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1 research paper A comparison of lenalidomide/dexamethasone versus cyclophosphamide/lenalidomide/dexamethasone versus cyclophosphamide/bortezomib/dexamethasone in newly diagnosed multiple myeloma Meaghan L. Khan, 1 Craig B. Reeder, 1 Shaji K. Kumar, 2 Marthy Q. Lacy, 2 Donna E. Reece, 3 Angela Dispenzieri, 2 Morie A. Gertz, 2 Phillip Greipp, 2 Suzanne Hayman, 2 Steven Zeldenhurst, 2 David Dingli, 2 John Lust, 2 Stephen Russell, 2 Kristina M. Laumann, 2 Joseph R. Mikhael, 1 P. Leif Bergsagel, 1 Rafael Fonseca, 1 S. Vincent Rajkumar 2 and A. Keith Stewart 1 1 Mayo Clinic, Arizona, Scottsdale, AZ, 2 Mayo Clinic, Rochester, MN, and 3 University Health Network, Toronto, ON, USA Received 16 July 11; accepted for publication 24 October 11 Correspondence: Dr Craig B. Reeder, Hematology-Oncology, Mayo Clinic Arizona, 134 East Shea Boulevard, Scottsdale, AZ 85259, USA. [email protected] Summary Novel agents are considered standard components of induction therapy for newly diagnosed patients with multiple myeloma. We retrospectively compared the results of three consecutive phase 2 clinical trials; RD (lenalidomide/dexamethasone, n = 34), CRD (cyclophosphamide/lenalidomide/dexamethasone, n = 53) and CyBorD (cyclophosphamide/bortezomib/dexamethasone, n = 63) (N = 15). Response rates after four cycles of treatment were: near complete response (ncr), 12% vs. 2% vs. 41%, P <Æ1 and very good partial response or better, 35% vs. 3% vs. 65%, P = Æ3, respectively. With all cycles of therapy considered, ncr was 35%, 15% and 41%, P =Æ6. However, there is no evidence that one regimen produced superior progression-free survival (PFS) (median: 3Æ2vs.2Æ3vs. 2Æ7 years,p =Æ11) or overall survival (3-year: 88% vs. 79% vs. 88%, P =Æ23). Transplantation did not impact PFS (median: 2Æ7 vs. 2Æ3 years, P = Æ41) but was associated with improved OS (3-year: 93% vs. 75%, P Æ1). High genetic risk patients (n = 4) had earlier relapse despite lenalidomide or bortezomib (median: 2Æ1 vs. 2Æ7 years,p = Æ45). Grade 3/4 toxicities were least with CyBorD while CRD had most toxicity. In conclusion, CyBorD demonstrated superior responses and less frequent serious toxicity but more neuropathy when compared to RD and CRD. Importantly, 8% of patients treated with modern therapeutic approaches are alive at 4 years. Keywords: multiple myeloma, lenalidomide, bortezomib, cyclophosphamide. Therapies for multiple myeloma (MM) have evolved significantly in the last several years. With the incorporation of autologous stem cell transplantation (ASCT) and novel agents including thalidomide, its analog lenalidomide, and the proteasome inhibitor bortezomib, considerable progress has been made in overall response rates, complete remission rate, progression-free survival (PFS) and overall survival (OS). Many patients are now living up to 1 years with this disease (Kyle & Rajkumar, 4; Barlogie et al, 6; Brenner et al, 8; Kumar et al, 8; Stewart et al, 9). Several combinations of these novel agents have been studied to identify regimens with superior response rates and lower toxicities. Lenalidomide is an analog of thalidomide and has demonstrated more potent activity compared to its parent drug with fewer reported side effects (Hideshima et al, ; Richardson et al, 2). We initially used lenalidomide in combination with dexamethasone (RD) in newly diagnosed patients, with responses seen in 91% of patients and with tolerable side effects (Rajkumar et al, 5; Rajkumar et al, 1; Lacy et al, 7). When compared to thalidomide plus dexamethasone, RD