Gertz, Morie A.

Abstract Abstract 3211 Poster Board III-148 Although autologous stem cell transplantation (ASCT) has become standard of care for many patients with hematologic malignancies, many patients fail to collect a minimum number of CD34 + stem cells to support high dose chemotherapy and ASCT. Recently, plerixafor, a CXCR4 antagonist, was FDA approved for use in combination with G-CSF for autologous peripheral blood stem cell mobilization in patients with NHL or Multiple Myeloma. In February 2009, we commenced a risk adapted approach to the utilization of plerixafor. The study was restricted to patients mobilized with GCSF alone and patients undergoing chemotherapy primed PBSC mobilization were excluded. Peripheral blood stem cell mobilization was commenced with G-CSF at 10 mcg/kg/day. On day 4, a peripheral blood (PB) CD34 count was measured. For patients whose PB CD34 was ≥10/μL, apheresis was commenced the following morning. For patients whose PB CD34 was <10/μL, it was measured again on day 5; if ≥10/μL then apheresis was commenced the following morning. If PB CD34 was <10/μL on day 5, plerixafor (0.24 mg/kg sc) was administered on the evening of day 5 and apheresis was commenced the following day (Group A). In addition, during apheresis, for patients whose collection yield was < 0.5 × 106 CD34/kg, in the absence of instrument failure or problems with the collection procedure, plerixafor was added (Group B). Morning administration of G-CSF and evening dosing of plerixafor continued daily until apheresis was complete. From February to July 2009, 174 mobilization attempts occurred; 27 with chemotherapy and 147 with cytokines alone. The 147 pts who underwent mobilization with cytokines alone are presented here. The underlying diagnosis was as follows: Myeloma 61 pts, NHL 54 pts, Amyloid 17 pts, Hodgkin 10 pts, POEMS 4 pts and 1 pt with a solid tumor. For the entire group the median number of CD34 cells collected was 5.5 × 106 CD34/kg (range 0.1-17). The median number of apheresis was 3 (range 1-12). 67 patients (46%) received plerixafor; 37 patients started plerixafor during mobilization (Group A) and 30 patients during collections due to a poor yield (Group B). 12 pts of the 37 received plerixafor on day 4 because of prior mobilization failure or high risk of mobilization failure and are included in Group A. Table 1 outlines the details of mobilization and collection by groups. By disease category, of the 61 patients with MM, 28 (46%) received plerixafor (8 Group A and 20 Group B). Median apheresis in all the MM pts was 2 (range 1-12) with a total of 6.8 × 106 CD34/kg (2.2-16.7). In the 54 NHL pts, 32 (59%) received plerixafor (24 Group A and 8 Group B). Median apheresis for all pts with NHL was 3 (range 1-7) with a total of 4.6 × 106 CD34/kg (range 0-11.4). Overall, only 7 of 147 (5%) mobilization attempts failed to achieve a minimum of 2 × 106 CD34/kg. This compares to a 22% failure rate prior to institution of this risk adapted approach. In conclusion, implementing this risk adapted approach allows poor mobilizers to be identified promptly and for plerixafor to be initiated during mobilization and collection, thereby reducing the number of mobilization failures. In patients who predictably would not have successful collection based on a PB CD34 <10/μL, addition of plerixafor results in a majority of patients achieving an adequate collection. This risk adapted approach may be more cost effective than reattempting mobilization after a prior failure or utilizing combination G-CSF and plerixafor for upfront mobilization. Table 1. Mobilization and Collection data. All patients N=147 Group A1 N=37 Group B2 N=30 No Plerixafor N=80 PB CD34 day 4 Median 11 0 7 19 Range 0-331 0-7 0-32 0-331 PB CD34 day 5 Median 10 4.5 12 15 Range 0-51 2-9 11-23 9-51 Apheresis Yield Median 5.5 4.4 6.0 6.2 Range 0.1-17 3.1-12.7 3.0-12.2 2-17 Number of Apheresis Median 3 3 5 2 Range 1-12 1-7 4-12 1-8 Days of Plerixafor Median n/a 3 2 n/a Rang 1-7 1-8 1 Group A – Plerixafor initiated prior to apheresis 2 Group B – Plerixafor initiated during apheresis Disclosures No relevant conflicts of interest to declare.

