Citations

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.

Abstract Introduction Immunoglobulin light chain amyloidosis (AL Amyloidosis) is a plasma cell disorder characterized by deposition of misfolded insoluble protein fibrils (composed of monoclonal κ or λ light chains) in tissues causing progressive organ dysfunction. Chemotherapy and autologous stem cell transplant (ASCT), when eligible, are standard treatment options but relapses remain inevitable for most patients. However, there is a paucity of literature describing relapsed or refractory patients. We performed a retrospective study to analyze the outcomes upon relapse and the impact of type of therapy and retreatment with the same therapy at relapse. Methods Clinical and laboratory data of 1327 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. Of these patients, 219 (16.5%) were lost to follow-up. Among the remaining 1108 patients, 366 patients experienced a documented hematological or organ relapse or progression requiring change of first line or start of second line therapy and form the current study population. Overall survival (OS) was calculated from start of second line treatment or progression mandating therapy until death from any cause or the date of last follow up. The OS was estimated using the Kaplan-Meier method and log rank test was used to estimate the difference in survival curves. Results The median age was 62.8 years (36.1 - 85.3); 63.1% were males; 64.7% / 59.3% / 11.4% had cardiac / renal / hepatic involvement and 24.2% / 32.1% / 23.3% / 20.3% had MS I/II/III/IV. The median estimated follow up for this cohort was 69.4 months (95% CI; 64.4, 76.8) from the start of first line therapy and 45.2 months (95% CI; 36.5, 50.6) from the start of second line therapy or progression requiring treatment. The median time to second line treatment or relapse /progression mandating therapy was 16.2 months (1-93) from the start of first line therapy. At relapse, 14 patients underwent ASCT, 165 were treated with proteasome inhibitor (PI) based therapy, 83 with immunomodulator (IMiD) based therapy, 33 with alkylator based therapy, 15 with a combination of PI and IMiD, 10 with steroids, 8 with other therapies and 38 did not receive treatment. Among the 366 patients, 124 (33.9%) required change or reinstitution of therapy during follow up at the time of analysis. The median time to third line treatment or relapse /progression mandating therapy was 31 months (95% CI; 24, 40.5) from the start of second line treatment. The median overall survival (OS) was 76.4 months (95% CI; 65.2, 83.6) from the start of first line therapy and 38.8 months (95% CI; 29.6, 52.6) from the start of second line therapy. The type of therapy at relapse (ASCT vs PI vs IMiD vs melphalan vs steroids and others) did not alter the time to next therapy (ASCT, 43.1m; PI, 31m; IMiD, 37m; melphalan, 20.8m; steroids and others, 20m; p=0.3) and OS (ASCT, 66.9m; PI, 51.1m; IMiD, 51.3m; melphalan, 37.2m; steroids and others, 80.7m; p=0.9) from the start of the second line treatment; as depicted in Figure 1. Retreatment with a different drug class (as the first line treatment) at relapse significantly reduced the time to next treatment (32.3m vs 22 m; p= 0.01) as compared to same therapy; but did not have any impact on survival (30.8m vs 51.1m; p = 0.5); as presented in Figure 2. Conclusion This study provides novel information about outcomes of patients with systemic AL amyloidosis who relapse or progress after first line therapy which could be useful in planning salvage therapies and designing clinical trials. Retreatment with a different therapy at relapse improves time to next therapy but does not impact OS. Hence, we conclude that the patients can fare well post relapse/ progression and can benefit from various treatment regimens including retreatment with the same agent. Disclosures Dispenzieri: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; pfizer: Research Funding; Alnylam: Research Funding; Celgene: Research Funding. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Kumar:BMS: Consultancy; Kesios: Consultancy; Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding.