had improved response rates as well as PFS and OS in newly diagnosed MM (Gay et al, 1). To build on the success of RD we and others next examined the combination of lenalidomide, cyclophosphamide, and dexamethasone (CRD) in the treatment of MM (Hideshima et al, ; Kumar et al, 7; Blansfield et al, 8). These studies demonstrated promising overall response rates of 87%, with 3% of patients obtaining a very good partial response First published online 23 November 11 doi:1.1111/j x ª 11 Blackwell Publishing Ltd, British Journal of Haematology, 156,

2 A Comparison of RD, CRD, and CyBorD in Multiple Myeloma (VGPR) but perhaps with more toxicities (Kumar et al, 7; Morgan et al, 7). The proteasome inhibitor, bortezomib has shown significant activity in both newly diagnosed and refractory MM. When combined with dexamethasone in newly diagnosed patients, response rates are near 9% with 1% of patients achieving a complete response (CR) (Jagannath et al, 5, 9; San Miguel et al, 8). More recently we have reported the use of bortezomib in combination with cyclophosphamide and dexamethasone (CyBorD) with an overall response rate of 88% with rapid results and manageable toxicities (Reeder et al, 9). Numerous studies continue to investigate bortezomib use in combination therapy (Kumar et al, 9a; Richardson et al, 9). Each of the above regimens has demonstrated significant improvements in response, however which combination of drugs is ultimately superior is unknown. We have previously reported the results of RD, CRD, and CyBorD but have not directly compared outcomes between each to determine superiority or lowest toxicity. The goal of this study was therefore to compare these three treatment regimens by analysing the early response rates, overall toxicity and survival data. Patients and methods Patients and treatment schedule Data from 15 patients with newly diagnosed, active MM participating in three consecutive Phase II trials at Mayo Clinic and Princess Margaret Hospital from 4 to 8 were retrospectively analysed. Analysis of RD (n = 34), CRD (n = 53), and CyBorD (n = 63) was performed after all patients had completed four cycles of therapy (Kumar et al, 7; Lacy et al, 7; Reeder et al, 9). Each study received approval from the Mayo Clinic Institutional Review Board. Patients met eligibility requirements and informed consent was provided prior to treatment. Patients receiving RD were enrolled between March 4 and October 4 (Table I). Treatment consisted of four 28-d cycles of oral lenalidomide 25 mg on days 1 21, and dexamethasone 4 mg on days 1 4, 9 12, and 17. Patients receiving CRD were enrolled between July 6 and May 8. Treatment consisted of four 28-d cycles of oral lenalidomide 25 mg on days 1 21, cyclophosphamide 3 mg/m 2 on days 1, 8, 15, and dexamethasone 4 mg on days 1, 8, 15, 22. Patients receiving CyBorD were enrolled between December 6 and October 8. Treatment consisted of four 28-d cycles of bortezomib 1Æ3 mg/m 2 intravenously on days 1, 4, 8, and 11, oral cyclophosphamide 3 mg/m 2 administered on days 1, 8, 15, 22, and dexamethasone 4 mg orally on days 1 4, 9 12, and 17 (n = 33) or alternatively, bortezomib 1Æ5 mg/m 2 intravenously and cyclophosphamide 3 mg/m 2 administered on days 1, 8, 15, 22, and dexamethasone 4 mg orally on days 1 4, 9 12, and 17 for two cycles then weekly for cycles 3 and 4 (n = 3). Results for both CyBorD schedules were identical (Reeder et al, 1). Dose reductions were permitted based on toxicity for each regimen. Patients were risk stratified into two groups using the Mayo Stratification of Myeloma and Risk