Dispenzieri, Angela

Abstract Background: Patients with early stage myeloma are typically observed without therapy until symptomatic disease occurs. We have reported early results of therapy with single-agent thalidomide as initial therapy for early stage multiple myeloma in an attempt to delay progression to symptomatic disease (Leukemia2003;17:775–9). We now report the long-term results of this phase II trial. Methods: Thirty-one patients with smoldering or indolent multiple myeloma were enrolled between April 1999–March 2002. All pts had bone marrow (BM) plasma cells >=10% and measurable disease defined as serum monoclonal (M) protein >=2gm/dL and/or urine M protein >=400mg/24 hours. Two patients were deemed ineligible because they were found to have received prior therapy for myeloma and were excluded from analysis. Thalidomide was initiated at a dose of 200 mg/day and increased as tolerated by 200 mg/day every 2 weeks to a maximum dose of 800 mg/day. The dose of thalidomide was decreased as needed to minimize toxicity. Treatment was continued until disease progression or serious toxicity, except for patients achieving less than a minor response (<25% paraprotein reduction) to therapy in whom therapy was stopped at one year. Response was defined as a decrease in serum and urine monoclonal (M) protein by 50% or higher. If the serum M protein was unmeasurable, a 90% or higher decrease in urine M protein was required. Responses need to be confirmed at least 4 weeks apart. Results: Ten patients (34%) had indolent myeloma, including 4 patients with lytic bone lesions, 3 patients with anemia (Hb <11gm/dL), and 3 patients with both anemia and lytic bone lesions. Median follow up of living patients is 5.6 years (range, 4.0–7.1 years). Of the twenty-nine eligible patients, ten (34%) had a partial response to therapy with at least 50% or greater reduction in serum and urine monoclonal (M) protein. Three patients are still on study and receiving therapy. The remaining have gone off-study: seven patients (27%)had progressive disease while on therapy; other reasons for ending study treatment included completed therapy per protocol (2 pts), patient refusal (2pts), toxicity (8 pts), alternate treatment (3 pts), other medical problems (1 pt), died on study (1 pt), and other (2 pts). The median time to progression (TTP) was 3.2 years (95% CI 2.1–5.6 yrs). Median progression free survival (PFS) was 3.0 yrs (95% CI 2.0–5.1 yrs). Median overall survival has not been reached; 5 year survival rate by the Kaplan Meier method is 60%. Major grade 3–4 non-hematologic adverse events at any time during therapy were noted in 34% of patients; this includes 14% with grade 4 toxicity. Grade 3–4 toxicities occurring in more than one patient include neuropathy (2 pts) and sinus bradycardia (2 pts). Conclusions: Thalidomide has activity in asymptomatic myeloma. This approach must be further tested in randomized trials to determine if the survival estimates are superior to observation. Given the activity of thalidomide, trials are also needed with lenalidomide.

Abstract Abstract 2928 Multiple myeloma (MM) is caused by the clonal expansion of malignant plasma cells (PCs) producing high levels of monoclonal immunoglobulin (Ig) or M-protein. However, ∼2% of all patients with monoclonal gammopathies (MG) have more than 1 M-protein, a condition termed biclonal gammopathy or double monoclonal gammopathy (DMG). These patients can express M-proteins with different heavy chain (HC) isotypes and different light chains (LCs) or different HCs that are LC-matched. Reports suggest that ∼87% of DMGs with different HCs have matched LCs, but without molecular analysis at the nucleotide level, clonal relationships are unknown. Thus, DMG patients may have either two independent malignant PC clones that coincidentally express the same type of LC or the two clones are related and reflect previous or ongoing class switch recombination (CSR). This latter variant would offer novel insight into the origin and differentiation of the malignant clone. Of note, prior reports of HC-dissimilar/LC-matched DMGs are limited to the analysis of single patients and with few exceptions; do not include molecular analysis of the variable regions in Ig HC or LC genes at the nucleotide level. In