Abstract BACKGROUND Light-chain amyloidosis (AL) is the most common form of systemic amyloidosis, with an incidence of approximately 1 case/100,000 person-years. Clinically relevant data with regard to the very young (≤ 40 years) patients (pts) are scant. We present a case-control study of very young pts with AL seen at a single institution. METHODS We reviewed the medical records of all pts with AL who were consecutively evaluated at Mayo Clinic, Rochester, MN between 01/01/1995 and 12/31/2015. The clinical characteristics and survival outcomes of very young pts at the time of AL diagnosis (cases) were compared to a 2:1 matched cohort of pts (controls) with AL who were 65 years or older and matched by the time of diagnosis. Upfront autologous stem cell transplantation (ASCT) was defined as transplantation within 6 months of the diagnosis of AL. The Kaplan-Meier method was used to all time-to-event analyses. The average years of life lost was computed by subtracting the mean survival from diagnosis observed in the cohort from the mean survival expected in the population based on life-tables. RESULTS Of 3433 pts with AL, 50 (1.5%) pts were ≤ 40 years of age at diagnosis (cases). Fatigue, peripheral edema, dyspnea and bleeding were less common at presentation in cases compared to controls (table A). The cases were also more likely to have liver or GI involvement (OR= 3.45, 95% CI: 1.6-7.2). Unusual initial clinical features in the cases included unprovoked splenic rupture (2%) and erectile dysfunction (4%) observed 6-15 months prior to the diagnosis of AL in cases; no such features were observed in the control group. The median time between the onset of symptoms and definitive diagnosis was 0.4 years (95% CI: 0.3-0.7) for the cases and 1 year (95% CI: 0.8-1.2) for controls (p<0.0001). The ECOG performance score at diagnosis was ≥2 in 51% of cases compared to 78% of the controls (OR= 0.29, 95% CI: 0.14-0.63). The involvement by 3 or more organs at diagnosis was comparable [24 (48%) cases compared to 34 (34%) controls (p=0.11)]. Concomitant myelomatous (AL-CRAB) features were evident in 12% of each group and 27 (54%) cases and 37 (41%) controls had >10% BMPCs without active myeloma (AL-PCMM) (p=0.16). Monoclonal light chain involvement without involvement of heavy chain was seen in 23 cases (50%) and 31 controls (32%), (OR= 2.1, 95% CI: 1.04-4.37). The median follow-up was similar for cases and controls, [10.9 years (95% CI: 7.6-12) vs 9.9 years (95% CI 8-14)], respectively. The estimated average years-of-life lost was 8.6 years over 20 years of follow-up in cases, (Figure 1a). In cases, 1 and 10-year overall survival (OS) from diagnosis was 73% and 51%, respectively (median OS 12.7 years; 95% CI: 4.0-NR) while, in controls, 1 year and 10 year OS was 62% and 15% respectively (median OS 2.1 years; 95% CI (1.0-3.6), p<0.001), (Figure 1b). Cardiac involvement was associated with a worse OS in both cohorts, (cases: median OS was 3.2 years with cardiac involvement (95% CI: 0.6-8.7) vs NR (95% CI: 8.0-NR) in those without; p=0.003; controls: median OS was 1.1 years with cardiac involvement (95% CI: 0.53-1.6) vs 4.8 years (95% CI: 3.7-8.1) in those without; p=0.02. Thirty one of 47 (66%) cases were eligible and 20 of 79 (25%) controls were eligible for upfront ASCT. In cases, upfront ASCT was associated with a longer OS. Median OS was NR (95% CI: NR-NR) in pts who underwent upfront ASCT (n=25) vs 4.0 years (95% CI: 0.5-8) in pts who did not, p≤0.0001. For controls, the median OS was 9 years (95% CI: 0.5-11) for pts who underwent upfront ASCT (n=7) vs 1.6 years (95% CI: 1.0-2.8) for pts who did not (n=93), p=0.26. In cases, six (12%) pts underwent solid organ transplantation (kidney 5, heart 1) and none in the control arm. CONCLUSIONS AL amyloidosis is infrequently encountered at the age of ≤40 years, but the loss of productive years of life and the disease burden are substantial in this cohort. A substantial delay in diagnosis from the onset of symptoms was noted in our study in the control population. Cardiac involvement remains a primary determinant of prognosis irrespective to age. Although over one-half of young pts are alive 10 years after the diagnosis (contrast ≈15% ≥ 65 years), early mortality remains substantial irrespective of age. An ASCT-based approach is associated with superior outcome in the young. A greater proportion of the young pts is fitter and ASCT-eligible at diagnosis, and should therefore be offered this approach. Disclosures Dispenzieri: Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding. Kumar:Array BioPharma: Consultancy, Research Funding; Kesios: Consultancy; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding.

