Abstract: Background: The proteasome inhibitor (PI) bortezomib is active in AL amyloidosis. Carfilzomib (CFZ) is a novel irreversible PI approved for relapsed/refractory multiple myeloma, with less neurologic toxicity than bortezomib, but its safety and efficacy in AL amyloidosis is not known. We report the first results of a multi-center, Phase I, dose-finding study of CFZ in AL (NCT01789242). Methods: Patients had relapsed AL after ≥1 prior therapy. Patients with advanced cardiac involvement (Mayo stage III, LVEF 〈 40%, or NYHA Class III/IV) were excluded. A standard 3+3 dose escalation schedule was used, with planned cohorts of 27, 36, 45, and 56 mg/m2. CFZ was given as a 30-minute infusion on days 1, 2, 8, 9, 15, 16 of a 28-day cycle, starting at 20 mg/m2 on cycle 1, days 1,2, then escalating starting day 8. Primary objectives were safety, tolerability, and determination of MTD. DLTs were defined in Cycle 1 only. Adverse events (AEs) were graded by NCI-CTCAE v4. Serial echocardiograms were performed at baseline, after cycle 3, and every 4 cycles thereafter. Hematologic and organ responses were assessed by updated AL Consensus criteria. Dexamethasone 20mg with each CFZ dose was added for patients without VGPR after cycle 4. After 8 cycles, patients could continue on a reduced-frequency (day 1, 2, 15, 16) schedule at investigator discretion. Two expansion cohorts (PI-naïve and PI-exposed, n=12 each) are currently enrolling at MTD. Results: As of 7/17/14, 12 patients have enrolled. Median age was 62 (range 58–81); 50% were male. Median time from diagnosis was 2.8 years, with median of 2 prior regimens (range 1-4). Eleven patients (92%) had prior bortezomib (5 were refractory); 50% prior IMiDs; 50% prior stem cell transplant. Median # of involved organs was 1 (range 1-2), including 5 patients with heart, 5 kidney, 1 liver, 2 GI tract, and 4 peripheral/autonomic nerve. Median NT-proBNP was 854 pg/ml (range 93 – 9702); 3 and 9 patients were Mayo cardiac stage I and II, respectively. Three patients each were treated at 20/27 and 20/36 mg/m2, with no DLTs. In the 20/45 mg/m2 cohort, there were 2 DLT's of grade 3 fatigue ≥7 days in 4 patients, establishing 20/36 mg/m2 as the MTD. Two additional patients have enrolled at MTD in the PI-exposed expansion cohort. Median number of cycles is 5 (range 1+-13+), with 7 patients still on study, and 5 discontinuing (3 AE, 2 patient withdrawal). Drug-related AEs occurring in 〉 20% of patients (n=11 evaluable) included fatigue (45%), nausea (36%), anemia, dyspnea, and diarrhea (27% each). Seven patients had at least one Grade ≥3 AE (any cause), including cardiac events (n=4 patients), fatigue (n=3), diarrhea (n=2), and nausea, hypoalbuminemia, and pneumonia (n=1 each). There have been 3 cardiac events possibly related to drug: 1 grade 4 cardiac arrest due to ventricular tachycardia during cycle 5; 1 grade 4 restrictive cardiomyopathy and CHF after cycle 3 (with negative endomyocardial biopsy for amyloid); 1 grade 3 drop in ejection fraction after cycle 7. Rising NTproBNP levels correlated with clinical and/or echocardiographic manifestations of CHF in these latter 2 patients. A 4th patient had exacerbation of atrial fibrillation during pneumonia, deemed unrelated. No deaths have occurred. Of 9 evaluable patients, 7 have responded hematologically, including 6 VGPR (≥PR rate=78%; Table 1). Responses have been seen at all dose levels, with median response duration of 3.8 months (range 0.3+ –10.9+) and no hematologic progression. Two patients had dexamethasone added after cycle 4, both improving response