Gertz, Morie A.

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 Introduction:In amyloid light chain (AL) amyloidosis, the most common form of systemic amyloidosis, misfolded light chain (LC) or a fragment of an LC produced by clonal plasma cells accumulates in tissue, resulting in the dysfunction of vital organs and systems (eg, heart, kidneys, nervous system). Current therapies used to treat AL amyloidosis limit LC production but do not directly target deposits underlying multiorgan failure. Approximately 75% of patients do not achieve organ responses and have persistent organ dysfunction. Amyloid-directed therapies may stabilize and potentially reverse organ damage by specifically targeting existing LC aggregates. NEOD001, a monoclonal antibody, targets misfolded LC and is thought to neutralize circulating LC aggregates and to clear insoluble deposits. We have previously reported that monthly infusions of NEOD001 were safe and well tolerated. In addition, NEOD001 was associated with renal and cardiac responses. Here we analyzed the association between organ response and depth and time since last plasma cell-directed (PCD) treatment in the entire cohort of 69 patients enrolled in both the dose-escalation and the expansion phases of the phase 1/2 study. Methods: Inclusion criteria for this trial were that patients complete ≥1 PCD treatment before enrollment, attain partial hematologic response (HR) or better to any previous therapy, and have persistent organ dysfunction. NEOD001 was administered intravenously every 28 days. During the dose-escalation phase, 27 patients received NEOD001 at 0.5, 1, 2, 4, 8, 16, or 24 mg/kg in a 3+3 study design. An additional 42 patients with renal, cardiac, or nerve involvement were enrolled and treated (24 mg/kg) in the expansion phase. We assessed cardiac and renal responses based on consensus criteria and neuropathy responses using the Neuropathy Impairment Score-Lower Limb (NIS-LL). For this analysis, we focused on the relationship between organ response after treatment with NEOD001 to the time since last or best HR and the depth of best and last HR. Results: A total of 69 patients were enrolled, 27 in the dose-escalation and 42 in the expansion cohorts. The entire population included 36 cardiac-evaluable patients, 35 renal-evaluable patients, and 11 patients evaluated for peripheral neuropathy; 39% were women, and the median age was 60 years. Time since diagnosis was 2.8 (0.4-12.8; median, range) years, and 45% of patients had undergone ≥3 previous PCD regimens. Of the patients evaluable for organ response, best response rates indicating organ response were observed in 53% of cardiac-evaluable patients (n = 19/36) and 63% of renal-evaluable patients (n = 22/35). NIS-LL scores indicated that 82% (n = 9/11) of patients met criteria for a peripheral neuropathy response to NEOD001. Cardiac and renal response rates for NEOD001-treated patients could not be attributed to previous PCD treatment regimens. For example, 37% of the NEOD001 cardiac responders and 35% of nonresponders received cyclophosphamide-bortezomib-dexamethasone. Similarly, for NEOD001 renal responders vs nonresponders, 27% vs 25% were treated with autologous stem cell transplantation and 27% vs 31% were treated with bortezomib-dexamethasone. There was no relationship between NEOD001 cardiac, renal, or peripheral nerve organ response and time since last chemotherapy, time since last or best HR, or depth of last or best HR. Finally, an equivalent percentage of evaluable patients experienced renal or cardiac response regardless of whether they had received their most recent PCD treatment ≤6 months or >6 months before NEOD001 initiation. The median time since last PCD treatment to the start of NEOD001 intervention for all patients was 6.5 (range, 0.6-85.8) months and the median time to first cardiac response after NEOD001 treatment for all cardiac responders was 2 months. NEOD001 treatment was safe and well tolerated. Conclusions: Patients treated with monthly NEOD001 infusions had high organ response rates that were independent of time since previous chemotherapy, depth of hematologic response, or predominant type of PCD treatment. Ongoing studies of NEOD001 include VITAL (phase 3 in patients with newly diagnosed AL amyloidosis) and PRONTO (phase 2b in previously treated AL amyloidosis patients with persistent cardiac dysfunction). Disclosures Liedtke: Gilead: Research Funding; Prothena: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Research Funding. Comenzo:Takeda: Consultancy, Research