolonged therapy may be associated with continued toxicity in some patients (although the latter 30 weeks of VMP therapy in VISTA, which used weekly bortezomib dosing for 2 of every 3 weeks, was associated with lower rates of grade 3/4 AEs compared with the first 24 weeks [26]), as well as the inconvenience of attending frequent hospital appointments for a long period of time. Therefore, our short-course VMP therapy and the reduced-intensity regimen being studied in the Spanish phase III study may represent highly active but more tolerable and convenient treatment options for some patients. Randomized studies of different VMP schedules with long-term follow-up would be required to assess the relative risks and benefits of each approach. 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