Abstract: Autologous hematopoietic stem cell transplantation in patients with primary and relapsed/refractory multiple myeloma induces a response in a significant proportion of patients, even in those who are refractory to proteasome inhibitors and immunomodulatory agents.

Abstract: Background: Hematopoietic cell transplantation (HCT) is an integral part of the treatment of multiple myeloma (MM). While autologous stem cell transplantation (auto-HCT) is most commonly used, the duration of response is typically finite. Allogeneic HCT (allo-HCT) can provide prolonged survival in some patients, given the added benefit of the graft-versus-myeloma effect. However, long-term data is needed to show this improvement. Method: We retrospectively reviewed a cohort of 37 consecutive patients with newly diagnosed MM who received allo-HCT as part of consolidation therapy between 1994 to 2016. Results: The median age was 54 years (range, 32 to 68), and 54% were male. The Revised International Staging System (R-ISS) stages were I, II, III, and unknown in 27%, 38%, 11%, and 24% of patients, respectively. High-risk cytogenetics (IMWG definition) was identified in 22% of patients. The median time from diagnosis to allo-HCT was 8.8 months (range; 3.3 to 34.3). For induction treatment, fourteen patients (38%) received a combination of immunomodulatory drug (IMiD) plus proteasome inhibitor (PI), sixteen patients (43%) received either IMiD or PI in combination with other agents, and seven patients (19%) did not receive either an IMiD or PI. Twenty-seven (73%) patients received auto-HCT before allo-HCT. Thirty-four (92%) patients received allo-HCT as part of various clinical trials. Median time from auto-HCT to allo-HCT was 4 months (2.5 to 27.3). Prior to allo-HCT, 1 (3%) patient was in complete remission (CR), 18 (48.5%) were in very good partial remission (VGPR), and 18 (48.5%) were in partial remission (PR). Twenty-three (62%) patients received non-myeloablative (NMA) conditioning, 10 (27%) reduced-intensity (RIC), and 4 (11%) myeloablative conditioning (MAC). The graft source was matched unrelated (MUD) in 16% and matched sibling donor (MRD) in 84% of patients. Ten (27%) patients received maintenance therapy after allo-HCT, including bortezomib (n=2), thalidomide (n=2), ixazomib (n=2), and lenalidomide (n=4). The median days to neutrophil and platelet engraftment was 12 (ANC ≥500/µL_ range; 10 to 59) and 13 (platelet count ≥20K/µL _range; 9 to 70), respectively. The cumulative incidence (CI) of non-relapse mortality (NRM) was 16% at 1-year and 19% at 3-years after allo-HCT. There was no difference in NRM between MAC or NMA/RIC conditioning. The overall response rate (PR or better) was 97%, with a 54% stringent CR+CR rate. The incidence of grade I-IV acute graft-versus-host disease (GVHD) was 35%, while chronic GVHD was seen in 62%. Causes of death were deemed to be disease-related in 8 patients, treatment-related in 11 patients, and 1 unknown. The median follow-up in surviving patients was 12.6 years (range; 2.8 to 15.8 years). The 3, 5, and 10-year actuarial overall survival (OS) rates were 70%, 56%, and 47%, respectively (Figure 1A). The 3, 5, and 10-year actuarial progression-free survival (PFS) rates were 66%, 50%, and 36%, respectively (Figure 1B). At the last follow up, 46% (n=17) of patients were alive in the entire cohort, 65% (n=11) of which survived for longer than 10-years from transplant. Sixteen percent (n=6) remained alive and in continued remission for more than 10 years from transplant, one-third of whom received maintenance treatment post allo-HCT. The longest ongoing remission was 15.8 years in this cohort. Conclusion: Allo-HCT may result in durable ( & gt;10 years) remission in a number of MM patients when performed early in the disease course. Larger studies would help identify the patients who would benefit the most, given the risk of graft-versus-host disease after allo-HCT. Disclosures Popat: Bayer: Research Funding; Novartis: Research Funding. Kebriaei:Pfizer: Other: Served on advisory board; Kite: Other: Served on advisory board; Amgen: Other: Research Support; Jazz: Consultancy; Novartis: Other: Served on advisory board; Ziopharm: Other: Research Support. Oran:Celgene: Consultancy; ASTEX: Research Funding; Arog Pharmaceuticals: Research Funding. Hosing:NKARTA Inc.: Consultancy. Manasanch:Adaptive Biotechnologies: Honoraria; GSK: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Takeda: Honoraria; Quest Diagnostics: Research Funding; Merck: Research Funding; JW Pharma: Research Funding; Novartis: Research Funding; Sanofi: Research Funding. Lee:Amgen: Consultancy, Research Funding; Genentech: Consultancy; Regeneron: Research Funding; Daiichi Sankyo: Research Funding; Sanofi: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Genentech: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Kaufman:Karyopharm: Honoraria; Bristol Myers Squibb: Research Funding; Janssen: Research Funding. Patel:Precision Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Cellectis: Research Funding; Janssen: Consultancy, Research Funding; Poseida: Research Funding; Oncopeptides: Consultancy; Nektar: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Orlowski:Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees. Thomas:Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; X4 Pharma: Research Funding; Pharmacyclics: Other: Advisory Boards; Xencor: Research Funding; Genentech: Research Funding. Shpall:Takeda: Other: Licensing Agreement; Magenta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Zelluna: Membership on an entity's Board of Directors or advisory committees. Champlin:Takeda: Patents & Royalties; Actinium: Consultancy; Johnson and Johnson: Consultancy; Omeros: Consultancy; Cytonus: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Genzyme: Speakers Bureau. Qazilbash:Bioclinica: Consultancy; Amgen: Research Funding; Angiocrine: Research Funding; Bioline: Research Funding; Janssen: Research Funding. Bashir:Celgene: Research Funding; Amgen: Other: Advisory Board; Purdue: Other: Advisory Board; Takeda: Other: Advisory Board, Research Funding; Acrotech: Research Funding; StemLine: Research Funding; KITE: Other: Advisory Board.