Funding; Karyopharm: Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding. Landau:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx/Amgen: Research Funding; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Sanchorawala:Prothena: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Weiss:Prothena: Other: Travel, accommodations, Research Funding; GlaxoSmithKline: Consultancy; Millennium: Consultancy, Other: Travel, accommodations; Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy. Zonder:Prothena: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Array Biopharma: Consultancy. Walling:Corcept: Consultancy; Stealth: Consultancy; Codexis: Consultancy; Exelixis: Consultancy; Newgen: Consultancy; Mateon (was Oxigene): Consultancy; Apex: Consultancy; Aduro: Consultancy; Prothena: Consultancy; Upsher Smith: Consultancy, Patents & Royalties; KaloBios: Consultancy; NuMedii: Consultancy; Pharm-Olam: Consultancy; Crown Bioscience: Consultancy; BioMarin: Equity Ownership; Amgen: Equity Ownership, Patents & Royalties. Kinney:Prothena: Employment, Equity Ownership, Other: Leadership. Koller:Prothena: Employment, Equity Ownership, Other: Travel, accommodations. Schenk:Prothena: Employment, Equity Ownership, Other: Leadership. Guthrie:Prothena: Employment, Equity Ownership, Other: Leadership. Liu:Prothena: Employment, Equity Ownership; Weston Brain Institute: Honoraria. Gertz:Annexon Biosciences: Research Funding; Ionis: Research Funding; Prothena Therapeutics: Research Funding; Novartis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Research to Practice: Honoraria, Speakers Bureau; Med Learning Group: Honoraria, Speakers Bureau; Celgene: Honoraria; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria.

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 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.

Abstract Introduction: Chemotherapeutic options for patients with systemic light chain amyloidosis (AL) who are not transplant candidates include bortezomib based therapy, melphalan with dexamethasone, and less commonly, immunomodulatory drugs (IMiDs). However, prospective clinical trial data comparing these regimens are lacking. This study aims to compare efficacy of bortezomib-based treatment to other therapies. Methods: All patients with AL seen within 90 days of diagnosis at our institution over a 10-year period (2006 to 2015) who did not undergo a stem cell transplant were identified from our institutional database. Data pertaining to demographics, diagnosis, treatment and follow-up were extracted from electronic medical records. Analyses were 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. Progression free survival (PFS) is defined as time to death, progression requiring treatment change or relapse requiring re-institution of treatment. PFS and overall survival was analyzed via the Kaplan-Meier method. Results: Seven hundred and twenty five patients met the inclusion criteria, of which 38% (n=275) received bortezomib containing regimens and 62% (n=450) received non-bortezomib based therapies. Bortezomib was used with dexamethasone in 24% (n=67) patients; and with other drugs, most commonly cyclophosphamide, in 76% (n=208) patients. Non-bortezomib treatment regimens included melphalan-based treatment in the majority (92%, n=414) followed by IMiDs with steroids and other drugs (8%, n=36). Baseline variables similar in both groups and their distribution in the entire cohort was as follows: gender distribution (63.3% males, n=459), median age of diagnosis (66.3 years, range 32.2 to 93.6), type of involved free light chain (FLC) (lambda 73%, n=523) and median plasma cell burden (10%, range 0 to 91). Median difference between the involved and uninvolved free light chain (dFLC) was higher in the bortezomib group (29 mg/dL vs. 23 mg/dL; p=0.017). There was no difference in organ involvement. In the bortezomib group, organ involvement was as follows: cardiac (81%, n=219), renal (62%, n=168) and hepatic (18%, n=48). In the non-bortezomib group, the rates of organ involvement were similar: cardiac (78%, n=346), renal (57%, n=247) and hepatic (19%, n=85). Median duration of first line treatment was similar in the 2 groups, with 178 days in the bortezomib cohort and 187 days in the non-bortezomib cohort. Response rates are illustrated in Table 1. Rates of very good partial response (VGPR) or better response were higher in the bortezomib group (64 % vs. 54%, p=0.0002). Patients treated with bortezomib achieved VGPR faster with higher rates of VGPR or better response seen at 3 months (48% vs. 27%, p <0.0001) and 6 months (57% vs. 34%, p < 0.0001) after