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Abstract Background: The combination of lenalidomide and dexamethasone (RD) has been shown to be highly effective as initial therapy for multiple myeloma. More recently, a phase III trial demonstrated improved survival with use of lenalidomide and low dose dexamethasone (Rd). Further improvements by incorporating other active agents may increase the depth of response and may improve long-term outcome. We report the results from a phase II trial combining lenalidomide and low dose dexamethasone with cyclophosphamide (RCd) as initial therapy for newly diagnosed MM. Methods: The trial was initiated in July 2006 and completed the initial target accrual of 33 patients by July 2007 (Cohort 1). Due to high rate of dose reductions in cohort 1, between July 2007 and May 2008 an additional 20 patients were enrolled with lower doses of cyclophosphamide (Cohort 2). The treatment protocol consisted of lenalidomide given orally at a dose of 25 mg daily on days 1–21 of a 28-day cycle. Dex was given orally at a dose of 40 mg on days 1, 8, 15, and 22 of each cycle. Cyclophosphamide at a dose of 300 mg/m2 was given on days 1, 8, and 15 of each cycle in cohort 1 and 300 mg on days 1, 8, and 15 of each cycle in cohort 2. Patients also received an aspirin once daily as thromboprophylaxis. Response was defined as a decrease in serum monoclonal (M) protein by 50% or higher and a decrease in urine M protein by at least 90% or to a level less than 200 mg/24 hours. Responses were assessed on intent to treat basis. Results: 53 patients were enrolled. The median age was 64 years (range, 37–82). 14 patients (29%) had ISS stage III disease. The median number of cycles was 4 (range: 1 – 20). The best response based on all enrolled patients on an intent to treat basis was 83%, including CR:1 (2%), VGPR: 20 (38%), PR: 23 (43%), and less than PR: 9 (17%). The CR plus VGPR rate was 40%. Among the 20 patients in cohort 2 who were enrolled after optimization of the cyclophosphamide dosing, 16 (80%) have already achieved a partial response or better with 17 patients in this cohort still receiving study treatment. Overall, 25 of the 53 enrolled patients have discontinued study treatment. Reasons for ending treatment are: completed study per protocol (14), disease progression (5), adverse event (3) and alternate treatment (3). This includes 3 patients from cohort 2, one completed treatment per protocol, one went to alternate therapy and one patient went off for progression. Hematological toxicity was the most common with grade 4 toxicity seen in 8 patients (only 1 from cohort 2). Non-hematological toxicities included neuropathy, diarrhea, cystitis, and thrombosis. There were 6 patients with grade 4 non-hematological toxicities (none from cohort 2) attributed to the drug (thrombosis, confusion, depression and sepsis). Thirteen patients had dose adjustments, most commonly due to hematological toxicity attributed to lenalidomide or cyclophosphamide. One patient has died off study, of intracranial hemorrhage. The median follow-up for the remaining patients is 7.8 months. Conclusions: The combination of lenalidomide, cyclophosphamide, and dexamethasone (RCd) has excellent activity in the setting of newly diagnosed myeloma. Seventeen patients continue on study and the response rates are likely to be higher with additional followup. Myelosuppression was a significant toxicity leading to dose reductions and cycle delays, and is lower with decreased dose of CTX in cohort 2 without any apparent loss of responses.