Abstract: Introduction: The role of autologous hematopoietic stem cell transplantation (auto-HCT) in the management of patients with Waldenström Macroglobulinemia (WM), a rare, indolent lymphoma, has not been established. We had previously published our experience with auto-HCT in a small cohort of WM patients1. Here, we present an updated analysis of auto-HCT with a larger cohort of WM patients. Methods and study population: The study cohort was comprised of 29 patients who underwent high-dose chemotherapy and auto-HCT at MD Anderson Cancer Center (MDACC). The Kaplan-Meier method was used to create survival curves. Overall survival (OS) was defined as the duration from date of transplant to death or last date of follow-up in living patients. Progression-free survival (PFS) was defined as the duration from date of transplant to either progressive disease or death, whichever occurred first. Results: Median age at auto-HCT was 60 (range, 43-75 years). Eight patients (28%) had concurrent light chain amyloidosis (AL). Of the five patients who had MYD88 testing completed, 3 were positive for the MYD88 mutation. Additionally, of these 3 patients, 2 were also positive for CXCR4 mutation. Patients received a median of 2 lines (range 1-6) of therapy prior to auto-HCT; 3(10%) patients had primary refractory disease, 8(28%) were in first remission, and 18 (62%) had relapsed disease. Median time from transplant to last follow-up for the surviving patients was 5.3 years. Preparative regimens received by the patients were: Melphalan (n=20), BEAM-R (n=2), Busulfan/Melphalan (n=1), Cyclophosphomaide/Etoposide/total body irradiation (n=1), Thiotepa/Busulfan/Cyclophosphamide (n=1), and Carmustine/Thiotepa (n=1). Three patients further went on to receive allogeneic transplant either after relapse from auto-HCT or due to disease transformation to aggressive lymphoma. Twenty-eight patients achieved engraftment with a median time to neutrophil engraftment of 11 days (range, 10-15 days). One patient suffered primary graft failure due to progression of disease and died 84 days after transplant. Non-relapse mortality was 3.4% at 1 year. All patients were eligible for response evaluation. The median OS from diagnosis was 12.2 years. Overall response rate was 96%: complete response (n=8, 27.6%), very good partial response (n=5, 17.3%), partial response (n=15, 51.7%), and progressive disease (n=1, 3.4%). PFS and OS at 5 years were 43.3% and 62.9%, respectively. Median PFS and OS from auto-HCT were 4.1 and 7.3 years (Fig. 1A). The median OS from auto-HCT in first remission + primary refractory and relapsed disease was 8.2 years and 4.1 years, respectively.16 patients were alive at the time of censoring while 13 patients had died. Causes of death include relapsed disease (n=6), secondary malignancy (n=2), infection (n=1), chronic graft-versus-host disease (n=1), and unknown (n=3). 8 patients (28%) were positive for concurrent AL amyloidosis. The sites of amyloid involvement were kidneys (n=2), lungs (n=1), bone marrow (n=1), heart(n=1), lymph nodes(n=1), gastrointestinal tract (n=1) and subcutaneous fat aspirate(n=5). The median overall survival for patients with amyloid involvement (n=8) was 12 years. On univariate analyses, the number of chemotherapy regimens prior to transplant (≤ 2 vs 〉 2 lines) was the strongest predictor of overall survival (p=0.03, HR 0.3, CI: 0.09-0.9, log-rank) and PFS (p=0.001, HR 0.24, CI: 0.07-0.85, log-rank). The median PFS in patients with ≤ 2 lines and 〉 2 lines of therapy was 71 months versus 19 months, respectively (Fig. 1B). Conclusion: Auto-HCT is safe and feasible in selected patients with WM, with a high response rate and durable remission even in patients with relapsed or refractory disease. References: Krina Patel et.al. Autologous Stem Cell Transplantation in Waldenstrom's Macroglobulinemia. Blood 2012 120:4533; Disclosures Thomas: Celgene: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Acerta Pharma: Research Funding; Array Pharma: Research Funding; Amgen Inc: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Takeda: Consultancy; Celgene: Consultancy; Spectrum Pharma: Research Funding; Janssen: Consultancy; Kite Pharma: Consultancy; Sanofi-Aventis: Consultancy; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