initiation of therapy compared to non-bortezomib treatment. Rates of organ response were similar amongst the 2 groups as shown in Table 1. However, median time taken to achieve a cardiac response was shorter in the bortezomib group (23 vs. 38 weeks, p=0.0026). In a multivariable model, bortezomib-based treatment and dFLC at diagnosis were predictors of VGPR. Relapse or progression requiring change in therapy was more common in patients treated with non-bortezomib based therapy (38%, n=143/372) compared to bortezomib-based treatment (28%, n=67/236); p =0.01). However, no difference in overall survival was observed in patients treated with bortezomib (2.2 years; 95% confidence interval (CI): 1.7 to 3.3) vs. non-bortezomib therapies (1.7 years; 95% CI: 1.3 to 2.5). Conclusion: Treatment with bortezomib-based regimens results in a deeper response including higher rates of early VGPR at 3 and 6 months from starting therapy. Moreover, these patients achieve cardiac response faster and have lower rate of relapse. However, no difference in overall survival was seen, which may be explained by subsequent use of bortezomib-based therapies in this population. Disclosures Dispenzieri: Celgene: Research Funding; Alnylam: Research Funding; pfizer: Research Funding; 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; Prothena: Membership on an entity's Board of Directors or advisory committees. Kumar:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Array BioPharma: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Kesios: Consultancy; Glycomimetics: Consultancy.

Abstract Background: Autologous stem cell transplantation is an integral part of myeloma therapy for patients who are able to undergo the treatment. While high dose melphalan has remained the typical conditioning regimen for ASCT in MM, recently there have been efforts to enhance the conditioning therapy by adding newer drugs to melphalan. Addition of bortezomib as well as carfilzomib have been attempted in phase 2 trials. Previous studies have shown that the combination of melphalan and total body irradiation (TBI) is an effective conditioning regimen. Pre-clinical studies have shown that bortezomib can sensitize MM cells to radiation, and based on this finding, we designed a clinical trial to examine the feasibility of combining low dose TBI with a combination of melphalan and bortezomib. Patients and Methods: The primary goal of the phase 1 study was to determine the maximally tolerated dose (MTD) of bortezomib that can be added to high dose melphalan and low dose TBI as part of conditioning chemotherapy in patients undergoing an ASCT for MM. The secondary goals were to examine the toxicities associated with addition of bortezomib to high dose melphalan and TBI in patients with MM and to determine the progression free rate at 1 and 2 years. Patients eligible to receive full dose melphalan conditioning regimen for ASCT were included as long as they had no more than 2 prior regimens and had not received a prior transplant. An accelerated design that was later converted to a standard 3+3 cohort design was used for dose escalation. Three patients were treated at a given dose level combination and observed for at least 36 days to assess toxicity. Melphalan 80 mg/m2 was given days -4, -3, with bortezomib at increasing doses given on day -5, -2 along with TBI of 200 cGY given on the same days of bortezomib, timed after bortezomib administration. Stem cells were infused day 0. Results: Eleven patients were enrolled; 6 were males, and the median age was 60 years. Median time from diagnosis was 5.4 months (range 3.4-7.0). Four dose levels were explored with increasing doses of bortezomib (0.7 mg/m2 to 1.6 mg/m2). No dose limiting toxicities were observed. The dose levels and the best response after ASCT are as shown in the Table. The overall response rate was 100%, including 7/11 with a CR or sCR. With a median follow-up of 12.5 months, two patients have progressed; median OS was not reached. Toxicity was mostly hematologic, with other AEs being grade 3 or less and attributable to the conditioning therapy. All patients engrafted their counts adequately. Conclusion: The combination of melphalan, bortezomib, and low dose TBI is a safe conditioning regimen in patients with MM with good efficacy. The regimen should be further examined in the phase 2 setting. Table Table. Disclosures Kapoor: Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Kumar:Noxxon: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Research Funding; Janssen: Research Funding; Skyline: Consultancy, Honoraria.