Abstract Background: Thalidomide and its analogue lenalidomide have high response rates among patients with newly diagnosed as well as previously treated myeloma. Pomalidomide (CC4047) is the newest immunomodulatory (IMiD) agent that has shown single-agent activity in phase I studies. We report on the first Phase 2 trial of pomalidomide combined with low dose dexamethasone (Pom/dex) in patients with relapsed or refractory multiple myeloma. Methods: 37 patients (21 male and 16 female) were enrolled. Pomalidomide was given orally 2 mg daily on days 1–28 of a 28-day cycle. Dexamethasone was given orally at a dose of 40 mg daily on days 1, 8, 15 and 22 of each cycle. Response was assessed by the International Myeloma Working Group Uniform Response criteria. All patients received aspirin 325 mg daily as prophylaxis against DVT. Results: The median age was 66 years (range, 40 – 88). All patients were evaluable for response and toxicity, and all analysis were done on intent to treat basis. All patients had received prior therapy; 38% had 3 prior regimens; 35% had 2 prior regimens and 27% had one prior regimen. 76% had previous autologous stem cell transplant (ASCT) and 24% had 2 prior ASCT. 62% had previous IMiD therapy. Toxicity was mild and consisted primarily of myelosuppression. Grade 3 neutropenia occurred in 31%; grade 3 thrombocytopenia 3%; grade 3 anemia 3 %. Other grade 3/4 toxicities seen in less than 5% pts included: diarrhea, atrial fibrillation, pneumonia, dehydration and renal insufficiency. 16 % had grade 1/2 neuropathy. No grade 3 neuropathy was seen and there have been no thromboembolic events. Thirty (81%) patients are continuing study treatment. Seven patients have discontinued treatment due to: disease progression (5), died on study (1) and the medical doctor’s discretion (1). Twenty three of 37 patients (62%) achieved an objective response to therapy; including 9 (24%) with VGPR; 14 patients (38%) with PR; 6 (16%) with stable disease. Objective responses were seen in 4 of 13 patients (29%) who were refractory to lenalidomide. Conclusions: Pomalidomide plus dexamethasone (Pom/dex) is highly active and well tolerated for treatment of relapsed/refractory multiple myeloma with an objective responserate of 62%, including a 29% response rate among patients who are lenalidomiderefractory.

Background: Primary amyloidosis (AL) is characterized by multi-organ deposition of light chain derived amyloid protein, resulting in organ dysfunction of varying severity. High dose chemotherapy and autologous stem cell transplantation (ASCT) is an effective treatment for AL, but is limited in applicability due to high transplant related mortality in patients with advanced organ dysfunction. Serum LDH, an enzyme that catalyzes the conversion of lactate to pyruvate, is present in large amounts in heart, kidney, liver, and muscle and is elevated with abnormalities in one or more of the organs. It is commonly elevated in a variety of hematologic malignancies. Given the multi-organ involvement in AL, we examined the prognostic value of LDH in AL. Methods: We examined our transplant database to assess the prognostic value of LDH. Laboratory values from pre-ASCT evaluation were used for the analysis. Results: Three hundred and thirteen pts who underwent ASCT between March 1997 and March 2007 were included in this analysis. The median age at ASCT was 57.5 years (range, 33–73); and 183 pts (58.3%) were male. The median duration from diagnosis to transplant was 4.1 months (range, 1–75) and the median follow up post transplant was 28.3 months (range, 1 m to 10 years) for the 229 pts (73%) alive at the time of analysis. The median LDH was 194 IU (range, 92-441) and 138 pts (44%) had an LDH > 200. The median overall survival post-ASCT for patients with an LDH > 200 was 59.4 mos (95% CI; 37.9, 80.8) compared to not reached for the rest (Figure). The prognostic value of LDH for post transplant OS was independent of cardiac troponin (cTnT). The median OS post ASCT for patients with cTnT > 0.035 (n=208) was 37.4 months (95% CI; 17, 57.9) compared to 97.5 months (95% CI; 64.8, 130.2) for the rest. In a Cox proportional hazards model, cTnT > 0.035 was associated with a 2.5 fold risk of death (p = 0.0013) and an LDH > 200 was associated with 1.7 fold risk (p = 0.04). We then examined if LDH added to the cTnT in a prognostic model for survival post ASCT. Pts with both cTnT < 0.035 and LDH < 200 (n=133) had a median OS that was not reached compared to 71 mos (95% CI; 48.3, 94) if one factor was abnormal (n=89) and 37.4 mos (95% CI; 16.1, 58.8) if both cTnT and LDH were abnormal as above (n=45); p < 0.001 (Figure 2). Conclusions: In this study we have demonstrated the prognostic value of serum LDH in AL pts undergoing ASCT. Serum LDH appears to add to the value of troponin in prognostic staging of these patients. These results need to be examined in a larger cohort of patients undergoing different treatments. It is possible that LDH is able to globally assess abnormalities of multiple organs including heart, liver and lung. Prospective studies looking at the different LDH fractions are ongoing. Figure Figure Figure Figure