Abstract: Abstract: Background: POEMS syndrome is a constellation of symptoms of polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. Other features often present in this syndrome include papilledema, extravascular volume overload, sclerotic bone lesions, Castleman disease, high vascular endothelial growth factor (VEGF) levels and thrombocytosis/polycythemia. The standard of care has not been established in the management of the disease. We had previously reported on the role of auto-HCT in a smaller cohort of POEMS patients at our institution1. Here, we present an updated analysis in a larger cohort of POEMS patients who underwent auto-HCT. Methods: We retrospectively reviewed the outcomes of POEMS patients who underwent auto-HCT at our institution from the period of January, 1999, through June, 2018. The Kaplan-Meier method was used to caculate progression-free survival (PFS) and overall survival (OS). Hematologic response was defined as per the International Myeloma Working Group (IMWG) criteria. OS was defined as the duration from the date of transplant to death or last date of follow-up in alive patients. PFS was defined as the duration from the date of transplant to either progressive disease or death, whichever occurred first. Results: 16 patients (13 males, 3 females) with POEMS syndrome received a total of 17 auto-HCTs. One patient underwent auto-HCT two times for multiple relapses. The median age at auto-HCT was 48 years (range: 18-75). The median time from diagnosis to auto-HCT was 15 months (2-141 months). All 16 (100%) patients had peripheral neuropathy and monoclonal gammopathy: IgG lambda in 7, IgA lambda in 6, IgG kappa in 2 and light chain in 1 patient. Other features were: osteosclerotic bone lesions in 13 (81%), endocrinopathy in 10 (69%), skin involvement in 8 (50%) and extravascular fluid overload in 7 (44%). Three (18%) patients had biopsy-proven co-existent Castleman disease. Among patients with available data (n=7), the mean serum VEGF level pre-transplant was 389 pg/ml (268-1622). The median HCT-CI (comorbidity index) score available for 15 patients was 2 (range 0-7). The median number of chemotherapies received before the transplant was 1 (range 1-3). Table 1 summarizes the prior systemic chemotherapies received before auto-HCT. Two patients also received plasmapheresis, and eight patients received radiation therapy for bone disease. The mobilization regimens used for collecting peripheral blood stem cells were granulocyte colony-stimulating factor (G-CSF) alone, cyclophosphamide+G-CSF and G-CSf+plerixafor in 16, 2 and one patient, respectively. The median number of CD34+ stem cells collected was 3.43 X 106 cells/kg (range 1.73 - 6.5). The overall response rate, as per the IMWG criteria, for the entire cohort was 94% (16/17): 5 (29.4%) CR, 4 (23.5%) nCR, 1 (5.8%) VGPR, and 6 (35.2%) PR. The mean serum VEGF levels improved from 389 pg/ml before transplant to a level of 35 pg/ml (31-86) post-transplant. Engraftment syndrome was seen only in 1 patient who required corticosteroid use. One-year transplant-related mortality was 0%. Median follow-up among surviving patients is 52 months (5-120 months). The median PFS and OS have not been reached yet. All 16 patients had a complete or partial resolution of their clinical symptoms after auto-HCT. 4-year PFS and OS rate for the entire cohort is 80.2% and 100% respectively. At ten years, PFS and OS rate is 59.4% and 80% respectively. Fourteen out of 16 patients were alive at the time of the last follow-up. One patient died six years after his auto-HCT secondary to gastrointestinal bleeding unrelated to his underlying disease, and the second patient died after 11 years post auto-HCT of unknown cause. Conclusions: Upfront Auto-HCT provides durable chemotherapy free remission and significant clinical improvement in patients with POEMS syndrome. References: Patel, K. et al. Durable responses with autologous hematopoietic SCT in patients with POEMS syndrome. Bone marrow transplantation49, 465-6 (2014). Figure. Figure. Disclosures Thomas: Acerta Pharma: Research Funding; Amgen Inc: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Celgene: Research Funding; Array Pharma: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Poseida: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals: Consultancy, Research Funding. Champlin:Sanofi: Research Funding; Otsuka: Research Funding. Patel:Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.