Abstract Introduction: IgM-secreting myeloma is rare, encompassing about 1% of all the myeloma cases. Given its rarity, the characteristics and survival of these patients have not been extensively studied. Therefore, we carried out a multicenter retrospective study in patients with IgM myeloma. Methods: The study protocol was reviewed and approved by the Institutional Review Board of each participating institution. Clinical data were gathered and included age, sex, hemoglobin, calcium, LDH, estimated glomerular filtration rate (GFR), presence of lytic bone lesions, International Staging System score, cytogenetic abnormalities, final outcome and overall survival (OS) time. OS was defined as the time in months from diagnosis to last follow-up or death. The Chi-square and the rank-sum tests were used to compare categorical and continuous variables, respectively. The Kaplan-Meier method was used to estimate OS and the log-rank waas used to compare groups. The Cox proportional-hazard regression method was used to fit univariate and multivariate survival models, reported as hazard ratio (HR) with 95% confidence intervals (CI). All reported p-values are two-sided, and were considered significant if less than 0.05. Results: A total of 159 patients with IgM myeloma from 20 centers from Europe, USA and Latin America were included in this analysis. Patients were diagnosed between 1996 and 2015. The median age at diagnosis was 65 years (range 37-86 years) with a male predominance (68%). The median serum IgM level was 2510 mg/dl (range 27-12,100 mg/dl) with 25% of patients having a serum IgM within normal limits but an IgM monoclonal spike detectable in serum electrophoresis. Hemoglobin levels <10 g/dl were seen in 49 patients (32%), serum calcium was elevated in 24 (16%), estimated GFR of 60 ml/min or less in 56 (37%), lytic lesions were detected in 86 (58%), and serum LDH was elevated in 28 (24%). ISS scores of 1, 2 and 3 were seen in 53 (36%), 63 (43%) and 31 (21%) of patients, respectively. Although immunohistochemistry and/or flow cytometry data were limited, CD20 expression was seen in 15/26 (58%) and cyclin D1 in 10/15 (67%) patients. The most common cytogenetic abnormalities were t(11;14) in 26/67 (39%), del13q in 25/76 (33%) and del17p in 6/76 (8%) patients. 149 patients (94%) received at least one line of systemic therapy for myeloma of which 13 (9%) received rituximab as part of initial therapy. After a median follow-up of 47 months, 74 patients (47%) have died. The median OS was 62 months (95% CI 51-79 months). Cause of death was known in 38 patients, and the most common was myeloma progression (74%). IN the univariate analysis, prognostic factors associated with a worse OS were age (HR 1.03, 95% CI 1.01-1.06; p=0.01) and ISS score (ISS 2: HR 1.43, 95% CI 0.83-2.48; p=0.2, and ISS 3: HR 3.03, 95% CI 1.54-5.98; p=0.001, using ISS 1 as reference group), while male sex was associated with a better OS (HR 0.56, 95% CI 0.34-0.90; p=0.02). Hemoglobin, calcium, estimated GFR and lytic lesions were not associated with OS. In the multivariate analysis, male sex was associated with a better OS (HR 0.57, 95% CI 0.35-0.95; p=0.03) and ISS with worse OS (ISS 2: HR 1.57, 95% CI 0.89-2.74; p=0.12, and ISS 3: HR 2.76, 95% CI 1.38-5.55; p=0.004, using ISS 1 as reference group). Conclusion: Patients with IgM myeloma apparently present with similar clinical characteristics as patients with non-IgM myeloma. Pathologically, CD20 and cyclin D1 expression is common. The most common cytogenetic abnormalities identified were t(11;14) and del13q. Survival does not appear shorter than non-IgM myeloma patients, and the ISS appears to have similar prognostic value. Disclosures Castillo: Millennium: Research Funding; Janssen: Honoraria; Otsuka: Consultancy; Biogen: Consultancy; Abbvie: Research Funding; Pharmacyclics: Honoraria. Ghobrial:Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Noxxon: Honoraria; Amgen: Honoraria. Hájek:Celgene: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; BMS: Honoraria; Takeda: Consultancy. Hungria:International Myeloma Foundation Latin America: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Consultancy; Roche: Consultancy; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding, Speakers Bureau. Reagan:Alexion: Honoraria; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees. Spicka:Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria. Gertz:Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Research Funding; Novartis: Research Funding; Prothena Therapeutics: Research Funding; Ionis: Research Funding; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria; Annexon Biosciences: Research Funding.