this study, we interrogate a cohort of MM patients with known HC-dissimilar/LC-matched DMGs for the frequency of clonal relatedness. The cohort was identified by searching our MG database for patients with: 1) HC-dissimilar/LC-matched Igs as determined by immunofixation; 2) >10% bone marrow (BM) PCs; and 3) no transplant prior to BM collection. Eight patients (7 MM and 1 smoldering MM/primary amyloid) were identified for further molecular evaluation. All 8 cases expressed IgG and IgA HCs. Three patients expressed kappa LC (K-LC) and 5 expressed lambda LC (L-LC). To determine if the IgG and IgA M-proteins were clonally related in each patient, we performed Ig HC variable gene (IGHV) PCR with sense primers to all IGHV genes and an antisense primer specific to IgG or IgA. In all 8 patients, a single productive IGHV gene was determined with IgG and IgA. In 2/8 patients, the IgG and IgA HC variable regions were clearly distinct and therefore genuinely biclonal. Of note, PCs from 6/8 patients used the same IGH V-D-J genes in both IgG and IgA transcripts. In 5 of these 6 patients, the entire IgG and IgA variable region and HCDR3 were identical at nucleotide and amino acid (AA) levels. Of interest, one patient had common, as well as distinguishing IGHV region somatic mutations (SHM) between the IgG and IgA transcripts. The HCDR3 regions (including N nucleotides) were highly homologous but differed by 7 nucleotides which resulted in 3 AA differences between the 2 clonally related sequences. While these are compelling data, it remained possible that the malignant PCs in these patients simultaneously expressed IgG and IgA as a result of long nuclear transcripts. To test this possibility, we used immunofluorescence (IF) and verified the presence of both IgG and IgA expressing PCs in all cases. Parallel analysis of both K-LC and L-LC variable gene by PCR was done on the 6 patients with the same IGHV gene in both IgG and IgA transcripts. In 3/6 patients, there was a single somatically mutated LC identified corresponding to the LC detected by immunofixation. These results were also confirmed by IF. The remaining 3 patients appeared to express more than 1 LC rearrangement. Taken together these results confirm that HC-dissimilar/LC-matched DMG can present with various phenotypes at the molecular level. We describe the largest cohort to date documenting the frequency of DMG patients that can be classified as expressing 2 identical HCs with either a single LC or >1 LC based on molecular analysis. The former case may reflect an original progenitor cell that divided with one daughter cell subsequently experiencing further CSR yet the LC remained untouched. In the case where the HCs were slightly different, there may have been CSR with additional SHM of a daughter cell, or the molecular differences may reflect random somatic mutations occurring independent of germinal center reactions. These results suggest that HC-dissimilar/LC-matched DMG may occur more often than thought. Larger studies tracking M-protein levels over time accompanied by cytogenetic analyses are needed to determine if the two clonally-related class switch variants in DMG patients exhibit similar biological properties. This analysis would offer new insight into the genesis of this unique subtype of MM. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1858 Systemic light chain amyloidosis (AL amyloidosis) is a condition where clonal plasma cells produce misfolded insoluble immunoglobulin light chains that deposit in various organs causing progressive organ dysfunction. Chemotherapy and autologous stem cell transplant (ASCT) when eligible is the standard treatment options for patients with AL amyloidosis. There are several studies who report long term outcomes of patient post ASCT. However, there is a paucity of literature describing the outcomes of patients who have received ASCT but have relapsed. We performed a retrospective study to assess the outcomes and treatment regimens employed following relapse after ASCT. Between 1996 and 2009, 410 patients received ASCT at the Mayo Clinic as first line therapy. Of those 410 patients 42 patients died within 3 months of transplant, 64 patients died without documented relapse, 158 patients were alive without documented progression, and 