to VGPR. With median follow-up of 5.1 months (range 0.2 to 12.3), no organ responses have yet been observed. Conclusions: Carfilzomib monotherapy is feasible and effective in relapsed/refractory AL amyloidosis, with MTD identified as 20/36 mg/m2 as a 30-minute infusion. Cardiac events are common in this population, and may be related to drug, underlying disease or both, suggesting a role for monitoring with cardiac biomarkers and serial echocardiograms. Preliminary hematologic response rates are promising in this bortezomib-exposed population, and organ assessments are ongoing. Further study is warranted. Table 1: Preliminary response data Carfilzomib Dose Cohort Hematologic response 20/27 (n=3) 20/36 (n=5) 20/45 (n=4) Total (n=12) VGPR 2 1* 3** 6 PR 0 1 0 1 SD 1 0 1 2 Not evaluable/ too early 0 3 0 3 *Dex added. **1 had dex added. Never escalated above 20mg/m2 Disclosures Cohen: Celgene: Member, Independent Response Adjudication Committee Other; Janssen: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Advisory Board, Advisory Board Other, Research Funding; Onyx Pharmaceuticals: Advisory Board, Advisory Board Other. Off Label Use: Carfilzomib treatment in amyloidosis . Scott:Onyx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liedtke:Onyx: Membership on an entity's Board of Directors or advisory committees. Kaufman:Spectrum: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Millennium: The Takeda Oncology Co.: Consultancy, Honoraria; Merck: Research Funding. Landau:Onyx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vesole:Onyx Pharmaceuticals: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Speakers Bureau. Gasparetto:Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lentzsch:Celgene: Consultancy, Research Funding; Novartis: Consultancy; Bristol Myers Squibb: Consultancy. Rosenzweig:Celgene: Speakers Bureau. Sanchorawala:Celgene: Research Funding; Millennium Pharmaceuticals: Research Funding; Onyx: Research Funding. Comenzo:Millennium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Durie:Millennium Pharmaceuticals: IRC, IRC Other; Onyx Pharmaceuticals: IRC Other.

Abstract: Background :Carfilzomib (CFZ) is a novel irreversible proteasome inhibitor (PI) approved for relapsed/refractory multiple myeloma, but its safety and efficacy in AL amyloidosis is not known. We report updated results of an investigator-initiated, multi-center, Phase I/II study of CFZ in AL (NCT01789242), including additional patients (pts) treated in the expansion cohort. Methods: Eligible pts (relapsed or refractory AL after ≥1 prior therapy; Mayo cardiac stage I or II; LVEF ≥40%; CrCl≥30; CFZ-naive) received CFZ over 30 minutes on days 1, 2, 8, 9, 15, 16 every 28 days, for 8 cycles, given at 20 mg/m2 on days 1, 2 of cycle 1, then at 27, 36, or 45 mg/m2 (depending on cohort) thereafter. Pre-CFZ hydration was recommended during cycle 1, but could be modified or omitted at investigator discretion. Responding pts could continue on a day 1, 2, 15, 16 schedule at investigator discretion. Dexamethasone 20mg with each CFZ dose was added if no VGPR after cycle 4. Primary objectives were safety and determination of MTD. A 3+3 dose escalation design was used, with a planned expansion cohort at MTD. Responses were based on updated AL consensus guidelines. Pts completing ≥2 cycles (or progressing before 2 cycles) were evaluable for response; all treated pts were evaluated for safety. Cardiac function was monitored in all pts by serial NT-proBNP and echocardiograms. Data cutoff was 6/23/16. Results: From June 2013 - June 2016, 28 eligible pts were