Adapted Therapy (msmart) classification (Kumar et al, 9b) (21 patients receiving RD were not risk stratified due to lack of available data). High risk patients (n = 4) were defined by the presence of at least one of the following: deletion of 17p13 (loss of TP53), translocation t(4;14) or t(14;16) by fluorescent in situ hybridization (FISH), cytogenetic hypodiploidy or deletion of chromosome 13, or plasma cell labelling index 3%. Standard Table I. Treatment schedules with RD, CRD, and CyBorD in four 28-d cycles. Regimen Dose Days administered Cycles N RD Lenalidomide 25 mg PO * 34 Dexamethasone 4 mg PO 1 4, 9 12, 17 CRD Lenalidomide 25 mg PO * 53 Cyclophosphamide 3 mg/m 2 PO or 1, 8, 15 3 mg PO 1, 8, 15 Dexamethasone 4 mg PO 1, 8, 15, 22 CyBorD Bortezomib 1Æ3 mg/m 2 IV or 1, 4, 8, 11 4* 63 1Æ5 mg/m 2 IV 1, 8, 15, 22 Cyclophosphamide 3 mg/m 2 PO 1, 8, 15, 22 Dexamethasone 4 mg PO 1 4, 9 12, 17 *Treatment could continue after four cycles at the physicians discretion. ª 11 Blackwell Publishing Ltd, British Journal of Haematology, 156,

3 M. L. Khan et al risk patients (n = 89) were identified as not possessing any of these abnormalities. Response and toxicity criteria Using the International Myeloma Working Group (IMWG) Uniform Response Criteria (The The IMWG, 3; Kyle & Rajkumar, 9), a haematological CR was achieved if patients met all of the following criteria: complete disappearance of serum and urine M-protein on immunofixation, 5% bone marrow plasma cells, no progression in lytic bone lesions, and disappearance of soft tissue plasmacytomas. Unique to the CyBorD protocol, patients meeting all of the above criteria with the exception of a positive immunofixation were classified as near complete response (ncr). VGPR required 9% reduction in serum M-protein, urine M-protein <1 mg/ 24 h, no worsening of lytic bone lesions, and disappearance of plasmacytomas. Partial response was defined as a 5% reduction in the serum monoclonal protein and 9% in 24-h urine M-protein or < mg. If serum M-protein was immeasurable, a 5% decrease in the difference between involved/uninvolved free light chain levels, 5% reduction in bone marrow plasma cells or 5% reduction in the size of soft tissue plasmacytomas were required. Progressive disease (PD) was documented if 25% increase in serum M-protein (absolute Æ5 g/l), 25% (absolute > mg/24 h) increase in urine M-protein, or, if monoclonal protein undetectable, a 5% increase in difference between involved/ uninvolved free light chains (absolute > Æ1 g/l) or >25% increase in bone marrow plasma cells. Progression-free survival was defined as the time from registration to first documentation of progression or death from any cause, whichever happened first. OS was defined as the time from registration to death from any cause. Toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3. (accessed on 1 April 1, Development/electronic_applications/ctc.htm#ctc_v3.). Statistical design and analysis The primary endpoint of this study was to compare early response rates and toxicity profiles as well as PFS, and OS between the three treatment regimens. Fisher s exact tests and Kruskal-Wallis tests were used to compare the baseline characteristics of each study. Response rates were computed with and without the ncr category. Patients receiving RD and CRD were classified as ncr upon meeting the requirements given in the CyBorD protocol (above). Alternatively, CyBorD patients meeting the ncr criteria were classified as VGPR for analysis. The Fisher s exact test was used to compare differences in nominal variables. The