Abstract Background: The advent of high-dose therapy and autologous stem cell transplantation (HDT-ASCT) has significantly improved response rates and survival for patients with multiple myeloma (MM). However this form of therapy is potentially toxic and does not cure patients from their disease. The response to HDT-ASCT is variable and approximately 40% of patients achieve a complete response (CR). Patients with a CR have a significantly improved time to progression (TTP) compared to patients who do not achieve CR (nCR). Optimal timing of HDT-ASCT and considerations of the relapse kinetics may assist treatment planning for this disease. We analyzed myeloma tumor burden and kinetics before and after HDT-ASCT in order to define optimal timing of this therapy for the individual patient. Patients and Methods: A cohort of 265 patients with MM who underwent HDT-ASCT at Mayo Clinic Rochester was studied. Disease burden before and after HDT-ASCT was estimated from serial M-spike measurements. The estimated tumor burden data were fitted to the Gompertz function and its parameters alpha and beta estimated using a non-linear least squares method. Cohorts of patients with CR and nCR were studied separately. Functions that coupled disease burden and kinetics with TTP were derived and used to determine the optimal timing of single and tandem transplantation. Results: The Gompertz parameters alpha and beta for patients who achieved CR and for those who did not achieve CR with HDT were determined. Our values were lower than those of Sullivan and Salmon although the ratio of alpha/beta was of a similar order (implying the same carrying capacity). Using the idealized Gompertz parameters, simulations of single versus tandem transplants were performed. Our model predicts that tandem transplantation increases CR rate by approximately 10%. When the time between transplants was studied as a variable, our model suggests that the optimal time between transplants is 7 months. Conclusions: Our modeling provides a theoretical understanding of tumor burden and kinetics for patients with MM who undergo HDT-ASCT. Patients who achieve CR with the first episode of HDT-ASCT should not be routinely offered tandem transplantation but carefully monitored and re-transplanted at an optimal disease burden. If CR is not achieved with a first cycle of HDT-ASCT, the probability of CR after a second trial of HDT is ~10% (similar to that reported by Attal et al 2003) although this depends on the tumor burden before the second transplant. TTP after tandem transplants (with its higher associated mortality) cannot be superior to TTP achieved with optimally timed serial transplants. Individualized HDT-ASCT for patients with MM is possible and may improve results.

Abstract Abstract 2142 Poster Board II-119 High-dose chemotherapy in conjunction with autologous SCT is the preferred treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma and newly diagnosed multiple myeloma. Failure to achieve optimal stem cell mobilization results in multiple subsequent attempts, which consumes large amounts of growth factors and potentially requires antibiotics and transfusions. We retrospectively reviewed the natural history of stem cell mobilization attempts at our institution from 2001 through 2007 to determine the frequency of suboptimal mobilization in patients with hematologic malignancy undergoing autologous transplant and analyzed the subsequent resource utilization in patients with initially failed attempts. Of 1,775 patients undergoing mobilization during the study period, stem cell collection (defined by the number of CD34+ cells/kg) was “ optimal” (≥5×106) in 53%, “low” (≥2 to 5×106) in 25%,“ poor” (<2×106) in 10%, and “failed” (<10 CD34+ cells/mL) in 12%. In the 47% of collections that were less than optimal, increased resource consumption included increased use of growth factors and antibiotics, subsequent chemotherapy mobilization, increased transfusional support, more apheresis procedures, and more frequent hospitalization. Other costs often omitted include the need for hospitalization, which was seen in 5% to 11% of the patients in our study. Parenteral antibiotics were needed when fever developed in 7% of patients with Hodgkin disease, 4% with non-Hodgkin lymphoma, and 24% with multiple myeloma who underwent mobilization using a chemotherapy pulse. When stem cell mobilization was not immediately optimal, subsequent attempts to mobilize failed completely in 3 of 42 patients (7%) with Hodgkin disease (3% of the original Hodgkin disease cohort), 56 of 157 (36%) with multiple myeloma (6% of the original myeloma cohort), and 50 of 328 (15%) with non-Hodgkin lymphoma (7% of the original non-Hodgkin lymphoma cohort). These usually unappreciated costs of stem cell mobilization failure highlight the need for more effective mobilization strategies. Disclosures: Gertz: genzyme: Research Funding.