enrolled and treated. Median age was 64 (range 43 - 81); 64% were male. Median time from diagnosis was 31 mos., with median of 2 prior regimens (range 1-5), including bortezomib (96%), IMiDs (43%) and stem cell transplant (46%). Thirteen (46%) were refractory to last therapy, and 10 (36%) were PI-refractory (9 bortezomib, 1 ixazomib). Involved organs included kidney (64%), heart (50%), nerve (25%), GI tract (21%), soft tissue (14%), and liver (11%); 13 pts had ≥2 major organs involved. Median baseline NT-proBNP was 542 pg/ml (range 20 - 13571), and median baseline difference in free light chains (dFLC) was 138 mg/L (range 44 - 4709). There were no DLTs at 20/27 and 20/36 mg/m2. At 20/45 mg/m2, there were 2 first-cycle DLTs of grade 3 fatigue ≥7 days, making 20/36 mg/m2 the MTD. Eighteen more pts have enrolled at MTD. Median number of cycles is 6 (range 1-25+), with 10 pts completing the planned 8 cycles (7 continuing on maintenance), 3 ongoing before cycle 8, and 15 stopping early (9 for AE's, 4 for no response, 2 other). Most common drug-related AE's to date are fatigue (36%), increased creatinine (29%), nausea (25%), dyspnea (18%), anemia (18%), diarrhea (14%), pyrexia, chills, and hypertension (11% each). Grade 3/4 AEs (all-cause) occurred in 20 (71%) pts, including several grade 3/4 cardiac or pulmonary AEs: hypoxia (n=1), lung infection (n=2), chest pain (n=1), hypotension (n=1), hypertension (n=3), decreased ejection fraction/CHF (n=3), and symptomatic ventricular tachycardia (n=2, 1 with cardiac arrest requiring defibrillation). There have been no grade 5 AEs. Of 24 response-evaluable pts, 15 (63%) have responded hematologically (3 CR, 8 VGPR, 4 PR), including 6 of 8 evaluable PI-refractory pts (1 CR, 2 VGPR, 3 PR). Responses have occurred at all dose levels (Table). Dex was added in 5 pts, with 3 response upgrades. Five (21%) pts have had organ responses (3 kidney, 1 GI, 1 liver) to date. With median follow-up of 16 mos. (range 0.5 - 32), 9 pts have had hematologic progression, and 2 have died. To date, 11 pts have had NTproBNP increases of ≥30% and ≥300 pg/ml on CFZ. For 5 this correlated with progressive clinical and/or echocardiographic signs of cardiac dysfunction; the other 6 lacked objective signs of worsening cardiac function, with either no symptoms (n=4) or progressive fatigue (n=2). Conclusions: CFZ monotherapy is feasible and effective in relapsed/refractory AL amyloidosis, with MTD identified as 20/36 mg/m2 as a 30-minute infusion. Hematologic response rates are promising in this bortezomib-exposed population, including in PI-refractory pts. Cardiac, pulmonary, and renal toxicities were common, warranting close monitoring and dose reductions as appropriate. Similar to IMiDs, NT-proBNP can increase in pts receiving CFZ, without always correlating with progressive cardiac dysfunction, potentially confounding its use as a marker of cardiac response/progression in this setting. Disclosures Cohen: Bristol-Meyers Squibb: Consultancy, Research Funding; Janssen: Consultancy. Landau:Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx/Amgen: Research Funding; Janssen: Consultancy. Scott:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. Kaufman:Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy; Incyte: Consultancy. Vesole:Janssen: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau. Lentzsch:BMS: Consultancy; Celgene: Consultancy, Honoraria. Gomes:Criterium, Inc: Employment. Comenzo:Karyopharm: Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Durie:Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy.