distribution of PFS and OS were estimated using the Kaplan Meier method (Kaplan & Meier, 1958). P < Æ5 were considered statistically significant. Data for this comparative analysis was frozen on January 14, 11. Results Patient characteristics Patient characteristics are listed in Table II. Baseline parameters were similar among each trial with the exception of International Staging System stage III at 11Æ8%, 27Æ5%, and Æ7% (P =Æ47) in the RD, CRD, and CyBorD groups, respectively. Median age was 62Æ5 years. Response was evaluated after four cycles of therapy but median range of cycles administered was higher for RD at 8, 5, and 4 (P <Æ1) cycles respectively, as patients on this regimen often elected not to undergo transplant. After four cycles of treatment, patients were eligible to undergo ASCT; surprisingly only 8 of the 15 patients were immediately transplanted. Efficacy Based on standard IMWG criteria, the response rate was higher in CyBorD patients compared to RD, and CRD (Table III). By intention-to-treat after four cycles of therapy with RD, CRD, and CyBorD, ncr/cr was 12%, 2%, and 41% (P <Æ1) with 35%, 3%, and 65% (P =Æ3) achieving a VGPR or better, respectively. Median duration of treatment was longer for RD (eight cycles) than for CRD (five cycles) or for CyBorD (four cycles). When all cycles of treatment were considered, ncr/cr was 35%, 15%, and 41% (P = Æ6), respectively for the three regimens. Survival The median duration of follow-up for survivors from diagnosis was 35 months for the entire cohort: 7Æ6 months in the RD group, 37Æ4 months in the CRD group, and 26Æ4 months in the CyBorD group. Two patients receiving RD and eight receiving CRD were still receiving treatment at the time of analysis. Median PFS for all 15 patients regardless of therapy was 2Æ6 years [95% confidence interval (CI): 2Æ3 3Æ1], with individual PFS of 3Æ2, 2Æ3, and 2Æ7 (P =Æ11) years for RD, CRD, and CyBorD, respectively (Fig 1). With relatively short followup, OS appeared similar between the three groups [3-year OS: 88% vs 79% vs 88%, (P =Æ23), respectively] while the 4-year median OS for all 15 patients was 8% (95% CI: 72 88) (Fig 2). Early death (during the first 4 months of therapy) was reported in one patient receiving CRD. Subgroup analysis The effect of therapy on high or standard risk patients according to the msmart classification was analysed. RD, CRD, and CyBorD had 2, 14, and 24 (n = 4) high-risk patients identified, respectively (21 patients receiving RD were excluded from risk stratification, due to lack of data). Response rates were similar between groups (Table IV), but earlier relapse of disease was observed in the high-risk group 328 ª 11 Blackwell Publishing Ltd, British Journal of Haematology, 156,

4 A Comparison of RD, CRD, and CyBorD in Multiple Myeloma Table II. Patient characteristics from each phase II study. RD (N = 34) CRD (N = 53) CyBorD (N = 63) Total (N = 15) P value Age (years), median (range) 64Æ (32Æ 78Æ) 64Æ (37Æ 82Æ) 61Æ (36Æ 74Æ) 62Æ5 (32Æ 82Æ) Æ8* Gender Female (%) 11 (32Æ4) 26 (49Æ1) 3 (47Æ6) 67 (44Æ7) Æ26 Male (%) 23 (67Æ6) 27 (5Æ9) 33 (52Æ4) 83 (55Æ3) ECOG performance score (%) 15 (44Æ1) 21 (39Æ6) 21 (33Æ3) 57 (38) Æ63 1 (%) 16 (47Æ1) 24 (45Æ3) 36 (57Æ1) 76 (5Æ7) 2 (%) 3 (8Æ8) 8 (15Æ1) 6 (9Æ5) 17 (11Æ3) Race White (%) 33 (97Æ1) 51 (96Æ2) 57 (91Æ9) 141 (94Æ6) Æ15 Black or African American (%) 1 (2Æ9) () 4 (6Æ5) 5 (3Æ4) Asian (%) () () 1 (1Æ6) 1 (Æ7) Not reported (%) () 2 (3Æ8) () 2 (1Æ3) Ethnicity Hispanic or latino (%) 1 (2Æ9) () 1 (1Æ6) 2 (1Æ3) Æ24 Not hispanic or latino (%) 33 (97Æ1) 51 (96Æ2) 62 (98Æ4) 