Abstract Abstract 2803 Poster Board II-779 Background. The rate of asymptomatic amyloidosis (asym-amyloidosis) detected in patients with newly diagnosed multiple myeloma (MM) or smoldering multiple myeloma (SMM) is unknown. This topic is significant because unrecognized AL may be associated with increased mortality may change the patient's management. The objective of the present investigation was to evaluate the number and clinical significance of asym-amyloidosis in MM and SM patients at the time of the diagnostic bone marrow (BM) biopsy for MM. Materials and Methods. The study population was selected from the Mayo Clinic Dysproteinemia database and consisted of consecutive patients with an established diagnosis of MM or SMM without recognition of symptomatic AL. Bone marrow biopsies at diagnosis of MM or SMM were retrospectively stained with Congo Red and reviewed by a single pathologist. A patient was considered to have asym-amyloid if Congo Red staining with apple green birefringence was found. Results. Biopsies from 144 (M 84, F 59) patients were evaluated: 77 had a diagnosis of MM and 67 of SMM. The median age was 59 (range 26-84) years. No differences were found regarding hemoglobin, platelets, prothrombin time, serum and urine proteins, serum albumin, alkaline phosphate, creatinine and β2-microglobulin among MM and SMM patients. At a median follow-up 76 months (range 0-216), 32% patients were alive, 65% dead and 2.7% lost to follow-up. Immunoglobulin isotypes were as follows: 96/144 (67%) had IgG 23/144 (16%) IgA, 12/144 (8%) had light chain only, 1/77 (1%) had IgD, none had IgM and 12/144 (8%) had biclonal or indeterminate; 84/144 (58%) were κ restricted. The presence of amyloid was found in only 2 cases (1%, 95% CI – 0.6 to 3.2), 1 in MM and 1 in SMM group. Neither of these patients had or developed signs or symptoms suggestive of organ involvement by amyloid. Among the 142 other patients without amyloid deposition in their index bone marrow, 1 (0.7%, 95% CI -0.6 to 2.0) developed symptomatic AL after 119 months of follow-up. Characteristics of these three patients are shown in table 1. Conclusions. We found only 2 cases (1%) of amyloidosis in the 144 cases of MM or SMM. Our estimates are lower than the rates which have been reported by others, perhaps because of our high level of suspicion for amyloid at our Amyloidosis Center. These data do not support the need for searching for asym-amyloidosis in patients with newly diagnosed MM or SMM as long as they have no clinical features of AL. Disclosures: Off Label Use: Hydroxyurea use in myelofibrosis. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Witzig:Novartis: Research Funding. Kumar:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Background: High dose therapy with autologous stem cell transplantation (HDT-ASCT) has prolonged survival in patients with multiple myeloma. Patients who achieve a complete response (CR) benefit the most from this form of therapy. Thus, achieving a CR is an important goal of therapy and it will be beneficial if the probability of achieving CR can be determined for any patient before transplant. Patients and Methods: A large cohort of patients with myeloma who received HDT-ASCT at Mayo Clinic Rochester was studied. The impact of various demographic, clinical and laboratory characteristics relating to the patients and their disease acquired were studied for their impact on response to HDT-ASCT, especially CR. Patients with a serum M-protein <0.1g/dL were excluded. Response definitions were as defined by established criteria. Survival analysis was performed according to the Kaplan-Meier method while univariate and multivariate analyses were performed with the proportional hazards method. We utilized knowledge of the rate of M-protein production by myeloma cells together with the clearance of the protein to estimate the pre-transplant disease burden. Results: We studied 224 patients with a median age of 56.5 years (32.6 – 71). Patients were transplanted a median of 8.7 months after diagnosis. Almost all patients had a response to HDT-ASCT and 78 (35%) achieved a CR. Those patients who achieved a CR had a longer time to progression (TTP) compared to those who did not achieve CR (Figure 1). The cohort was thus divided into two groups: patients who achieved CR and those that did not. The clinical and laboratory characteristics of the two groups were compared. Among the pre-transplant parameters tested, only the size of the serum M-spike was a predictor for CR (p<0.0001). A simple function that describes the probability of achieving CR based on the serum M-spike before HDT-ASCT is described. The estimated rate of tumor re-growth after HDT-ASCT in patients who obtain a CR and in patients who only get a partial response are presented. Conclusions: The pre-transplant disease burden in myeloma is the main determinant of response to HDT-ASCT. The individual probability of achieving CR can be estimated from simple clinical parameters providing a quantitative risk assessment prior to such a high-risk procedure. There is significant expansion of myeloma cells after HDT-ASCT. The design of clinical trials may benefit from knowledge of the kinetic aspects of the disease. Figure Figure