Abstract: Autologous hematopoietic cell transplantation, or autotransplantation, is effective in light-chain amyloidosis (AL), but it is associated with a high risk of early mortality (EM). In a multicenter randomized comparison against oral chemotherapy, autotransplantation was associated with 24% EM. We analyzed trends in outcomes after autologous hematopoietic cell transplantation for AL in North America. Patients and Methods Between 1995 and 2012, 1,536 patients with AL who underwent autotransplantation at 134 centers were identified in the Center for International Blood and Marrow Transplant Research database. EM and overall survival (OS) were analyzed in three time cohorts: 1995 to 2000 (n = 140), 2001 to 2006 (n = 596), and 2007 to 2012 (n = 800). Hematologic and renal responses and factors associated with EM, relapse and/or progression, progression-free survival and OS were analyzed in more recent subgroups from 2001 to 2006 (n = 197) and from 2007 to 2012 (n = 157). Results Mortality at 30 and 100 days progressively declined over successive time periods from 11% and 20%, respectively, in 1995 to 2000 to 5% and 11%, respectively, in 2001 to 2006, and to 3% and 5%, respectively, in 2007 to 2012. Correspondingly, 5-year OS improved from 55% in 1995 to 2000 to 61% in 2001 to 2006 and to 77% in 2007 to 2012. Hematologic response to transplantation improved in the latest cohort. Renal response rate was 32%. Centers performing more than four AL transplantations per year had superior survival outcomes. In the multivariable analysis, cardiac AL was associated with high EM and inferior progression-free survival and OS. Autotransplantation in 2007 to 2012 and use of higher dosages of melphalan were associated with a lowered relapse risk. A Karnofsky score less than 80 and creatinine levels 2 mg/m 2 or greater were associated with worsened OS. Conclusion Post-transplantation survival in AL has improved, with a dramatic reduction in early post-transplantation mortality and excellent 5-year survival. The risk-benefit ratio for autotransplantation has changed, and randomized comparison with nontransplantation approaches is again warranted.

Abstract: Background: Reduced intensity conditioning (RIC) regimens have allowed the use of allogeneic hematopoietic stem cell transplantation (HSCT) in older and high risk individuals, though Graft versus Host Disease (GVHD) remains an issue. Host antigen presenting cells have been implicated in the pathogenesis of GVHD. Extracorporeal photopheresis (ECP) has been shown to modulate host antigen presenting cell function. Tufts Medical Center developed a novel RIC regimen incorporating ECP, pentostatin and reduced dose total body irradiation (PPT). We now report our 14 year experience with this regimen in 206 consecutive patients not eligible for a myeloablative HSCT. Methods: The Tufts BMT database, the Center for International Bone Marrow Transplantation Registry (CIBMTR) database, and chart review were used to gather data. All patients received a conditioning regimen consisting of ECP administered on days -6 and -5, pentostatin 4mg/m2 by continuous infusion over 48 hours on days -4 and -3, a total dose of 600 cGy TBI administered in 3 fractions on days -2 and -1. No antithymocyte globulin was given. All patients received GVHD prophylaxis with cyclosporine and 2 doses of methotrexate. Supportive care was provided per institutional guidelines. Overall survival (OS) was calculated from day 0 using the Kaplan Meier method. Cumulative incidence of non-relapse mortality (NRM) was calculated treating death due to primary hematologic malignancy or relapse as competing risks. Univariate associations between patient characteristics and outcomes were estimated using logistic regression or Cox proportional hazards models as appropriate. Results: 206 patients (56% males) underwent allogeneic HSCT with the PPT regimen between October 1999 and December 2013. Median age at transplant was 53 years (19-70 years) with 45% being older than 55 years. 31% had a prior autologous HSCT. Median time from diagnosis to transplant was 17 months (range 1-180 months). 59% of the transplants were from matched siblings and 41% were from unrelated donors. Marrow was utilized as the source of stem cells in 72% of the transplants. 92% transplants were HLA matched with 8% mismatched at one antigen. The most common indications for transplant were Acute Myelogenous Leukemia (AML) (35%), Myelodysplastic Syndrome (MDS) (16%) and Non-Hodgkin Lymphoma (NHL) (12%). Of the 73 patients with AML 33% were in first complete remission (CR1), 18% were in a second or greater complete remission (CR ≥2) and 49% had active disease at the time of transplant. Median times to neutrophil and platelet engraftment were 17 and 19 days, respectively. 