146 patients had documented progression. Those 146 patients are the subject of our study. The median time to hematologic relapse was 2 years (range: 0.2–15.5 years). At relapse, 59 patients were treated with IMiD based therapy, 36 with alkylator based therapy, 24 with bortezomib, 15 with steroids, and 5 with second ASCT. The respective hematologic response rates were 58%, 33%, 50%, 53%, and 60%. The remaining six patients were not evaluable for response for one other following reasons: organ transplants; no further therapy; inevaluable disease. With a median post relapse follow up of 3.6 years, the median overall survival (OS) from the first post ASCT relapse was 4.6 years. The median post transplant follow up was 6.1 years, the median OS for these patients was 7.3 years from the time of transplant. These data provide novel information about outcomes after SCT relapse, which should be useful not only for patients and doctors but also for investigators designing studies for salvage therapies post-transplant. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Myeloma remains incurable due to a stem cell/proliferative component that responds poorly to standard treatments. We have shown that aberrant IL-1beta stimulates the generation of paracrine IL-6, a central myeloma growth factor. A Phase II trial was completed using IL-1 receptor antagonist (IL-1Ra/Anakinra), which inhibits paracrine IL-6 production, and low dose Dexamethasone (Dex), which decreases IL-1 levels through myeloma cell apoptosis, in patients with SMM/IMM. SMM/IMM patients are most likely to benefit from anti-cytokine therapy in order to delay/prevent the development of active myeloma. Methods: Patients that had ≥ 10% bone marrow plasma cells and/or an IgG or IgA M-spike ≥ 3 g/dL and did not require immediate chemotherapy were eligible. All patients received 100 mg of IL-1Ra SQ qd for 6 months unless clinical progression occurred. Non-progressors were allowed to continue on therapy with IL-1Ra alone. Low dose Dex (20 mg qweek) was added after 6 months of IL-1Ra or for evidence of clinical progression; the dose was adjusted based on response/toxicity. Results: To investigate the effects of IL-1Ra and Dex alone and in combination in vitro, we co-cultured IL-1beta transduced +/− myeloma cells with stromal cells +/− dexamethasone, IL-1Ra, or both for 48 hours and quantitated the percent apoptotic cells by flow cytometry and IL-6 production by ELISA. The results showed that: 1) IL-1Ra was superior to Dex at inhibition of IL-6 but caused no myeloma apoptosis; 2) Dex induced apoptosis was inhibited by IL-6 3) Dex and IL-1Ra combined induced maximal IL-6 inhibition and apoptosis of myeloma cells. In the clinical trial, data were available on 47 patients; smoldering (79%) / indolent (21%). All patients received IL-1Ra initially and 20/47 subsequently received IL-1Ra/Dex. Seven patients had a decrease in the plasma cell labeling index (PCLI), a marker of cell proliferation, on IL-1Ra alone which paralleled a decrease in the high sensitivity C-reactive protein (CRP). Interestingly, in one patient treated with Dex alone for 6 months, Dex induced a decrease in the M-protein and IL-1 levels, however, the PCLI and CRP values increased. The IL-1Ra/Dex combination has resulted in stability of disease in the majority of the 47 patients; 28 continue on therapy with a median overall progression-free survival (PFS) of 37.5 months. Four of the 47 pts achieved a minor response (MR) with IL-1Ra alone, and an additional 6 pts achieved a MR/PR after addition of dex. The continuous measure of % reduction in CRP was significantly associated with time to progression (p=0.02). Similarly, those patients who had a >5% decrease in serum M protein also had a longer PFS (p<0.001). Of note, 2 patients with high PCLI values of 6.4 and 3.0, characteristic of poor prognosis, responded with a reduction in the PCLI values and continue on combination therapy for 3 and 1.5 years, respectively with stable disease. Conclusion: Agents such as IL-1Ra that specifically inhibit paracrine IL-6 production are more effective at targeting the proliferative component than apoptosis inducing agents such as Dex; the combination may be especially useful in patients that have an elevated PCLI at presentation.