Abstract Background: High dose melphalan followed by autologous stem cell transplant (ASCT) is an effective treatment of immunoglobulin light chain amyloidosis (AL). However, the high treatment related mortality (TRM, death before day 100) remains a serious concern and is the major drawback of this therapy. A better understanding the risk factors contributing to TRM could help physicians choose the most appropriate therapy for these patients. We performed a retrospective study to identify risk factors that contribute to TRM after ASCT in AL patients. Methods: All patients who underwent ASCT for AL at our institution from 7/96 to 12/04 were studied. Data were collected on age, sex, septal thickness, glomerular filtration rate (GFR), B2M, CRP, proteinuria, albumin, cardiac troponin T (cTnT) and alkaline phosphate. Results: A total of 218 patients underwent ASCT for AL during this time period. One patient refused consent for this study. Pretransplant cTnT was available on 161 (73.9%) patients. The overall TRM rate for the 217 patients was 12.4%. By univariate analysis, septal thickness, GFR, albumin, alkaline phosphatase and cTnT were found to be associated with TRM. In the multivariate analysis, only albumin, alkaline phosphatase and cTnT remained independent predictors of TRM. Cutoffs were identified using receiver-operator characteristic (ROC) curve. The cutoff for albumin was 2.85 g/dL, 249 U/L for alkaline phosphatase and 0.02 ng/mL for cTnT. The percentage of patients with low albumin, elevated cTnT and alkaline phosphatase were 51.1%, 20.5% and 12.4% respectively. The TRM rate of patients with low albumin was 18.0%, 27.3% for elevated cTnT and 29.6% for high alkaline phosphatase. Risk of TRM increased significantly with each additional risk factor (Table). Discussion: In our AL population, low serum albumin, elevated alkaline phosphatase and cTnT were independent risk factors of TRM after ASCT. Patients with 2 or more risk factors are at significant risk of TRM during ASCT. In these high risk patients, alternative therapy should be considered in order to avoid excessively high incidence of TRM. Treatment Related Mortality by Number of Risk Factors Risk Factors 0 1 2 3 Rate of TRM 1.8% 8.4% 35.0% 66.0% Odds Ratio 5.0 29.1 108.0

Abstract Background: FLC is a valuable diagnostic tool to monitor response in patients with AL and oligosecretory MM. It is also prognostic in patients with MGUS. Its value in patients with non-oligosecretory myeloma has not been defined. Because of the short half-life of free-light chains, an early drop in free-light chain might be predictive for long term outcome post PBSCT. Methods: Between 8/1/03 and 12/10/04, 45 patients with multiple myeloma and abnormal FLC ratios (less than 02.6 or greater 1.65), who were undergoing PBSCT consented to have waste serum from routine post-transplant daily blood draws collected and frozen for future FLC analysis. The immunoglobulin FLC assay (Binding Site, U.K.) was run on samples collected from day +1 until patients were dismissed from our transplant center. Hematologic response was coded according to standard IBMTR criteria at approximately 3 months status post transplant (BJH 1998). Two types of immunoglobulin FLC response were coded: 50% reduction (FLC50) and 90% reduction (FLC90) of the difference of the involved and uninvolved FLC (Leukemia 2006). Two time periods of FLC response were analyzed: early (day 7); and delayed (day 19, range 13 to 24). Endpoints analyzed were overall response (>=PR), complete response rate (CR), progression free survival (PFS), and overall survival (OS). Results: The median age of the myeloma group was 59 years, and 53% were male. Thirty-three patients were monoclonal kappa, and 12 lambda. Forty-two percent were transplanted in response/plateau, 22% were primary refractory, and 36% relapsed disease. The overall hematologic response rate was 93% with a CR rate of 33%. Twenty-five patients have relapsed at a median of 14.2 months. Twelve patients have died, and median overall survival for the group has not been reached at a median follow-up of 24.6 months. Forty-nine and 58 percent of patients had early and delayed FLC90, respectively. Early FLC90, but not delayed FLC90, predicted for complete response (p<0.001). Neither early nor delayed FLC90 predicted for either PFS or OS. In addition, 89% and 96% of patients had an early and delayed FLC50, respectively. FLC50 at either time point did not predict for overall response, CR, PFS, or OS. Conclusion: Immunoglobulin free light chain responses are seen within the first weeks post high dose chemotherapy with peripheral blood stem cell transplant. A 90% reduction in FLC seen within the first seven days predicts for complete response. However, this does not yet translate into prolonged PFS or OS, but with longer follow-up separation of the survival curves may be seen.