Background: High dose chemotherapy and autologous stem cell transplant (SCT) remains the preferred therapy for eligible patients with multiple myeloma (MM). Several studies have demonstrated an improvement in median survival with use of SCT. Patients with myeloma may undergo SCT immediately following 4–6 cycles of ‘induction’ therapy or at the time of relapse from the initial plateau phase. Available evidence does not suggest a survival difference between the two approaches. Methods: We retrospectively evaluated our experience with autologous single SCT for MM to compare the results of delayed SCT to early SCT. We identified from our transplant database, 202 patients with MM, who underwent SCT between October 1992 and November 2002. 101 patients, who responded to induction chemotherapy, had stem cells collected in plateau phase, received maintenance chemotherapy and had SCT at the time of first relapse (delayed SCT group). The remaining 101 patients, after initially achieving a response underwent upfront SCT (early SCT group). Patients refractory to initial therapy were excluded from this study. Most of the early transplants were done in the recent years and hence this group has a shorter follow up. Results: The study cohort had a median age of 55 years (range 29 – 72) at diagnosis consisting of 126 males (62%), with no significant demographic difference between the two groups. As expected measures of tumor burden (M protein, B2M and marrow plasma cell percentage) were significantly higher in the delayed group. Plasma cell labeling indices and presence of abnormal cytogenetics were higher in the delayed SCT group as well at transplant. TBI containing regimens were used more often in the delayed group reflecting a difference in the time periods of transplant. There was no difference between the groups in terms of overall response to transplant though complete response rate was higher for the early transplants. (Table). There was no difference in the time to overall response between the groups (P=0.13, Kaplan Meier estimate). Though the median progression free survival (PFS) from transplant was shorter for the delyaed SCT group, the overall survival (OS) from diagnosis of MM was comparable for the two groups (Table). The overall survival estimate at 5 year from diagnosis was 60% for both groups. Conclusions: Review of our experience demonstrates comparable overall survival for an early SCT compared to SCT at the time of relapse. Although there is an advantage for early SCT in terms of more chemosensitive disease as shown by a longer PFS from SCT, there is no benefit in OS from time of diagnosis. Patient preference and other co-morbidities should play a role in the decision regarding timing of transplant. This study has the disadvantage of being retrospective in nature and the two groups being spread over different periods in time. Early (n=101) Delayed (n=101) P Overall Response 100 (99%) 94 (94%) 0.07 Complete Response 43 (42%) 28 (27%) 0.04 Median PFS (From Transplant) 26.7 months 14.8 months <0.0001 Median OS (From diagnosis) 67 months 70 months 0.1

Abstract Abstract 4986 The plasma cell disorder POEMS syndrome is defined by the following major features: peripheral neuropathy (P), organomegaly (O), endocrinopathy (E), monoclonal (immunoglobulin) protein expression (M), and skin changes (S). One of the most noticeable characteristics of this disease is that virtually all patients have lambda (γ) rather than the kappa (κ) restricted clonal plasma cells. We hypothesized that this restricted expression and possibly mutated heavy and light chain genes may be linked to the pathogenesis of POEMS. To this end, we analyzed light and heavy chain gene sequences from 21 POEMS patients at Mayo Clinic Rochester. We found that 16 of these patients had dominant light chain gene sequences, and that the expression of light chain was restricted to IGLV 1 subfamily and more specifically, to the IGLV1-40 or the IGLV 1-44 subtype. In contrast, no such stereotypy was observed at the immunoglobulin heavy chain locus (IGHV), though IGHV gene expression indicated a high degree of clonality. We aligned these sequences with their corresponding germline consensus sequences in IMGT database to assess similarity and divergence. IGLV1-40 and IGLV 1-44 sequences from POEMS patients were also aligned with the sequences in the light chain library on Boston