Abstract Abstract 3138 Background: Several recent reports have suggested that doxycycline can inhibit amyloid fibril formation in different in vitro and in vivo model systems. Doxycycline is the antibiotic of choice for infectious disease prophylaxis in patients with penicillin allergy, following autologous peripheral blood stem cell transplantation for various hematological malignancies. We examined the outcome of patients with light chain amyloidosis (AL) undergoing autologous stem cell transplantation to study the impact of doxycycline used as antibacterial prophylaxis. Patients and methods: We studied 455 patients who underwent autologous stem cell transplant (ASCT) for AL between March 1996 and December 2011. We excluded 44 patients who died of transplant related complications or did not survive beyond 100 days after transplant. Patient records were reviewed to ascertain the prophylactic antibiotic used. Survival was estimated using Kaplan Meier method and the survival curves were compared using log-rank test. Cox proportional hazard model was used to estimate the prognostic impact of different variables. Results: The median age of the patients was 58 years (range, 26–74); 290 (67%) were male. The median estimated follow up for the entire cohort was 73 months (95% CI; 66, 79) and 314 (69%) were alive at last follow up. Doxycycline was used a prophylaxis in 106 (23%) of the patients, with most of the remaining receiving penicillin. The usual reason for using doxycycline was a history of penicillin allergy. Hematological response to transplant occurred in 377 (87%) patients, and there was no significant difference between patients receiving doxycycline prophylaxis compared with the rest. The median OS for the entire cohort was 161 months (95% CI; 101, NR). The median OS for those receiving doxycycline prophylaxis was not reached compared with 113 months for the rest (P=0.09). Looking specifically at those patients with a hematological response, the median OS was not reached for the doxycycline group compared with 161 months for the rest (P=0.04, figure). There was no difference in the OS between the groups among those with no hematological response. The impact of the prophylaxis was independent of the number of organs involved as well as organ response to SCT. Conclusions: The results of the current study appear to demonstrate a survival advantage for patients with AL who receives doxycycline prophylaxis, in the setting of hematological response from SCT. The results are consistent with the data regarding the effect of doxycycline on amyloid fibril formation. These initial findings should form the basis of clinical exploration of doxycycline as an adjunctive therapy in patients receiving other standard therapies for AL. Such a study can further clarify if use of doxycycline for longer duration can be of additional benefit. Disclosures: Kumar: Cephalon: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Celgene: Research Funding; Merck: Consultancy, Honoraria; Genzyme: Research Funding.

Abstract Abstract 2973 Eukaryotic translation initiation Factor 5A (eIF5A) has been implicated in the regulation of apoptosis and is the only known protein to be modified by hypusination. Hypusinated eIF5A is the predominant form of eIF5A in cancer cells. However, in its unhypusinated form, eIF5A is pro-apoptotic. SNS01-T, designed to treat B-cell cancers, consists of two active components: a plasmid DNA expressing eIF5AK50R (human eIF5A containing a lysine to arginine substitution at position 50) which remains pro-apoptotic because it cannot be hypusinated, and an siRNA against an untranslated region of native eIF5A mRNA. When these two components are combined with linear polyethyleneimine (PEI), the nucleic acids are condensed into nanoparticles for protection from degradation in the blood and enhanced delivery to tissues. The eIF5AK50R transgene is under the control of the B29 promoter and enhancer, which restricts expression to B cells. The mode of action of SNS01-T is to use an eIF5A-specific siRNA to deplete the pool of hypusinated eIF5A in myeloma cells while simultaneously adding pro-apoptotic eIF5AK50R. In vitro cell studies and in vivo xenograft studies have demonstrated the efficacy of this approach. Eligible patients are enrolled sequentially into four cohorts of increasingly higher doses. Each cohort will receive SNS01-T by intravenous infusion twice weekly for 6 consecutive weeks and then be observed every 4 weeks during a 24-week follow-up period. Eligible patients must have been diagnosed with multiple myeloma according to IMWG criteria, have measurable disease, have relapsed disease after two or more prior treatment regimens, have a life expectancy of at least 3 months, and not be eligible to receive any other standard therapy known to extend life expectancy. The primary objective is to evaluate the safety and tolerability of multiple ascending doses of SNS01-T. Secondary objectives include pharmacokinetics, immunogenicity studies, proinflammatory cytokine quantitation, and therapeutic efficacy. The required number of 3 patients completed the dosing schedule in Cohort 1 from a total of 6 patients enrolled. Two of three patients had not progressed on treatment, based on standard response criteria including the monoclonal protein, and were considered stable at week 3 and week 6 the end of the dosing regimen. Three patients were withdrawn from the study by their physicians due to disease progression before completing treatment. One of the responding patients has continued to have stable disease at week 10, a month after the end of treatment with SNS01-T. The first group of patients received 0.0125 mg/kg, approximately 1 mg per patient by intravenous infusion. The planned dose levels for the second, third and fourth groups are 0.05, 0.2 and 0.375 mg/kg, respectively. The results to date of this first in man clinical trial indicate that SNS01-T was safely administered without dose-limiting toxicities in the first group of multiple myeloma patients. The MTD has not yet been reached. (Clinical Trials.gov Identifier: NCT01435720.) Disclosures: Hamadani: Celgene Corp: Speakers Bureau; American Cancer Society 116837-IRG-09–061–01: Research Funding; ASBMT & Millennium New Investigator Award: Research Funding; Conquer Cancer Foundation of ASCO: Research Funding. Barranco:Senesco Technologies: Employment. Thompson:Senesco Technologies Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Taylor:Senesco Technologies Inc.: stock options Other. Dondero:Senesco Technologies Inc.: Employment.