Abstract Abstract 2877 Poster Board II-853 Background and Objective: In newly diagnosed multiple myeloma (MM) patients, treatment with lenalidomide plus high-dose dexamethasone (RD) was superior to high-dose dexamethasone in terms of both response rates and 1-year progression-free survival (PFS) (Zonder JA et al, Blood 2007;110:77). Preliminary results suggest that the combination lenalidomide plus low-dose dexamethasone (Rd) compared to the RD regimen yields significantly better 2-year overall survival (OS) (Rajkumar SV et al, J Clin Oncol 2008;26:8504). The combination of melphalan, prednisone, and lenalidomide (MPR) has been investigated in a phase I/II study showing promising results (Palumbo A et al, J Clin Oncol 2007; 25:4459-4465). The goal of this case –control study was to compare the efficacy and the toxicity of the lenalidomide/dexamethasone (len/dex) combination vs MPR as primary therapy for newly diagnosed elderly MM patients, to determine the additive value of melphalan compared to a regimen of lenalidomide plus corticosteroid. Patients and methods: Data from 51 newly diagnosed MM patients enrolled in Italy in a phase I/II dose-escalating trial, from January to October 2005, with MPR, were analyzed. For comparison of their outcome, 37 patients were identified among newly diagnosed patients seen at the Mayo Clinic from March 2005 to December 2008 who received len/dex as primary therapy and were enrolled in phase II or III trials. Patients treated with MPR received 9 monthly cycles of oral melphalan (doses ranging from 0.18 to 0.25 mg/kg on days 1-4), prednisone (2 mg/kg on days 1-4) and lenalidomide (doses ranging from 5 to 10 mg/day on days 1-21). After 9 cycles, patients started maintenance with lenalidomide alone (10 mg, days 1-21) until relapse or progression. Patients treated with len/dex received oral lenalidomide (25 mg/day, days 1-21) plus dexamethasone, either at low-dose (n=17) (40 mg orally days 1, 8, 15, 22) or at high-dose (n=21) (40 mg orally on days 1-4, 9-12, and 17-20). Treatment was continued until progression, relapse or unacceptable toxicity, or could be stopped at the physician's discretion. Patients (n=13) were allowed to receive transplant if they wished and were deemed eligible. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method and comparisons were determined by the log-rank test and the Cox proportional hazards model. Results: On intention-to-treat analysis, 15.7% versus 23.7% patients, respectively in the MPR and in the len/dex group, (p=0.342) achieved a complete response, and 43.2% vs 47.4%, (p=0.691) achieved at least a very good partial response. Time-to-progression (TTP) (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.04; 95% CI 0.55-1.98; p=0.903), PFS (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.03; 95% CI 0.55-1.92; p=0.926) and OS (2-year OS: 86.2% in MPR group vs 89.1% in len/dex, HR 0.86; 95% CI 0.38-1.98; p=0.730) were not significantly different between the 2 groups. No significant differences in TTP, PFS and OS were reported when MPR patients were compared with the subgroup of patients treated with low-dose dexamethasone plus lenalidomide. Similar results were found when the analysis was restricted to MPR patients and len/dex pair mates receiving lenalidomide plus low/dose dexamethasone, matched according to age and sex, and who did not received transplant. The toxicity profile was different in the two groups. Hematologic grade 3-4 toxicities were more common with MPR compared with len/dex, in particular neutropenia (66.7% vs 21.1%, p < 0.001) and thrombocytopenia (31.4% vs 2.6%, p < 0.001), respectively. Grade 3-4 gastrointestinal events (13.2% vs 2.0%, p= 0.080), thrombotic events (13.2 vs 5.9, p= 0.279) and fatigue (10.5% vs 3.9%, p= 0.395) were more common with len/dex compared with MPR. Conclusion: Results of this case-control study show that both MPR and Rd are efficacious regimens for elderly MM patients. Data need however to be carefully evaluated and randomized control trials are needed to confirm these results. Disclosures: Off Label Use: research drug in combination to standard of care. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; novartis: Research Funding; genzyme: Research Funding. Dispenzieri:celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria. Lacy:celgene: Research Funding. Musto:celgene: Honoraria. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Petrucci:celgene: Honoraria; Janssen Cilag: Honoraria. Greipp:celgene: Research Funding. Boccadoro:jansen Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; pharmion: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria.

Abstract Abstract 2868 Poster Board II-844 Background and Objective: In newly diagnosed multiple myeloma (MM), the combination of lenalidomide plus high-dose dexamethasone (RD) is superior to high-dose dexamethasone (Zonder JA et al, Blood 2007;110:77). Preliminary results show that lenalidomide plus low-dose dexamethasone (Rd) has better 2-year overall survival (OS) compared with RD (Rajkumar SV et al, J Clin Oncol 2008;26:8504). The addition of clarithromycin (Biaxin) to lenalidomide and low-dose dexamethasone (BiRd) has been investigated in a phase II study, demonstrating a high response rate and 2-year OS (Niesvizky R at al, Blood 2008;111:1101-1109). However, the additive value of clarithromycin is not known. No randomized trials have compared Rd versus BiRd, none are planned. The objective of this case–matched study was to compare the efficacy and the toxicity of BiRd vs Rd as initial therapy for newly diagnosed MM. Patients and methods: Data from 72 newly diagnosed MM patients treated at the New York Presbyterian Hospital–Cornell Medical Center, from December 2004 to December 2006, with BiRD, were analyzed. For comparison, an equal number of pair mates were selected among newly diagnosed patients seen at the Mayo Clinic who received Rd, from March 2005 to December 2008. Case matching was performed with respect to age, gender, and transplant status. Patients treated with BiRd received oral lenalidomide (25 mg/day, days 3-21 of cycle 1; days 1-21 of subsequent cycles); dexamethasone (40 mg days 1, 2, 3, 8, 15, 22 of cycle 1; days 1, 8, 15, and 22 of each subsequent cycle); clarithromycin (500 mg twice daily, from day 2 of cycle 1). Patients treated with Rd received oral lenalidomide (25 mg/day, days 1-21) plus low-dose dexamethasone (40 mg days 1, 8, 15, 22). In both groups patients were allowed to discontinue treatment to pursue transplant, but treatment until progression, relapse or unacceptable toxicity was permitted at the physician's discretion. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method; comparisons were determined by the log-rank test and the Cox proportional hazards model. Results: Median duration of treatment was 11.8 months in the BiRd group vs 6 months in the Rd group. On intention-to-treat analysis, complete response was significantly higher with BiRd compared to Rd (45.8% vs 13.9%, respectively, p<0.001); similarly very good partial response (VGPR) or better was higher with BiRd (73.6% vs 33.3%, p<0.001). Rates of VGPR or better, after 6 months and 1 year of therapy, were significantly higher in BiRd patients. Both time-to-progression (TTP) (median 48.3 months vs 27.5 months; HR 0.51; 95% CI 0.25-1.06; p=0.071) and PFS (median 48.3 months vs 27.5 months, HR 0.50; 95% CI 0.25-0.98; p=0.044) were higher with BiRd. Median time to next treatment (TTNT) was not reached in BiRd group compared to 29.9 months in Rd patients (HR 0.37 95% CI 0.20-0.66, p<0.001). There was a trend toward better OS with BiRd, (3-year OS: 89.7% vs 73.0%), but the difference was not statistically significant (HR 0.48; 95% CI 0.17-1.37; p=0.170). Thirty-two patients in each group received transplant; median time to transplant was longer in BiRd group (13.5 vs 5.9 months). Results of survival, for patients