University Amyloid Database (http://pulm.bumc.bu.edu/aldb), and POEMS IGHV sequences were compared to IGHV sequences reported in the literature for multiple myeloma, MGUS (monoclonal gammopathy of unknown significance) and CLL (chronic lymphocytic leukaemia). We found that: i) both the restricted light- and the non-restricted heavy chain genes in POEMS patients varied significantly (>2%) from their germline counterparts; ii) the incidence of somatic hypermutation in IGHV was higher in POEMS than that reported for other plasma cell disorders like multiple myeloma, MGUS and CLL, iii) in IGLV, mutations occurred at non-random, clustered hotspots located in specified areas of the gene (such as the structural elements that contribute the antigen binding CDR domain); iv) mutations occurring in the CDR regions tended to be conserved (the amino acid in POEMS was similar to that in germline in its physicochemical properties), and v) the histidine residue at position 40 (H40) in IGLV1-40 and the threonine at position 38 (T38) in IGLV1-44 are POEMS-specific. These observations suggest that an antigen driven somatic hypermutation mechanism may mark a post-germinal precursor plasma cell for selection, but further transformation of this selected cell into a malignant POEMS clone occurs via a different, hitherto unknown, mechanism. They also highlight the significance of H40 (in IGLV 1-40) and T38 (in IGLV 1-44) residues, which seem to be highly POEMS-specific (occurring seldom in other plasma cell disorders), and which may bias the selected plasma cell clone towards POEMS syndrome phenotype. Disclosures Lacy: celgene: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kumar:CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding.

Abstract Introduction: Mortality rates associated with stem cell transplantation are considerably higher than those of autologous stem cell transplantation for other hematologic malignancies. The efficacy of stem cell transplantation in amyloidosis largely is determined by treatment-related mortality rates (range, 11%-25%). Appropriate patient selection is essential to avoid this high mortality rate. Patients & Methods: The primary end point of the study was death from any cause between 4 days before transplantation and d+100 after transplantation. Patient characteristics are shown. Patient characteristics (N=271) Characteristic Median (range) Comment Age, y 58 (33–75) Male 159 (59%) Renal involvement 184 (68%) Cardiac involvement 147 (54%) Peripheral neuropathy 30 (11%) Hepatic involvement 28 (14%) Albumin, g/dL 2.8 (0.8–4.4) Creatinine, mg/dL 1.1 (0.6–12.0) 90% of patients had levels ≤1.7 mg/dL Alkaline phosphatase, U/L 93 (31–1,395) 25% of patients had levels >132 U/L Urinary total protein, g/d 3.35 (0.01–35.4) Percentage of plasma cells in the marrow 7 (0–78) 90% of patients had <17% plasma cells Interventricular septal thickness, mm 13 (7–25) Ejection fraction, % 65 (28–84) Time between diagnosis and stem cell transplantation, mo. 4 (0.8–75) Troponins,μg/L 0.01 (0.01–1.0) 75% of patients had levels ≤0.03 g/L 90% of patients had levels ≤0.08 g/L Results: Among 271 patients undergoing stem cell transplantation, troponin T was a powerful predictor of treatment-related mortality. Patients with troponin levels of 0.06 mg/L or higher had a day 100 all-cause mortality rate of 28%. Day-100 Survival Rate (N=271) Patients Troponin level ≥0.06 μg/L, no. of patients (n=40) Troponin level <0.06 μg/L, no. of patients (n=231) Total no. of patients *P<.001 Died before day 100* 11 16 27 Survived beyond d+100 29 215 244 Patients with troponin levels less than 0.06 mg/L had a day-100 all-cause mortality rate of 7% (P<.001). Figure Figure Despite possibly having multiple causes of death, for 7 of 11 patients with elevated troponin levels, cardiac causality could be inferred. For patients with low levels of troponin, clear cardiac causality was observed in 4 of 16. Among the 40 patients with troponin levels of 0.06 mg/L or higher, the conditioning dosage of melphalan was reduced for 31 patients (78%). Among the patients with troponin levels less than 0.06 mg/L, the dosage of melphalan was reduced for 29% of patients. Conclusion: Troponin levels should be measured in all patients before transplantation. Those with troponin levels exceeding 0.06 mg/L should be considered for less toxic therapies until the clinically optimal use of stem cell transplantation is better defined by randomized clinical trials. The chemotherapy dosage was reduced for 77% of patients in the high troponin group, but acceptable treatment-related mortality rates were not achieved. Clearly, a risk-adapted approach that modified the dosage of conditioning chemotherapy did not compensate for poor patient health or advanced cardiac involvement.