146 (97Æ3) Not reported (%) () 2 (3Æ8) () 2 (1Æ3) Months from diagnosis to Æ2 (Æto17Æ7) Æ5 (Æto39Æ3) 1Æ1 ()1Æ4 to 128Æ6) Æ5 ()1Æ4 to 128Æ6) Æ2* registration, median (range) Follow-up status Alive (%) 27 (79Æ4) 44 (83) 6 (95Æ2) 131 (87Æ3) Deceased (%) 7 (Æ6) 9 (17) 3 (4Æ8) 19 (12Æ7) Months of follow-up 59Æ5 (9Æ3 73Æ9) 29Æ5 (1Æ6 45Æ8) Æ5 (3Æ7 37Æ6) 27Æ (3Æ7 73Æ9) <Æ1* (alive patients), median (range) Progression status No. progression (%) 12 (35Æ3) 28 (52Æ8) 48 (76Æ2) 88 (58Æ7) Progression (%) 22 (64Æ7) 25 (47Æ2) 15 (23Æ8) 62 (41Æ3) Cycles administered, median (range) 8 (2 71) 5 (1 45) 4 (1 8) 4 (1 71) <Æ1* Durie salmon stage at diagnosis I (%) 8 (23Æ5) 4 (7Æ5) 2 (3Æ4) 14 (9Æ7) Æ3 2 II (%) 1 (29Æ4) 18 (34) 27 (46Æ6) 55 (37Æ9) III (%) 16 (47Æ1) 31 (58Æ5) 29 (5) 76 (52Æ4) Stage a (%) 34 (1) 52 (98Æ1) 51 (86Æ4) 137 (93Æ8) b (%) () 1 (1Æ9) 8 (13Æ6) 9 (6Æ2) ISS stage I (%) 16 (47Æ1) 18 (35Æ3) 25 (43Æ1) 59 (41Æ3) Æ47 II (%) 14 (41Æ2) 19 (37Æ3) 21 (36Æ2) 54 (37Æ8) III (%) 4 (11Æ8) 14 (27Æ5) 12 (Æ7) 3 (21) ECOG, Eastern Cooperative Oncology Group. *Kruskal-Wallis test. Fisher s exact test. despite the use of either lenalidomide or bortezomib. Median PFS was 2Æ1 years (95% CI: 1Æ5 NR) in the high-risk group compared to 2Æ7 years (95% CI: 2Æ4 3Æ1) in the standard group (P = Æ37) (Fig 3). Three-year PFS in high-risk patients was reduced: 36% (95% CI: 22 6) vs. the 42% (95% CI: 3 56) seen in standard risk patients. Likewise, OS appeared shorter in the high- versus standard-risk patients, with median survival of 4Æ8 [95% CI: 4Æ2 not achieved (NA)] vs. 6Æ3 years (95% CI: 5Æ7 NA), respectively though this did not reach statistical significance (P = Æ23). Patients who underwent ASCT (n = 8) demonstrated no statistical difference in PFS when compared with un-transplanted patients: median PFS was 2Æ7 years (95% CI: 2Æ4 3Æ4) vs. 2Æ3 years (95% CI: 1Æ8 3Æ2) (P = Æ41) respectively (Fig 4). OS was superior in transplanted patients however, demonstrating a 3-year OS of 93% vs. 75% (P < Æ1) (Fig 5). However, given that the choice of ASCT was physician- and patient-driven, a selection bias clearly existed. Safety Major grade 3 or 4 toxicities with RD, CRD and CyBorD are listed in Table V. A total of 17 (5%), 26 (49%), and 21 (33%) (P =Æ15) grade 3 toxicities and 2 (6%), 13 (25%), and 5 (8%) ª 11 Blackwell Publishing Ltd, British Journal of Haematology, 156,

5 M. L. Khan et al Table III. Response rates after four cycles and all cycles of treatment. Table IV. Response rates by msmart risk classification. RD (%) CRD (%) CyBorD (%) P value* High (%) Standard (%) P value* Intent to treat at cycle 4 N Response rate (PR+) 3 (88) 42 (79) 56 (89) Æ33 VGPR+ 12 (35) 16 (3) 41 (65) Æ3 ncr/cr 4 (12) 1 (2) 26 (41) < Æ1 Intent to treat (using all cycles of treatment) N Response Rate (PR+) 32 (94) 45 (85) 57 (9) Æ41 VGPR+ 16 (47) 25 (47) 42 (67) Æ6 ncr/cr 12 (35) 8 (15) 26 (41) Æ6 PR, partial response; VGPR, very good partial response; ncr, near complete response; CR, complete response. *Fisher s exact test. Intent to treat at cycle 4 N 4 89 Response Rate (PR+) 36 (9) 74 (83) Æ42 VGPR+ 24 (6) 39 (44) Æ13 ncr/cr 8 () 21 (24) Æ82 Intent to treat (using all cycles of treatment) N 4 89 Response Rate (PR+) 36 (9) 78 (88) Æ78 VGPR+ 25 (63) 5 (56) Æ57 ncr/cr 11(28) 28 (31) Æ68 msmart, Mayo Stratification of Myeloma and Risk Adapted Therapy; PR, partial response; VGPR, very good partial response; ncr, near complete response; CR, complete response. *Fisher s exact test. % Alive and progression free RD CRD CyborD Fig 1. Kaplan Meier progression-free survival curves. % Alive RD