17% of the patients never dropped their platelet counts below 20,000/mm3. The estimated 5 year overall survival (OS) for the entire cohort was 29% [95% CI (23%-36%)]. The estimates of OS by diagnosis are shown in Figure 1. The estimated non-relapse mortality (NRM) at 100 days was 17% [95% CI (13%-23%)] . The incidence of grade 3-4 acute GVHD was 20%. 54% of the patients developed chronic GVHD, of which only 17% were extensive stage. On univariate analysis for the entire cohort, the variables significant for a higher risk of death were 1-antigen mismatch [HR 1.96, p-value=0.01] and KPS 〈 80 [HR 10.66, p-value 〈 0.001]. Age, stem cell source and having an unrelated donor were not found to be significant. On multivariate analysis in the AML cohort, advanced age [aHR 1.37, p-value=0.02] and active disease [aHR 3.02, p-value=0.002] were significant factors for death. OS by remission status in the AML cohort is shown in Figure 2. Conclusions: PPT was well tolerated with low NRM and survival outcomes comparable to other RIC regimens. OS was independent of graft type (related versus unrelated) or stem cell source. Rates of severe acute and extensive chronic GVHD were low, possibly due to the use of ECP and its modulation of the host antigen presenting cells. OS in patients with AML was comparable to other RIC regimens despite almost half of the patients having active disease at the time of transplant. Our long term follow-up data of 14 years shows that PPT remains a novel regimen for patients not eligible for full intensity conditioning. Figure 1. Overall Survival of Patients Receiving PPT Conditioning by Diagnosis Figure 1. Overall Survival of Patients Receiving PPT Conditioning by Diagnosis Figure 2. Overall Survival of AML Patients by Remission Status. Figure 2. Overall Survival of AML Patients by Remission Status. Disclosures No relevant conflicts of interest to declare.

Abstract: Abstract 2968 Background: Bortezomib, the first-in-class proteasome inhibitor approved for treatment of all phases of multiple myeloma (MM) and used to treat light-chain amyloidosis (AL), was approved for the subcutaneous route of administration in 2012 based on phase III data in relapsed patients (Lancet Oncology 2011;12:431). We report our experience in a tertiary care center with subcutaneously administered bortezomib in newly diagnosed patients with MM and AL. Patients and Methods: With IRB approval, we performed a retrospective study of all newly diagnosed patients with MM or AL treated at our center between 4/1/11, when the hospital pharmacy approved and implemented the option of subcutaneous administration of bortezomib, and 7/31/12. Patients who received subcutaneous bortezomib as part of the first line of therapy were identified through the pharmacy database. Data was abstracted from the medical records; demographics, disease profiles, toxicities, responses, and survival data were collected. Results: Nineteen newly diagnosed patients with symptomatic MM (n=10) or AL (n=9) received bortezomib as part of first line therapy between 4/1/11 and 7/31/12. Median follow-up was 252 days (25–416). They included 12 men and 7 women with a median age of 70 years (range, 49–80), and a median time from diagnosis to treatment of 21 days (3–130). MM patients were ISS stage I (n=4), II (n=3) and III (n=2), and six AL patients had cardiac involvement, stage II (n=5) and III (n=1), respectively. Four MM patients had high-risk cytogenetics and 1 AL patient had del17p. Treatment regimens included cyclophosphamide, bortezomib and dexamethasone on the 35-day schedule (CyBorD-35) (n=12), CyBorD-28 (n=3), CyBorD-21 (n=1), and weekly BD (n=3). Median initial bortezomib dose was 1.5mg/m2 (1.3–1.5), and patients received a median of 4 cycles of therapy (1–8). With respect to side effects, no patients developed rash or grade 3 or 4 peripheral neuropathy. One patient developed grade 3 diarrhea and two grade 3 thrombocytopenia. The latter were the only patients requiring dose reductions (5%, 2/19). Five patients (MM=3, AL=2) proceeded to consolidation with stem cell transplant (SCT) after a median of 4 cycles (1–5). Overall best hematologic responses, including post-SCT patients, in MM were CR/VGPR/PR/SD in 3, 2, 4 and 1 patient, and in AL as per new consensus criteria (Blood 2010;116:1364a) were CR/VGPR/PR in 2, 5 and 2 patients. One MM patient with high risk disease (del17p, del5q) died 118 days after diagnosis status post 3 cycles of CyBorD with SD. One AL patient with del17p relapsed 6 months after achieving a VGPR. Aggregate hematologic response rate 〉 VGPR (CR 6, VGPR 6) was 63%, and 〉 PR was 95% (18/19). Conclusions: With the use of subcutaneous bortezomib in combination regimens in newly diagnosed patients with MM or AL, there was a high overall response