Abstract Background: Patients with monoclonal gammopathies typically have a single clone making a unique type of monoclonal protein, one heavy chain and one light chain. In a small proportion of patients, more than one (typically two) types of monoclonal protein can be seen and differ with respect to the heavy chain or light chain or both. There is limited information on the clinical course of patients with more than one monoclonal protein identified in their serum or urine. Objectives: We report outcomes of patients with more than one monoclonal protein at our institution over the past thirty years. Patients and Methods: We queried the existing clinical database to identify all patients with at least two different monoclonal protein types identified on serum or urine studies during the course of their disease. Retrospective chart review was performed on 551 patients, who had more than one type of monoclonal protein on electrophoresis and/or immunofixation. Results: Among the entire study cohort (N=551), 461 pts (84%) had a biclonal pattern, 7 (1%) had a triclonal pattern and the remaining 83 (15%) had a monoclonal pattern at the time of initial positive study. The median age at the time of initial diagnosis was 69.7 years (range; 32-93); 359 (65%) were male. Among these, 390 were diagnosed as MGUS/BGUS, 18 with SMM, 36 with MM, 20 with WM, and rest with another lymphoproliferative disorders. The median duration between the initial detection of monoclonal protein and the emergence of the biclonal protein was 40 months for the 83 patients, who were monoclonal initially. The distributions of the dominant monoclonal proteins were GK (30%), GL (21%), MK (22%), ML (9%), AK (9%), and AL (8%). The distributions of the second monoclonal proteins were GK (27%), GL (24%), MK (16%), ML (15%), AK (10%), and AL (7%). Overall, 20 patients with a MGUS/BGUS progressed to smoldering or symptomatic myeloma, while 12 patients with an initial diagnosis of SMM progressed to MM. The median estimated follow up for the MGUS/BGUS group and those with SMM were 6.5 years (95% CI; 5, 7) and 9.8 (95% CI; 4, 13), respectively. This translates to 20 progressions over 3822 person years of follow up for the MGUS/BGUS patient group and 12 progressions over 131 person years of follow up for the SMM group. The rate of progression was ~1% per year for patients with MGUS/BGUS and the median estimated time to progression was 2.6 years for the SMM group. (Figure). In majority of patients, the dominant M spike increased with the disease progression. Conclusion: Patients with biclonal gammopathies appear to have a similar rate of progression compared to what has been historically described for MGUS/ SMM population. For the patients who progressed and received treatment, both M proteins typically responded to therapy, and during relapse, the original dominant M protein typically reemerged as the dominant M protein. Figure 1 Figure 1. Disclosures Kumar: Janssen: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi-Aventis: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Millennium: The Takeda Oncology Co.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Skyline Diagnostics: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Among patients with immunoglobulin light chain (AL) amyloidosis, there is little consensus on when reinstitution of chemotherapy should occur (Milani and Dispenzieri, International Society of Amyloidosis 2016). AL amyloidosis patients who are treated with high dose chemotherapy followed by autologous stem cell transplant (ASCT) are a relatively low-risk and homogenous population, making them an ideal group to study practice patterns. Methods: We conducted a retrospective study to evaluate the patterns of relapse or progression and the timing of re-initiation of therapy among 146 patients who were initially treated with ASCT at Mayo Clinic between 1996 and 2009 and who received second-line therapy between 7/9/1997 and 4/12/2012. Results: The median time from ASCT to second-line therapy was 23.6 months and the median follow up post ASCT was 57.5 months. The indications for second-line treatment were: 1) both hematologic and organ progression 24.7% (36 patients); 2) organ progression only 41.1% (60); 3) hematologic relapse only 34.2% (50). The median dFLC at the time of starting second-line therapy was 10.5 mg/dL (1.6 - 59.5 mg/dL), which was 44.9% (13.8-167.2%) of dFLC level at diagnosis. Increase in proteinuria by > 50% from nadir (that was also at least 1g/24 hours, i.e. renal progression) was present in 35.8%. Increase in NT proBNP by >30% from nadir and minimum of 300 pg/mL was present in 48.9% of patients. The respective 4 years overall survival rates from the time of ASCT were 87.8%, 63.9%, and 56.7% (p=0.0016) for patients who had hematologic relapse, organ progression only and both organ and hematologic progression. Comparisons of laboratory markers at diagnosis, nadir of post ASCT and initiation of second-line therapy are listed in the table. Conclusions: Our study investigated the patterns of relapse / progression following upfront ASCT. This provides some insights on practice patterns of when physicians re-initiate therapy. Table Table. Disclosures Gertz: NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Novartis: Research Funding; Prothena Therapeutics: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria; Ionis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Annexon Biosciences: Research Funding. Kumar:Millennium: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Research Funding; Kesios: Consultancy. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Celgene: Research Funding; Jannsen: Research Funding; pfizer: Research Funding; GSK: 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.