Abstract AL amyloidosis is a systemic disease with profound effects on organ function. However, despite the broad array of disease manifestations, the effect of AL amyloidosis on thyroid function is underreported. We explored the frequency of thyroid function abnormalities in 961 untreated AL amyloidosis patients seen in our clinic between 8/2005-8/2015, with emphasis on association with other organ involvement and tumor burden. Thyroid function was assessed using the thyroid stimulating hormone assay (TSH, normal range 0.3-5 mIU/L). If TSH was abnormal, measurement of free thyroxine (FT4) and thyroid peroxidase (TPO) antibodies was routinely performed. Patients' median age was 62 [interquartile range (IQR) 56-69], 62% were male (Table). The median number of organs involved was 2 (IQR 1-3), 29% of patients had more than 2 involved organs. Seventy-seven percent of patients had cardiac involvement, 61% renal, 23% peripheral/autonomic neuropathy, 19% hepatic and 15% gastro-intestinal (GI) involvement. The median difference between involved and uninvolved light chains (dFLC) was 24.4 [interquartile range 10.6-65.2 mg/dL]. The median TSH was 3 mIU/L (range 0.1-50.1); 22% had levels above the normal range and 8% of patients had TSH greater than 7.5 mIU/L. Baseline characteristics by TSH ≤5 mIU/L and TSH >5 mIU/L subgroups can be viewed in Table. Patients with renal or hepatic involvement had higher TSH values compared to no renal or no hepatic involvement (3.2 vs 2.6 and 2.8 vs 3.8, respectively; P<0.001 for both comparisons). There was a borderline significance for higher TSH in patients with >2 organ involvement compared to 1-2 affected organs (3.3 vs 2.8; P=0.05), with a strong trend for higher TSH for dFLC ≥18 mg/dL compared to dFLC<18 mg/dL (P=0.07). In patients with renal involvement, presence of proteinuria > 2 grams/day was associated with a higher likelihood of TSH >7.5 mIU/L (13% vs 5%; P=0.003). Free thyroxine (FT4) measurements were performed in 214 (22%) of patients with a median value of 1.1 ng/dL(range 0.3-72), 6% had levels below the lower limit (0.8 ng/dL). One-hundred and sixty five patients (17%) were screened for TPO antibodies, of which 16% (n=27) had an elevated titer. L-thyroxine (median dose 100 mcg/d, range 25-350 mcg/d) was already prescribed to 157 of the patients (16%) at their first visit, but duration of treatment prior to AL amyloidosis diagnosis could not be determined. Seventeen patients (1.5%) were prescribed amiodarone (median dose 200mg/d, range 100-400 mg/d), and although numbers were low, patients with amiodarone treatment had a TSH twice as high as patients without this treatment (6 vs 2.9 mIU/L, P=0.006). In conclusion, thyroid function abnormalities are frequent at the time of AL amyloidosis diagnosis and are influenced by type of organ involvement as well as disease burden assessed by dFLC and/or number of affected organs. Amiodarone, although infrequently used in this disease, can cause a profound disturbance in thyroid function among these patients. Disclosures Dispenzieri: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; pfizer: Research Funding; Celgene: Research Funding; Alnylam: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding. Kumar:AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; Glycomimetics: Consultancy; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Kesios: Consultancy; BMS: Consultancy; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Abstract Background Despite significant progress, MM remains an incurable disease. Synergistic activity of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) has been established in preclinical and clinical studies. Data with respect to combination of newer IMiDs and PIs are scant. Recently, a small study (n=32) found the novel therapeutic regimen consisting of carfilzomib, pomalidomide and dexamethasone (KPd) to be well-tolerated and active in RRMM patients, but only 7% of patients in that study had ECOG > 1. KPd has not been extensively studied outside of clinical trials. Therefore, we evaluated real-world outcomes of KPd in RRMM patients seen in our routine dysproteinemia practice. Methods Records of MM patients