rate and minimal toxicity. Five percent of patients required dose reductions of bortezomib for thrombocytopenia. No patients experienced grade 3 or 4 peripheral neuropathy. These results are consistent with the findings of the phase III study in relapsed patients and provide a basis for further studies comparing new proteasome inhibitors to subcutaneous bortezomib in combination regimens for newly diagnosed patients with MM or AL. Disclosures: Comenzo: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract: Background: High-dose chemotherapy followed by ASCT remains the standard of care for patients aged ≤75 years with NDMM. The ability of novel agents, such as lenalidomide and bortezomib, to produce treatment response rates comparable to those seen with ASCT has raised questions about the necessity for upfront ASCT in transplant-eligible NDMM patients. This analysis aimed to compare the efficacy and safety of continuous Ld versus Ld+ASCT in patients with NDMM. Methods: Data were pooled from two randomized clinical trials (NCT01731886 and NCT00807599) that compared Ld alone versus Ld+ASCT in NDMM patients aged ≤75 years. Patients received four 28-day cycles of Ld (lenalidomide 25mg daily on days 1-21; dexamethasone 40mg on days 1, 8, 15, and 22) followed by stem-cell mobilization and collection, and either a) Arm A: continuous Ld (an additional 4 cycles +/- lenalidomide maintenance in NCT01731886, or continuous lenalidomide at the last tolerated dose until disease progression plus dexamethasone 20mg for 1 year following treatment initiation in NCT00807599); or b) Arm B: ASCT conditioned with high-dose melphalan, and followed by lenalidomide maintenance therapy. In both trials, patients were withdrawn if they developed progressive disease (PD) at any time, or had stable disease (SD) after cycle 4 of Ld induction. We evaluated overall response rate (ORR; defined as a partial response or better), progression-free survival (PFS), overall survival (OS), and adverse event (AE) incidence rates, focusing on those randomized patients who responded to 4 cycles of Ld induction. Results: Sixty patients were enrolled into NCT01731886, and 63 into NCT00807599. The analysis included a total of 85 patients who had been randomized and achieved a response to 4 cycles of Ld induction: 41 in Arm A, and 44 in Arm B. Mean ages in Arm A versus Arm B were 61.8 versus 61.7 years; median (range) follow-up times were 3.97 (0.27-6.19) versus 3.71 (0.16-5.66) years. Baseline cytogenetic risk profiles were similar overall, although Arm A contained a higher percentage of intermediate-risk patients (17.1% versus 11.4%). More than half of all patients included in the analysis had International Staging System stage 1 disease: 63.4% of patients in Arm A, and 47.7% of those in Arm B. Median PFS was similar with the two treatment approaches: 4.3 versus 4.4 years (Figure 1; p = 0.9107). OS also did not differ significantly between the two arms (Figure 2). As expected, both treatment regimens were well tolerated. Clinically significant grade 3 and 4 AEs occurring outside of the transplant period included the following: anemia (17.1% Arm A versus 15.9% Arm B); neutropenia (36.6% versus 38.6%); thrombocytopenia (17.1% versus 18.4%); infectious complications (14.6% versus 27.3%); thromboembolic events (7.3% versus 6.8%); and secondary malignancies (7.3% versus 4.5%). Conclusions: The findings of this pooled analysis suggest that, in transplant-eligible patients responsive to Ld induction, continuous Ld results in similar PFS and OS to Ld+ASCT. Larger phase III trials addressing this question are awaited. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Lentzsch: Celgene: Consultancy; BMS: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Axiom: Honoraria. Landau:Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria; Prothena: Consultancy, Honoraria; Janssen: Consultancy; Onyx: Honoraria, Research Funding; Takeda: Research Funding. Lesokhin:Efranat: Consultancy; Genentech: Research Funding; Aduro: Consultancy; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Kewalramani:Celgene: Consultancy; Abbvie: Consultancy; Getchell v Doon East Community Hospital, Alfred Wakeman et al.: Consultancy. Comenzo:Karyopharm: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding; Takeda Millennium: Research Funding; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees. Landgren:Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Medscape: Honoraria; Onyx: Honoraria; International Myeloma Foundation: Research Funding; Onyx: Research Funding; BMJ Publishing: Consultancy; BMJ Publishing: Honoraria; Medscape: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Onyx: Consultancy. Hassoun:Novartis: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Research Funding.