Abstract Background: Patients (Pts) with multiple myeloma (MM) who relapse within 12 months of autologous stem cell transplantation (SCT) have a poor prognosis. As reported by Mahmood et al. (ASCO 2007), of 432 pts who received SCT at the Mayo Clinic between 1994–2005, those with early relapse within 12 months (94/432– 22%) showed poorer median overall survival. Kaplan-Meier estimates of 12-month survival from the date of first relapse were 37% for pts relapsing within 12 months after SCT as compared to 85% for those relapsing after 12 months. In that study, pts had received regimens other than B. In a recent report of a large, phase III study (DOXIL-MMY3001), the combination of PLD+B improved time to progression (TTP) as compared to B alone (Orlowski et al. JCO 2007). The present analysis examined the 12-month post-randomization survival of patients who had early (<12 months) vs. late (≥12 months) relapse following SCT, as well as the effect of PLD+B vs. B alone in pts who had relapsed early. Methods: This was a retrospective analysis of 646 pts who received intravenous B, 1.3 mg/m2 on days 1,4,8 and 11 of every 21-day cycle ± PLD, 30 mg/m2 on day 4. Results: 359 pts had previously received transplant, 114 (32%) of whom relapsed within 12 months from SCT. The median age, gender distribution, time from diagnosis trial enrollment, measures of disease burden (M-Protein levels and B2M) and renal function were comparable between the early and late relapse groups. There was no difference in overall response rates [complete + partial response (CR+PR)] or very good PR (VGPR) rates between the two groups, or between treatment arms within each group. There was no significant difference in TTP between early vs. late relapse groups (HR=0.94). 12-month survival from randomization was significantly lower in the early relapse group as compared to late relapse (83% vs. 92% respectively, p=0.009). However, within the early relapse group 12-months post-randomization survival rate was significantly superior following treatment with PLD+B as compared to B alone [52/56 patients (93%) vs. 43/58 patients (74%) respectively, p=0.01]. Correspondingly, TTP was better in this group with PLD+B vs. B alone (276 days vs. 205 days respectively, p=0.13). Overall, the toxicity profiles of the combination and B alone were comparable regardless of early or late relapse following SCT. Conclusions: The present analysis of the MMY3001 study corroborates the prior Mayo observation of lower survival in MM pts relapsing within 12 months of SCT. Importantly, it demonstrates that PLD+B may provide a therapeutic advantage for high-risk MM pts with early relapse following SCT.