Abstract Background: The presence of circulating plasma cells (CPCs) is associated with an adverse prognosis in multiple myeloma along the entire spectrum of disease. However, the impact of CPCs prior to autologous stem cell transplantation (ASCT) has not been defined in the era of novel agents. The objective of this study is to assess the impact of the presence and number of CPCs before transplant using 6-color multiparameter flow cytometry (MFC). We also explored the additional prognostic implications of CPCs over the current paradigm for risk stratification at transplant, including high-risk (HR) cytogenetics and disease status at transplant by the IMWG criteria. Methods: A total of 1113 consecutive patients transplanted between 2007 and 2015 in Mayo Clinic were included in the study. Flow-cytometry of peripheral blood to identify clonal CPCs is routinely performed in all patients before ASCT in Mayo Clinic, Rochester. The mononuclear cells from peripheral blood samples are isolated by Ficoll gradient and subsequently stained with antibodies to CD19, CD38, CD45, CD138 and cytoplasmic kappa (κ) and lambda (λ) immunoglobulin light chains. Clonality is assessed by light chain restriction (κ:λ expression ratio of 4:1 [κ restricted] or <1:2 [λ restricted]). The target for collection is >150,000 cellular events. For samples where less than 150,000 clonal events are examined, the number of final clonal events is adjusted to 150,000 events. HR cytogenetics by fluorescence in situ hybridization (FISH) on bone marrow (BM) plasma cells was defined by one of the following abnormalities: t(4;14), del(17p), t(14;16), t(14;20) or +1q, detected at any time point from diagnosis to transplant. Patients who had insufficient plasma cells for FISH analysis in BM specimens were not included in the denominator to calculate the percentage of patients with HR cytogenetics. The primary end-points of this study were post-transplant response, PFS and OS. Result: CPCs were detected in 238 out of 1113 (21.4%) patients, with the median number of CPCs being 82 (range, 1-102381) per 150,000 events. The median age of patients at transplant was 62 years. A total of 1097 (99%) patients had received novel agent based induction therapy with PIs and IMiDs, including 458 (41%) patients who had received both PIs and IMiDs. 401 (36%) patients had received post-transplant maintenance or consolidation therapy. The frequency of t(4;14) in BMPCs was significantly higher in patients with CPCs compared to those without [15.2 vs 7.0% for t(4;14); P<0.001]. The median follow-up from transplant for survivors was 45 months. The 5-year OS rate in patients with and without CPCs was 34% (95% CI, 27-42) and 70% (95% CI, 66-74) respectively (P<0.001). After exploring several cut-offs for the number of CPCs per 150,000 events, we chose a simple pre-transplant risk stratification model: No CPCs (n=874; 78.5%), 0<CPCs≤400 (n=188; 16.9%) and CPCs>400 (n=51; 4.6%). The number of patients achieving stringent complete response post-transplant in groups with no CPCs, 0<CPCs≤400 and CPCs>400 was 310 (36%), 31 (16%) and 3 (6%) respectively (P<0.001). The median PFS in the 3 groups was 27 months (95% CI, 25-30), 15 months (95% CI, 13-18) and 6 months (95% CI, 4-10) respectively (P<0.001) and 5-year OS rates were 70% (95% CI, 66-74), 42% (95% CI, 34-51) and 12% (95% CI, 5-26) respectively (P<0.001). Kaplan-Meier curves for PFS and OS are depicted in Figure I (A and B). In a multivariate model (Table I), the groups with 0<CPCs≤400 and CPCs>400 had an increased risk of death, independent of the presence of HR cytogenetics and disease status at transplant. Conclusion: Our study shows the strong negative prognostic impact of CPCs prior to transplant on post-transplant response and survival in MM in the era of novel agents. The proposed risk stratification model can be easily employed with simple equipment and should be routinely incorporated in the pre-transplant workup. Detailed epigenomic, genomic and transcriptomic analysis of CPCs is urgently needed to uncover the biological basis of resistance to both high-dose cytotoxic therapy and novel agents and identify potential avenues of targeted therapy against CPCs. Disclosures Kumar: Onyx: Consultancy, Research Funding; Kesios: Consultancy; Celgene: Consultancy, Research Funding; Glycomimetics: Consultancy; AbbVie: Research Funding; BMS: Consultancy; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding. Dispenzieri:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Jannsen: Research Funding. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Gertz:Sandoz Inc: Honoraria; NCI Frederick: Honoraria; Celgene: Honoraria; Alnylam Pharmaceuticals: Research Funding; GSK: Honoraria; Novartis: Research Funding; Research to Practice: Honoraria, Speakers Bureau; Med Learning Group: Honoraria, Speakers Bureau; Ionis: Research Funding; Prothena Therapeutics: Research Funding; Annexon Biosciences: Research Funding.