consecutively seen at Mayo Clinic, Rochester from 01/ 2013 to 05/ 2016 were reviewed. Forty-five MM patients who received KPD in the R/R setting were identified and included in the analysis. The international uniform response criteria (IMWG 2006) were used to assess response rates. Additionally, minor response (MR) was assessed to determine the clinical benefit rate (CBR or ≥MR). Toxicity was evaluated using the Common Terminology Criteria for Adverse Events version 4. Duration of response was calculated for patients who have achieved a PR or greater response from time of first response to progression of disease. The time-to-event analyses were performed from the time of initiation of KPd therapy using the Kaplan-Meier method. All but one patient received K at 20/27 mg/m2 (days 1, 2, 8, 9 15, 16) dosing, P at 2 mg or 4 mg (day 1-21), and dexamethasone at 20 or 40 mg (day 1, 8, 15, 22), with 28-day cycles. Results The median age at KPd initiation was 65 years (range 29-75), 25 (56%) patients were males. 71% had an ECOG performance score of 0 to 1, and 29% had an ECOG >1. Forty percent were mSMART standard risk, while 60% were intermediate to high risk. Median time from MM diagnosis to KPd was 44 months (range 6-188), and the median number of prior treatment lines was 4 (range 1-14). Three (7%) patients were quadruple refractory to bortezomib (V), lenalidomide (R), P, and K. Ten (23%) were triple refractory to V, R, and P or K. Twenty seven (60%) were dual refractory to V and R. Table 1 shows prior treatment agents and refractoriness. The median duration of treatment with KPd was 2 months (range 0.3-16.4). KPd was used as a bridge to autologous stem cell transplant (ASCT) in 5 patients. One patient discontinued therapy due to toxicity (infection, weakness). Response was evaluable in 44 patients. The median time to first response was 1.4 months (range 0.5-6). Overall response rate (ORR) was 36%, [stringent complete response (sCR) in 1 (2%) patient, complete response (CR) in 3 (7%) patients, very good partial response (VGPR) in 2 (5%) patients, partial response (PR) in 10 (22%) patients]. Minimal response (MR) was seen in 3 (7%), leading to a CBR of 43%, while an additional 10 (23%) patients had stable disease (SD). Progressive disease (PD) was noted in 15 (34%) patients. At the time of analysis 20 (43%) patients were deceased, all from PD. The median follow up from initiation of KPd was 16.3 months (95% CI: 8.6-19.4). The median overall survival (OS) from KPd was 16.1 months (95% CI: 10.6-20.4). Median OS for dual refractory was 15.6 (95% CI: 10.6-20.5). Median OS for triple/quadruple refractory was similar to those with lesser degree of refractoriness [19.1 (95% CI: 0.92 - 27.1) months vs 13.6 (95% CI: 8.9-20.5), p= 0.82]. The median progression-free survival (PFS) was 3.3 months (95% CI: 1.9-6.4) and the median time-to-next therapy (TTNT) was 3.5 months (95% CI: 2.2-6.7). The media duration of response was 12.9 months (95% CI: 2.5-19.6). The median OS from KPd for patients who achieved at least a PR was 20.4 months (95% CI: 13.6-NR), compared to 11 months (95% CI: 8.3-NR) for others (p=0.05). Grade ≥3 hematologic toxicity was seen in 19 (42%) of evaluable patients [grade ≥3 neutropenia (29%), thrombocytopenia (31%) and anemia (22%)]. The most common non-hematologic adverse events were fatigue (38%), infections (31%), diarrhea (12%) and dyspnea (12%). Of the 4 (9%) patients who developed venous thromboembolism (VTE), two were on aspirin prophylaxis while the other two were not receiving any VTE prophylaxis. Conclusions KPd shows activity in RRMM patients although the short PFS reflects the challenges encountered with managing heavily pretreated and often less fit patients in the real world setting outside of clinical trials. Disclosures Dispenzieri: Prothena: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; pfizer: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Kumar:BMS: Consultancy; Kesios: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Glycomimetics: Consultancy; AbbVie: Research Funding; Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Kapoor:Amgen: Research Funding; Celgene: Research Funding; Takeda: Research Funding.