Background: Despite development of new therapies and advances in autologous hematopoietic stem cell transplantation (HSCT), MM remains, for the most part, an incurable condition. Allogeneic HSCT, through induction of a graft-versus-myeloma effect, can potentially overcome resistance to conventional therapy and induce prolonged disease control. Such approach is limited by the risk of acute and chronic GVHD and the high treatment-related mortality and has been restricted to young patients with aggressive or refractory disease. We reviewed our experience with allogeneic HSCT at Mayo Clinic, Rochester, MN. Methods: Retrospective single-institution review of consecutive allogeneic transplants performed for multiple myeloma between 1991 and 2006. Results: Thirty-three patients underwent a myeloablative (52%) or reduced-intensity conditioning (48%) HSCT 3.2 months to 15 years after their diagnosis of multiple myeloma (n=31) or plasma cell leukemia (n=2). Median age at the time of HSCT was 48 years (range 33–61) and 19 patients (57%) had received one (n=12) or two (n=7) prior autologous HSCT. Donors were HLA-matched siblings in 25 cases (76%), matched unrelated (n=8), and 5/6 (n=1) and 6/6 (n=1) match, non-sibling family members. Source of HSC was peripheral blood exclusively in 21 (64%) and bone marrow in 12 (35%) transplants. Outcomes are being reported after a median follow up of 21.8 months (25.6 for survivors). Day+100 mortality was 21.2% and the incidences of any grade and grades 3/4 acute GVHD were 54.5% and 33.3% respectively. Among the 26 patients surviving beyond day+100, 57.7% developed chronic extensive GVHD. All 6 patients transplanted after a complete response (CR) to prior therapy remained so after the transplant. Of the 27 patients with measurable disease, disease reassessment could be performed for 20 after the transplant. Ten patients (50%) achieved a CR or near-CR and 8 patients (40%) obtained a partial response. Median time to progression and overall survival (Figure) after HSCT were 21.8 and 40.6 months respectively. Twenty-one patients have died, 10 as a consequence of disease progression. Twelve patients are alive, including 6 patients in CR, 8.3 to 172.7 months after the transplant. In a multivariate model the use of a non-sibling donor and peripheral blood HSC were associated with decreases risk of relapse, but had no effect on overall survival. Conclusion: Allogeneic HSCT is a feasible treatment for young patient with adverse disease features. Graft-versus-myeloma can induced myeloma eradication and prolonged disease control. Figure Figure

Abstract Background: Patients with newly diagnosed multiple myeloma is at increased risk of thrombotic events, primarily venous thrombosis. The risk is significantly increased in patients receiving certain therapeutic regimens such as the combination of thalidomide and dexamethasone. Deep vein thrombosis, especially if complicated by pulmonary embolism, can result in death. It is not clear if venous thrombotic events can result in compromised survival in this group of patients. Methods: We studied patients enrolled in the Eastern Co-operative Group trial (E1A00) that randomized patients with newly diagnosed myeloma to single agent dexamethasone or thalidomide and dexamethasone. Patients with grade 3 or greater thrombotic events (DVT, or myocardial ischemia, or stroke) were identified. Wilcoxon rank sum test (for continuous variables) or Fisher’s exact test (for categorical variables) was used to compare age, baseline M-protein, hemoglobin, WBC, platelets count, creatinine, beta2-microglobulin, or ECOG PS between patients with and without thrombotic events. Results: Among the 207 patients enrolled, 36 patients (17.4%) had grade 3 or greater thrombotic events with any treatment attribution, of whom, 27 patients had DVT, 3 patients had an MI and 6 pts had a stroke. However, in only 31 of these patients were the event considered treatment-related (possible, probable, or definite) and among these 24 had a DVT. The baseline characteristics did not differ between the patients with thrombosis and those without, irrespective of its relationship to treatment. Similarly, the baseline characteristics did not diff for those with venous or arterial thrombosis. The overall survival was similar among the patients developing a DVT compared to those without a thrombotic event, when all DVT events were considered irrespective of the treatment attribution (Figure). However, majority of the patients with an arterial event (3 patients with MI and 6 with stroke) had a short overall survival. Conclusion: Venous thrombosis remains a common complication in patients with myeloma, especially when treated with thalidomide and dexamethasone. While occurrence of thrombosis clearly contributes to morbidity and often leads to dose reductions and missed doses, it does not appear to have an adverse impact on the overall survival of these patients. Figure Figure