CRD CyborD Fig 2. Kaplan Meier overall survival curves. (P =Æ3) grade 4 or higher toxicities were reported in patients receiving RD, CRD, and CyBorD, respectively. Grade 3 4 haematological adverse events (AEs) (18% vs. 57% vs. 21%, respectively, P < Æ1) were more frequent in the CRD group. Neutropenia of any grade was most common in CRD (35% vs. 77% vs. 25%, P < Æ1) while thrombocytopenia was documented in 12% vs. 51% vs. 56% (P <Æ1) of patients treated with RD, CRD, and CyBorD, respectively. Related neuropathy of any grade (21% vs. 15% vs. 59%, P <Æ1) was more frequent in CyBorD and related thrombosis (3% vs. 9% vs. 2%, P =Æ15) was more frequent in the CRD group (Table VI). Fatigue (68% vs. 77% vs. 48%, P <Æ3) and musculoskeletal weakness (24% vs. 8% vs. 3%, P =Æ6) were reported in RD, CRD and CyBorD, respectively. One grade five event occurred in a patient receiving RD documented as pneumonia with a grade 2 neutropenia. Other non-haematological related AEs of any grade were similar among the three treatment groups. Discussion The treatment of MM has evolved rapidly over the past decade. The clinical development and successful application of novel agents have led to markedly improved response rates, PFS, and OS in newly diagnosed MM as well as overall improvements in patient outcomes. With the increasing use of ASCT, the need for less stem-cell toxic induction therapies has become a priority. This has led to the investigation of newer agents, such as thalidomide, lenalidomide, and bortezomib, with the addition of cyclophosphamide. We have explored RD, CRD and CyBorD in consecutive Phase II trials. Although each of these combinations have proven to be efficacious with less toxicity and overall improved PFS from previous conventional treatments in MM, a formal comparison had yet to be done. To address this issue, we retrospectively analysed a sequential series of 15 newly 33 ª 11 Blackwell Publishing Ltd, British Journal of Haematology, 156,

6 A Comparison of RD, CRD, and CyBorD in Multiple Myeloma 1 High risk Standard risk Table V. Grade 3 or 4 adverse events regardless of attribution. % Alive and progression free RD (%) CRD (%) CyBorD (%) P value* Evaluable 34 (1) 53 (1) 63 (1) Grade 3 17 (5) 26 (49) 21 (33) Æ15 Grade 4 2 (6) 13 (25) 5 (8) Æ2 Haematological 3 5 (15) (38) 12 (19) Æ3 Haematological 4 1 (3) 1 (19) 1 (2) Æ2 Non-haematological 3 16 (47) 18 (34) 18 (29) Æ18 Non-haematological 4 1 (3) 5 (9) 5 (8) Æ66 *Fisher s Exact Test. Fig 3. Kaplan Meier progression-free survival curves by msmart risk. 1 Transplant No transplant Table VI. Most commonly reported adverse events of any grade at least possibly related to treatment. RD (%) CRD (%) CyBorD (%) P value* % Alive and progression free Thrombosis 1 (3) 5 (9) 1 (2) Æ15 Neuropathy 7 (21) 8 (15) 37 (59) <Æ1 Neutropenia 12 (35) 41 (77) 16 (25) <Æ1 Thrombocytopenia 4 (12) 27 (51) 35 (56) <Æ1 Fatigue 23 (68) 41 (77) 3 (48) Æ3 *Fisher s exact test Fig 4. Kaplan Meier progression-free survival curves by transplant status. % Alive Transplant No transplant Fig 5. Kaplan Meier overall survival curves by transplant status. diagnosed MM treated with RD, CRD, or CyBorD. The primary goal was to interpret early response rates and degree of toxicity between each regimen. We demonstrated that CyBorD had superior early response rates when compared to RD and CRD. After four cycles of therapy, depth of response was significantly higher with improved ncr/cr and VGPR rates noted in CyBorD. Despite this success, with a relatively short duration of follow-up, there was no statistical difference between