Abstract: Background Risk-adapted melphalan and stem cell transplant (SCT) is standard initial therapy for a minority of patients with systemic AL amyloidosis (Blood 2013;121: 5124; Blood 2011;118: 4298). Stem cell mobilization is often accomplished with high dose G-CSF (16μg/kg/d) (Blood 2011;118:4346). In the current era with effective new agents such as bortezomib, many AL patients are receiving initial therapy and achieving profound rapid cytoreduction with organ improvement (Blood 2012;119:4391; Blood 2011;118:86). But not all patients respond and in some cases the duration of response is limited. In addition, the use of SCT for consolidation after an initial response, although reasonable, has not been systematically evaluated. Whether SCT is employed as consolidation or as a second- or third-line option, the efficacy and tolerance of mobilization become important issues. Because AL patients have organ involvement limiting chemotherapy-based mobilization options, we decided to explore the option of Plerixafor and G-CSF for stem cell mobilization, based on the phase III experience in MM (Blood 2009;113:5720). We now report the first experience with this mobilization approach in AL. Patients and Methods Patients were evaluated and diagnosed by standard criteria including, in all cases, tissue biopsies showing amyloidosis. They were mobilized and collected between 4/16/12 and 6/19/13 with G-CSF 10μg/kg/d subcutaneously (SC) for 5 days (continued through collection process) and Plerixafor adjusted for renal function starting on day 4 and continuing until collection was completed. Results We report on 10 patients whose median age at mobilization was 58 years (range 46-72), 60% of whom were men. Median number of organs involved was 2 (range 1-3). Heart and kidneys were the most frequently involved organs (7 patients in each group). Median time from diagnosis to mobilization was 9 months (range 2-123). Eight patients had received prior bortezomib-based therapy. The median number of cycles was 3 (range 0-6). One had received a prior MEL 140 transplant 10 years prior and had relapsed, and 2 were treatment naïve, one of whom was 1 year status post orthotopic heart transplant. At the time of mobilization, 3 patients had non-responsive hematologic disease, 3 had achieved PR, 1 VGPR and 1 had achieved CR. Five patients had a creatinine ≥ 1.5 mg/dL including 2 patients on hemodialysis. The target cell dose was 10x106CD34/kg for all but one patient (with previous history of transplantation). The median number of collections was 2 (range 2-3). On day one, the median number of CD34+ cells collected per kg was 3.6 x106 (0.4-6x106) and on day two 6.4 x106 (2.7-19x106). The median total CD34+ cells collected per kg was 12.5x106 (5-18x106). Two patients had grade 1 bleeding from the catheter site during apheresis and one patient had dyspnea with suspected fluid overload which responded to a single dose of intravenous furosemide. There were no significant toxicities observed with Plerixafor in mobilization. All patients went on to receive high dose chemotherapy with melphalan followed by autologous stem cell transplant. The median length of hospital stay was 25 days (18-32). The median stem cell dose infused was 7.6x106CD34/kg and median days to ANC 〉 500 was 11 (10-22), to platelets 〉 20K untransfused 22 (15-44) and to lymphocytes 〉 500/μl 14.5 (11-25). One patient who had VOD and persistent thrombocytopenia was given the remainder of his stem cells on day +31 with full recovery and normalization of the blood counts by day +65. Conclusions In the era of more effective initial therapies, an era in which AL patients are living longer, many with moderate organ damage, mobilization with Plerixafor and G-CSF was well tolerated and made it possible to collect ample numbers of CD34+ cells with limited leukaphereses in previously treated patients and in those with advanced renal failure. This approach not only allowed the collection of sufficient CD34+ cells for optimal immediate stem cell dosing but also permitted the cryopreservation of aliquots for post-SCT boost and potentially for future cell-based therapies. Disclosures: Comenzo: Millenium: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Prothena: Research Funding; Teva: Research Funding.