Abstract Background: Combination regimens incorporating bortezomib (VELCADE®, Vc), lenalidomide (REVLIMID®, Rev), dexamethasone (Dex) and cyclophosphamide (Cy) (Vc–Dex, Rev–Dex, Vc–Dex–Rev [VDR], and Vc–Dex–Cy [VDC]), have all shown substantial activity in previously untreated multiple myeloma (MM). A combination of all four agents (VDCR) may result in even greater activity. This randomized multi-center 3-arm phase I/II EVOLUTION study is investigating the efficacy and safety of VDR, VDC, and VDCR as initial therapy in previously untreated MM patients (pts). We now report safety and efficacy results from the phase l dose-escalation portion of the study, which sought to determine the maximum tolerated dose (MTD) of the VDCR regimen. These results represent the first clinical data with this novel 4-drug combination that includes bortezomib, lenalidomide, an alkylator, and a corticosteroid. Methods: Pts received Vc 1.3 mg/m2 IV (d 1, 4, 8, 11), Dex 40 mg PO (d 1, 8, 15), Rev 15 mg PO (d 1–14), plus Cy 100, 200, 300, 400, or 500 mg/m2 PO (d 1, 8) for up to eight 21-d cycles, followed by Vc 1.3 mg/m2 (d 1, 8, 15, 22) for four 42-d maintenance cycles. Pts received prophylactic antibiotics, acyclovir, transfusion support and concomitant anticoagulants as required. Eligible pts wishing to receive autologous stem cell transplant (ASCT) could undergo stem cell mobilization any time after cycle 2, and discontinue therapy for ASCT any time after cycle 4. The MTD was defined as the highest dose of Cy in combination with VDR resulting in ≤1 dose-limiting toxicity (DLT) in 6 pts. A DLT was defined as: platelet count <25,000/mm3 lasting >7 days or any platelet count <10,000/mm3; grade 4 neutropenia lasting >7 days; any ≥grade 3 non-hematologic toxicity considered to be related to Cy except for inadequately treated nausea, vomiting, and diarrhea, or any toxicity resulting in a >2 week treatment delay. Results: Twenty-six pts were enrolled; 1 pt was not dosed due to a heart problem and was excluded (dose level 4) and 4 pts were not evaluable for DLT. In the 25 treated pts, median age was 61 years (range 49–79); 52% were male; 48% had ISS Stage lI and 4% Stage III disease, and 44% had KPS ≤80%. At data cut-off, 11 pts remain on treatment and 9 have undergone successful ASCT. To date, median treatment duration is 4 cycles (range 2–11). Two pts experienced DLT: 1 grade 4 febrile neutropenia at dose level 4 (Cy 400 mg/m2), and 1 grade 3 herpes zoster virus reactivation despite antiviral prophylaxis at dose level 5 (Cy 500 mg/m2). The recommended phase II dose of Cy in the VDCR regimen was the highest planned dose of 500 mg/m2. The most common treatment-emergent AEs were constipation (64%), fatigue (60%), and nausea (52%). Hematologic toxicities were acceptable, with grade 3 neutropenia in 16% of patients, grade 4 in 4%, and grade 4 thrombocytopenia in 4%. Peripheral neuropathy (56%), included 8% grade 3 but no grade 4; no deep-vein thrombosis/pulmonary embolism events were reported. Overall rate of serious AEs was 40%; the only SAE reported in >1 pt was febrile neutropenia (2 pts). Best responses to date by International Uniform Response Criteria are shown in the table. Preliminary response rates are: 100% ≥PR, 68% ≥VGPR, 32% CR/nCR, 28% CR/stringent CR and 20% sCR. Ten pts have undergone stem cell mobilization with median CD34+ yield of 4.95×106/kg. Conclusions: VDCR was well tolerated and hematologic toxicities were manageable. The current study shows that the VDCR regimen is feasible and highly active in newly diagnosed myeloma and merits further testing in clinical trials. Enrollment to the 3 arms (VDR, VDC and VDCR) of the phase ll portion of the study and testing for minimal residual disease by flow cytometry are ongoing. Best unconfirmed response to date with VDCR Dose level 1 2 3 4 5 Cyclophosphamide dose, mg/m2 100 200 300 400 500 Enrolled 3 4 4 8 7 Treated 3 4 4 7 7 Still on treatment – 1 1 2 7 Best unconfirmed response to date CR (sCR) 2 (2) 1 (1) 1 (1) 2 1 (1) VGPR (nCR) 1 – 3 (1) 4 2 PR – 3 – 1 4