PFS and OS with a median PFS of 2Æ6 years for all 15 patients. Transplantation did not impact PFS but was associated with improved OS, with 93% of transplanted patients alive at 3 years. As expected, patients with high-risk features had earlier relapse of disease than those with standard risk despite the use of these novel agents. The AEs reported were consistent with the established toxicity profile for lenalidomide and bortezomib. CyBorD demonstrated less overall serious toxicities when compared to RD, and CRD. The rate of grade 3 4 haematological AE was highest in the CRD group, followed by RD. Neutropenia and fatigue were the most commonly reported AE s in all groups. Thrombosis was reported more frequently in CRD. However, neuropathy of any grade was documented with significantly higher frequency in patients receiving CyBorD. Limitations to our analysis include a relatively short duration of follow-up for CyBorD and small sample size for each clinical trial. Despite similar patient eligibility, definitions, and methods of monitoring disease improvement or progression, the results are retrospective comparisons of three separate trials, lacking uniform controls and randomization. Among patients receiving RD, 21 were excluded from msmart risk stratification due to lack of included data. Additionally, the decision to undergo ASCT was patient- and physician-driven, which may have created a selection bias. Despite these limitations, the comparison of these agents provides insight ª 11 Blackwell Publishing Ltd, British Journal of Haematology, 156,

7 M. L. Khan et al into their use for the treatment of MM, particularly in a setting where rapid results are needed. In conclusion, the results of this analysis suggest the superiority of CyBorD when retrospectively compared with RD and CRD in terms of early response rates and similar or less serious toxicity after four cycles of therapy. Nevertheless, a higher rate of neuropathy and no associated improvement in PFS or OS was seen. Larger phase III studies are needed to further assess this issue. Interestingly, recent comparisons of VRD, CVRD and CyBorD have similarly demonstrated high response rates but little perceived differences in outcomes between the regimens (Kumar et al, 9a). High-risk patients continue to demonstrate earlier relapse than standard risk patients regardless of initial therapy, however patients who went on to ASCT did have a longer OS. Finally and encouragingly, 8% of patients treated with these modern therapeutic approaches remained alive at 4 years. Acknowledgements SPORE CA929752, P1 CA62242, R1 CA83724, ECOG CA 21115T, Predolin Foundation, Mayo Clinic Cancer Center and the Mayo Foundation. Conflict of interest Dr Reeder receives research funding from Celgene and Millennium; Dr Kumar has served as principle investigator on clinical trials funded by Celgene; Dr Gertz receives honoraria from Celgene and Millennium; Dr Bergsagel serves on the advisory board for Celgene; Dr Stewart receives honoraria from Celgene, honoraria and research funding from Millennium, and serves as a consultant and receives research funding from Onyx; Dr Fonseca has received a patent for the prognostication of MM based on genetic categorization of the disease. He has received consulting fees from Medtronic, Otsuka, Celgene, Genzyme, BMS and AMGEN. He also has sponsored research from Cylene and Onyx. The remaining authors have no conflicts of interest. Rafael Fonseca is a Clinical Investigator of the Damon Runyon Cancer Research Fund. 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