who received transplant and patients who did not, were similar to those of the total population. On subset analysis, among patients presenting with International Staging System (ISS) stage I/II at diagnosis, TTP, PFS and TTNT were significantly longer in BiRd patients; no significant differences were found among patients with ISS stage III. Main grade 3-4 toxicities of BiRd were hematological, in particular thrombocytopenia (23.6% vs 8.3%, p=0.012); rate of neutropenia was similar between the 2 groups (19.4% vs 16.7%, p=0.665). Infections (16.7% vs 9.7%, p=0.218) and dermatological toxicity (12.5% vs 4.2%, p=0.129) were higher in patients who received Rd. Rate of venous thromboembolism was similar in the 2 groups (9.7% vs 12.5%, respectively in Rd and BiRd patients, p=0.596). Conclusion: Results of this case-control analysis suggest superiority of BiRd in terms of response rate and survival, compared with Rd, and suggest that there may be a significant additive value when clarithromycin is added to Rd. These data indicate the need for randomized prospective phase III studies to evaluate BiRd versus Rd in the treatment of MM. Disclosures: Off Label Use: research drug in combination to standard of care. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; novartis: Research Funding; genzyme: Research Funding. Mark:celgene: Research Funding. Dispenzieri:celgene: Research Funding. Gertz:celgene: Honoraria; genzime: Honoraria; millenium: Honoraria; amgen: Honoraria. Leonard:celgene: Consultancy. Lacy:celgene: Research Funding. Witzig:celgene: Research Funding. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Greipp:celgene: Research Funding. Niesvizky:celgene: Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Proteolix: Research Funding, data monitoring committee.

Abstract Background: Patients with AL and congestive heart failure have a median survival of less than one year. Methods: Between 1994 and 2005, 11 patients underwent sequential heart transplant followed by autologous peripheral blood stem cell transplant (SCT) for treatment of AL. Patients had heart dominant AL with minimal/no other organ impairment and no evidence of multiple myeloma. Results: Patients ranged in age from 35 to 63 years (median 54). All had biopsy proven amyloidosis and monoclonal protein detectable in serum (73%) or urine (100%). Free light chain assay was available prior to SCT in 6 and was abnormal in all. All patients presented with NYHA Class III or IV heart failure. All but two patients had no other organ involved at the time of heart transplant. One patient had his heart transplant at another facility and had renal involvement at the time of heart transplant. One patient had peripheral nerve involvement documented prior to heart transplant. Five patients had progression of amyloid to involve other organs by the time of SCT. These included: renal (6), peripheral nerve (2), macroglossia (3), gastrointestinal (2). The median time from diagnosis to heart transplant was 3 months (range 1 to 5). The median time from heart transplant to SCT was 8 months, (range 3 to 24). Conditioning chemotherapy consisted of melphalan 200 mg /m2 (6 patients) or melphalan 140 mg/m2 (5 patients). Two patients died of complications before day +100, (TRM of 18%). Hematologic remissions were seen in 8 and organ responses in 3. Five were unable to be evaluated for organ response due to the heart transplant. Three died from progressive amyloidosis at 66, 56.7, and 55 months following SCT. The median survival is 56.7 months from SCT. Six are alive with a median follow-up of 24 months, range 9 to 90 months. Among the 6 surviving patients, one patient relapsed and one patient has failed to improve, but 4 patients are in continued remission. One patient developed secondary myelodysplastic syndrome. Conclusions: Heart transplant followed by SCT is feasible and offers durable remissions for carefully selected patients with cardiac AL. Figure Figure