Abstract Introduction High dose chemotherapy and autologous stem cell transplantation (ASCT) is an effective therapy for eligible patients with newly diagnosed systemic AL amyloidosis. Dose attenuated melphalan is used in patients with older age, renal dysfunction, and multi-organ involvement in an effort to limit treatment related mortality. Reducing the dose of melphalan compromises response rates and survival outcomes, but this is often contributed to frailty of these patients. The revised Mayo staging (MS) system improves risk stratification and helps develop risk-adapted therapies. We analyzed the outcomes of ASCT following standard [(200 mg/m2); SD group] versus risk adapted [(140-160 mg/m2); RD group] melphalan conditioning, in the context of the factors typically leading to dose modification. Methods Three hundred and twenty nine patients with newly diagnosed systemic AL amyloidosis who underwent conditioning with melphalan followed by ASCT at Mayo Clinic between 2006 and 2015 were identified using existing databases. The clinical and laboratory data, treatment and follow - up details were collected by chart review and analyzed retrospectively. Overall survival(OS) was defined as the time from start of initial therapy until death from any cause or last follow up. Progression free survival(PFS) was defined as the time to relapse or progression requiring change or reinstitution of treatment or death from any cause. The OS and PFS curves were estimated using Kaplan-Meier method while log rank test was used to estimate their difference. Multivariate survival analysis was performed using the Cox proportional hazards model. Results Among the 329 patients, 240 patients were in SD group and 89 patients were in RD group (1 patient received 120 mg/ m2, 2 received 160 mg/m2 and the rest received 140 mg / m2). In the SD group, median age was 58.5 years (25.6 - 72.3); 59.6% were males; 38.7% / 61.7 %/ 7.5% had cardiac / renal /hepatic involvement; and 47.1% / 35.7% / 8.8% / 8.4% had MS I/II/III/IV. In the RD group, median age was 60.8 years (40 - 73.7); 62.9% were males; 66.3% / 71.9 %/ 11.2% had cardiac / renal /hepatic involvement; and 26.2% / 32.5% / 21.2% / 20% had MS I/II/III/IV. The response rates for patients in the SD group [complete response (CR) - 53.7%, very good partial response (VGPR) - 19.6%, partial response (PR) - 12.5%, no response (NR) - 1.2%, progressive disease (PD) - 1.6%] were significantly higher than patients in the RD group (CR - 34.8%, VGPR - 20.2%, PR - 15.7%, NR - 10.1%, PD - 1.1%) (85.8 vs 70.7%; p < 0.002). The PFS and OS for both the groups according to Mayo stage are presented in Figure 1. Multivariate survival analysis for PFS and OS was performed using age (≤ vs > 70 years), serum creatinine (≤ vs > 2 mg/dL), number of major organs involved (heart, kidney, liver, gastrointestinal tract and autonomic neuropathy), MS (1 vs 2 vs 3 and 4) and dose of melphalan (SD vs RD). The dose of melphalan (p=0.0002), MS (p=0.03) and the number of organs involved (p=0.04) were significant for PFS while the dose of melphalan (p=0.0001) and the MS (p = 0.004) were significant for OS. Conclusion Reducing the dose of melphalan during conditioning for frontline ASCT in systemic AL amyloidosis renders more patients eligible for transplant but compromises on the response rates. There is no impact on PFS and OS in Mayo stage I patients. However the OS as well as PFS in Mayo stage II, III and IV were significantly lower in RD group as compared to SD group. These results suggest a suboptimal outcome with use of reduced dose melphalan, even after accounting for the pother prognostic factors, suggesting that high dose therapy should potentially be limited to those eligible to receive the full dose conditioning. Disclosures Dispenzieri: Jannsen: Research Funding; pfizer: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Takeda: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Kumar:Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; Kesios: Consultancy; Noxxon Pharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding.