Abstract Background: In the pivotal FIRST trial, at the pre-specified planned analysis for progression-free survival (PFS), treatment (Tx) with lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous) improved outcomes for transplant-ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM) compared with melphalan, prednisone, and thalidomide (MPT), as well as Rd for 18 cycles (Rd18; Benboubker, NEJM 2014). Rd18 was added as a third arm to investigate whether Rd continuous Tx would control progression of NDMM longer than Rd18. Here, we present the final analysis of the overall survival (OS) data from the trial. Methods: Transplant-ineligible pts with NDMM were randomized 1:1:1 to Rd continuous (with lenalidomide given on days 1-21 of 28-day cycles until disease progression), Rd18 (with lenalidomide given on days 1-21 of eighteen 28-day cycles), or MPT (twelve 42-day cycles); both Rd18 and MPT were 72 weeks in duration. The primary endpoint was PFS and the key secondary endpoint was OS; the primary comparison was Rd continuous vs MPT. Other secondary endpoints included time to second therapy (TTST) and safety. Time from randomization to second progression or death (PFS2) was an exploratory analysis. Response assessment used for PFS and PFS2 analysis was determined by investigators based on International Myeloma Working Group criteria. Results: At the time of cutoff for the final OS analysis (January 21, 2016), 52 of the 535 pts in the Rd continuous arm and none of the pts in the Rd18 (n = 541) and MPT (n = 547) arms continued to receive Tx. The median follow-up for surviving pts was 67.0 months (range, 0-86.8 months). In the pre-specified final OS analysis for the primary comparison, a statistically significant advantage in OS was shown with Rd continuous over MPT (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67-0.92; P = .00234; Table). OS for Rd continuous vs Rd18 was evaluated (HR, 1.02; 95% CI, 0.86-1.20). In this updated analysis, a PFS advantage continued to be seen for Rd continuous vs MPT (HR, 0.69; 95% CI, 0.59-0.79; P < .00001) and vs Rd18 (HR, 0.70; 95% CI, 0.60-0.81). Median TTST was longer for Rd continuous vs MPT (HR, 0.63; 95% CI, 0.54-0.73; Table). More pts in the Rd18 and MPT arms started second-line therapy (n = 377 and 381, respectively) compared with the Rd continuous arm (n = 299). Pts received a variety of Tx at progression, with bortezomib-based regimens the most common in the Rd continuous (n = 179; 59.9%), Rd18 (n = 208; 55.2%), and MPT (n = 170; 44.6%) arms. Pts who received bortezomib after Rd continuous or Rd18 had better outcomes than those who received it after MPT. PFS2 for Rd continuous was improved vs MPT (HR, 0.74; 95% CI, 0.64-0.85). Grade 3/4 adverse events (AEs) occurred in 86.3%, 80.2%, and 88.7% of the 532, 540, and 541 pts in the safety populations of the Rd continuous, Rd18, and MPT arms, respectively; the most common grade 3/4 AEs were neutropenia (29.5%, 26.5%, and 44.9%) and infections (31.6%, 21.9%, and 17.2%), and no new safety signals were seen compared with earlier analyses. Study discontinuation was most commonly due to disease progression and was less common in the Rd continuous vs Rd18 and MPT arms (50.7% vs 66.9% and 61.6%, respectively). Discontinuation due to AEs was similar across the Rd continuous, Rd18, and MPT arms (12.0%, 13.1%, and 13.9%). Solid tumor second primary malignancies (SPMs) occurred in 6.0, 6.9%, and 5.9% of pts, and hematologic malignancies occurred in 0.8%, 0.4%, and 2.6% of pts in the Rd continuous, Rd18, and MPT arms, respectively. Conclusions: Rd continuous significantly prolonged PFS and OS, and improved other secondary endpoints compared with MPT in transplant-ineligible pts with NDMM. Rd continuous also showed a PFS benefit compared with Rd18, delaying the time to next Tx. PFS2 outcomes suggest that Rd does not induce resistant relapses. Few hematologic malignancies occurred in the Rd arms, and the incidence of SPMs was similar between Rd continuous and Rd18. Rd continuous remains a standard of care for transplant-ineligible pts with NDMM. Disclosures Facon: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel and expense, Speakers Bureau. Dimopoulos:Genesis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Celgene: Research Funding. Belch:Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria. Weisel:BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Ludwig:Janssen: Speakers Bureau; BMS: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau. Bahlis:BMS: Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria. Delforge:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Cavenagh:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Geraldes:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Oriol:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. De La Rubia:Amgen, Bristol, Celgene, Janssen: Consultancy, Speakers Bureau. White:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria. Attal:janssen: Consultancy, Research Funding; amgen: Consultancy, Research Funding; celgene: Consultancy, Research Funding; sanofi: Consultancy. Ervin-Haynes:Celgene: Employment, Equity Ownership. Chen:Celgene: Employment, Equity Ownership. Houck:Celgene: Employment. Hulin:celgene: Honoraria; Bristol: Honoraria; Janssen: Honoraria; Amgen: Honoraria; takeda: Honoraria. Benboubker:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Melphalan based chemotherapy is commonly used for treatment of light chain amyloidosis (AL). Patients with AL often receive chemotherapy before autologous stem cell transplantation (ASCT) if they have high plasma cell burden or while awaiting ASCT. Melphalan is an alkylator and can affect bone marrow stem cells. Limited data is available on the effect of melphalan on stem cell mobilization in patients with amyloidosis. This study aims to identify the impact of melphalan therapy on collection of stem cells and ASCT in amyloidosis. Methods: All patients with AL seen at our institution within 90 days of diagnosis over a 10-year period (2006 to 2015) who underwent stem cell harvest were identified from an institutional database. Data pertaining to demographics, diagnosis, treatment, stem cell harvest and ASCT was extracted from the electronic medical records. Analysis was carried out by chi-square and Fisher's exact test for categorical variables and Kruskal-Wallis and Wilcoxon rank sum test for ordinal and continuous variables. Results: Three hundred and seventy two patients with AL who met the inclusion criteria were identified, of whom 10% (n=38) received melphalan based chemotherapy prior to harvesting, 28.5% (n=106) received non-melphalan based chemotherapy and 61.3% (n=228) received no chemotherapy prior to stem cell collection. Bortezomib based regimens were the most common (78%, n=83) non-melphalan based chemotherapy. All three groups were similar in terms of median age at diagnosis (59.1 years), median age at collection (59.4 years), gender distribution (59% males, n=221) and type of involved free light chain (FLC), with lambda being more common (72.2%, n=268). Patients who received melphalan-based chemotherapy had more cardiac (73.8% vs. 45.2% vs. 46.4%, p=0.005) and renal (84.2% vs. 50.9% vs. 68%, p=0.0002) involvement compared to other chemotherapy and no chemotherapy groups, respectively. In contrast, patients who received non-melphalan based chemotherapy had higher plasma cell burden (15% vs. 6% vs. 10%, p< 0.0001) and greater difference between involved and uninvolved FLC (44.2 mg/dL vs. 13.3 mg/dL vs. 13.2 mg/dL, p< 0.0001) compared to melphalan and no chemotherapy, respectively. Median duration of melphalan based chemotherapy was shorter at 54 days (34.5 to 79.5) or estimated 2 cycles compared to 101 days (60 to 135.5) or estimated 4 cycles (p=0.0019). Despite shorter duration of chemotherapy, total stem cell yield (million CD34/kg) was lower in patients who received melphalan based chemotherapy (5.54) compared to non-melphalan based chemotherapy (8.14) or no prior chemotherapy (7.94); p<0.0001. Similarly, day one stem cell yield (million CD34/kg) was the lowest in the melphalan group (2.71), followed by other chemotherapy group (3.63) and highest in no chemotherapy group (4.84); p<0.0001. This trend persisted for average stem cell yield per collection as illustrated in table 1. Filgrastrim (GCSF) alone was the most common mobilizing agent. However, patients with any chemotherapy prior to harvesting had higher utilization of plerixafor; 26.3% (n=10) in the melphalan group and 39.6% (n=42) in the non-melphalan group compared to 11.6% (n=27) if no prior chemotherapy (p<0.0001). However, no statistically significant difference was seen for melphalan vs. non-melphalan chemotherapy groups (p=0.44). In patients who underwent ASCT (85%, n=315), median stem cell dose (million CD34/kg) was different in the melphalan (3.66), non-melphalan (4.2) and no chemotherapy groups (4.44) (p=0.047), though the difference was not statistically significant amongst the 2 chemotherapy groups (p=0.34). There was also no difference in time to engraftment (table 1). Conclusions: Melphalan based chemotherapy, even if used for a short duration of time, significantly decreases both total stem cell yield and the yield on day one. It therefore has the potential to add to resource utilization with more collections needed. As much as possible, limited cycles of melphalan based chemotherapy or non-melphalan based treatment should be utilized in patients who are transplant eligible. Disclosures Dispenzieri: 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; Jannsen: Research Funding; Celgene: Research Funding; pfizer: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Kumar:Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Glycomimetics: Consultancy; BMS: Consultancy; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Kesios: Consultancy.