Abstract: AL (amyloid light-chain) amyloidosis is an uncommon plasma cell disorder in which depositions of amyloid light-chain protein cause progressive organ failure and death in a median of 13 months. Autologous stem-cell transplantation is effective therapy for multiple myeloma and therefore, we evaluated its efficacy for AL amyloidosis. Patients with adequate cardiac, pulmonary, and renal function had stem cells mobilized with granulocyte-colony stimulating factor and were treated with dose-intensive intravenous melphalan (200 mg/m2). Response to therapy was determined by survival and improvement of performance status, complete response or persistence of the clonal plasma cell disorder, and change in the function of organs involved with amyloid at baseline. We enrolled 25 patients with a median age of 48 years (range, 29-60), all of whom had biopsy-proven amyloidosis with clonal plasma cell disorders. Twenty-two (88%) were Southwest Oncology Group performance status 1 or 2 within a year of diagnosis, and 16 (64%) had received no prior therapy. Predominant amyloid-related organ involvement was cardiac (n = 8), renal (n = 7), hepatic (n = 6), neuropathic (n = 3), and lymphatic (n = 1). Fifteen patients had one or two organ systems involved, whereas 10 had three or more involved. With a median follow-up of 24 months (12-38), 17 of 25 patients (68%) are alive, and the median survival has not been reached. Thirteen of 21 patients (62%) evaluated 3 months posttransplant had complete responses of their clonal plasma cell disorders. Currently, two thirds of the surviving patients (11 of 17) have experienced improvements of amyloid-related organ involvement in all systems, whereas 4 of 17 have stable disease. The improvement in the median performance status of the 17 survivors at follow-up (0 [range, 0-3]) is statistically significant versus baseline (2 [range, 1-3] ; P 〈 .01). Significant negative prognostic factors with respect to overall survival include amyloid involvement of more than two major organ systems and predominant cardiac involvement. Three patients have experienced relapses of the clonal plasma cell disorder at 12 and 24 months. Dose-intensive therapy should currently be considered as the preferred therapy for patients with AL amyloidosis who meet functional criteria for autologous transplantation.

Abstract: The past decade has witnessed a paradigm shift in the initial treatment of multiple myeloma with the introduction of novel agents such as thalidomide, lenalidomide, and bortezomib, leading to improved outcomes. High-dose therapy and autologous stem cell transplantation remains an important therapeutic option for patients with multiple myeloma eligible for the procedure. Before the advent of the novel agents, patients underwent stem cell collection prior to significant alkylating agent exposure, given its potential deleterious effect on stem cell collection. With increasing use of the novel agents in the upfront setting, several reports have emerged raising concerns about their impact on the ability to collect stem cells. An expert panel of the International Myeloma Working Group (IMWG) was convened to examine the implications of these therapies on stem collection in patients with myeloma and to develop recommendations for addressing these issues. Here we summarize the currently available data and present our perspective on the problem and potential options to overcome this problem. Specifically, we recommend early mobilization of stem cells, preferably within the first 4 cycles of initial therapy, in patients treated with novel agents and encourage participation in clinical trials evaluating novel approaches to stem cell mobilization.