Abstract Introduction Immunoglobulin light chain amyloidosis (AL Amyloidosis) is a monoclonal plasma cell proliferative disorder that is characterized by tissue deposits of misfolded insoluble κ or λ light chain derived amyloid fibrils, leading to organ dysfunction. The prognosis of patients depends on the number and severity of organ involvement, especially cardiac involvement. Autologous stem cell transplant (ASCT), if eligible, alkylator (melphalan) and novel drugs like proteasome inhibitors (PI) and immunomodulators (IMiD) have improved the overall survival (OS) during the past decades. But still, nearly half of the patients die within a year of diagnosis. We analyzed the factors predicting early relapse / progression or death (within 12 months) after first line therapy for systemic AL amyloidosis. Methods Clinical and laboratory data of all consecutive patients with systemic AL amyloidosis seen at Mayo Clinic within 90 days of their diagnosis, between 2006 and 2015, was collected by chart review and analyzed retrospectively. Patients who died within 3 months of starting the first line treatment were excluded from analysis. Early relapse (ER) was defined as relapse / progression requiring treatment change / re-institution or death within 12 months of starting first line treatment. Patients in the cohort with ER were compared with patients with a follow up of more than 12 months who had a relapse / progression beyond 12 months or had continuing response at the time of analysis. Categorical variables were analyzed using chi - square and Fisher's exact test and continuous variables using Kruskal- Wallis test and Wilcoxon rank sum test. Multivariate analysis was done using logistic regression model. Results Seven hundred and eighty six patients with newly diagnosed systemic AL amyloidosis met the study criteria and were included in the analysis. Among these, 230 (29.3%) patients had ER within 12 months of starting initial therapy while 556 (70.7%) patients either relapsed after 1 year or had continuing response at the time of analysis. Baseline demographics, organ involvement and type of first line therapy are presented in Table1. The median estimated follow up for the entire cohort from start of initial therapy was 62.9 months (95% CI; 59.9, 67.3). The variables included in the univariate and multivariate analyses for factors predicting ER were age at diagnosis (≤ vs > 70 years ), revised mayo stage (I and II vs III and IV), bone marrow plasma cell percentage (BMPC; ≤ 10% vs > 10%), presence of any chromosomal abnormalities, trisomies or IgH translocations by fluorescence in situ hybridization (FISH), multiorgan involvement [(>1 vs 1) (heart, liver, kidney, gastrointestinal tract, autonomic neuropathy), incorporation of ASCT in initial therapy. In univariate analysis, mayo stage (p<0.0001), multiorgan involvement (p=0.0008) and inclusion of ASCT as part of initial therapy (p<0.0001) were significantly associated with ER, while age (p=0.06), BMPC(p=0.9), FISH abnormalities (p=0.2) were not. However, in multivariate analysis, only mayo stage (III + IV vs I + II; p=0.01) and non-inclusion of ASCT in first line treatment (p=0.0001) were significantly predictive of ER. Conclusions Despite the introduction of ASCT and novel drugs, the early mortality in systemic AL amyloidosis remains high. This study demonstrates that patients with ER are older with higher prevalence of cardiac involvement and multiorgan involvement and higher Mayo stage (III and IV). Incorporation of ASCT as part of the initial therapy was associated with reduced early relapse, but it is difficult to separate the influence of the eligibility for ASCT from the effect of ASCT itself. This will help us in characterizing these patients to better understand their mechanisms of resistance to therapy and gives an insight to the type of initial therapy that benefits them. Disclosures Dispenzieri: GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; pfizer: Research Funding. Kapoor:Takeda: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Kesios: Consultancy; BMS: Consultancy; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Glycomimetics: Consultancy; Millennium: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; AbbVie: Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding.