Kumar, Shaji

Background: Multiple myeloma is typically characterized by clonal expansion of malignant plasma cells within the bone marrow compartment. Presence of extramedullary disease (EMD) either in the form of soft tissue plasmacytoma or circulating plasma cells can be seen at diagnosis but is more common in the relapsed and refractory patients. Presence of EMD is typically associated with a poor prognosis, both in the newly diagnosed and relapsed setting, but trials designed specifically for patients with EMD are sparse. Treatment of EMD can be challenging and the responses even when seen are often short lasting, highlighting the need for developing specific treatment approaches aimed at these patients. Based on initial trials suggesting activity of pomalidomide in the setting of EMD and the increased tissue distribution with the oral proteasome inhibitor ixazomib, we designed this trial to examine if the all oral combination of ixazomib, pomalidomide and dexamethasone can be effective in the setting of EMD. Patients and Methods: Patients with previously treated multiple myeloma, with adequate hematologic and organ function were enrolled if there was evidence, at study entry, of EMD defined as one or more plasmacytomas, outside the bone marrow that were non-contiguous with a bone lesion and had a single diameter of ≥2 cm OR as plasma cell leukemia, with circulating plasma cells > 5% of peripheral blood leukocytes or at least 0.5 X 109/L or 200 cells/150000 events by flowcytometry. Patients were treated on 28-day cycles, with ixazomib 4 mg on days 1, 8, and 15 along with pomalidomide 4 mg PO daily on days 1-21 and dexamethasone 40 milligrams weekly until disease progression or unacceptable toxicity. The goals of the study were to determine confirmed response rate (≥ PR), toxicities of this combination, differential response rates and progression-free survival (PFS). Confirmed response rate, differential response rates and PFS were estimated using Duffy and Santner approach, exact binomial distributions and Kaplan Meier curves, respectively. The study was designed to accrue 30 patients. Results: This study was designed to enroll up to 30 patients but was closed after enrolling 17 patients due to slow accrual. The baseline characteristics are as indicated in Table 1. Eleven patients were enrolled with an extramedullary plasmacytoma while the remaining six patients had plasma cell leukemia. Median number of lines of prior therapy was 3 (range: 1, 7). Overall, 10 (58.8%) patients had progressive disease and 11 (64.7%) patients have died, median (range) follow-up for the live patients is 22.2 (2.1, 37.9) months. Patients were treated for a median of 2 (range 1-34) cycles. A grade 3+ AE, at least possibly attributed, was seen in 53%. Grade 3+, at least possibly related, hematologic toxicity was noted in 41%, with 29% experiencing grade 3+ neutropenia. Notable grade 3+ non-hematologic toxicities (regardless of attribution), with >10% incidence rate were anemia, hypoxia, infections and lung infection. The confirmed response rate in evaluable patients was 35% (1 CRs and 5 PRs), with a 90% CI of 6% - 37%. While 33% (4/12; 95% CI: 1-8%) of patients reported a biochemical response, 40% (2/5; 95% CI: 0-4%) of patients reported an extramedullary response. The median PFS was 4.5 (95% CI: 2-11.8) months. Conclusions: The combination of ixazomib, pomalidomide and dexamethasone resulted in disease response in a third of this group of high-risk patients with EMD; however, the responses were not very durable, with a median PFS of only 4.5 months. The trial highlights the feasibility of doing clinical trials specifically targeted towards this high-risk patient population. Future trials should explore combinations of novel agents, including monoclonal antibodies through multicenter collaborative efforts. Disclosures Kansagra: Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics: Other: Advisory Board. Witzig:Spectrum: Consultancy; Immune Design: Research Funding; Karyopharm Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Consultancy; AbbVie: Consultancy; MorphSys: Consultancy; Celgene: Consultancy, Research Funding. Kumar:Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genecentrix: Consultancy; Carsgen: Other, Research Funding; Cellectar: Other; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Kite Pharma: Consultancy, Research Funding; Novartis: Research Funding; Adaptive Biotechnologies: Consultancy; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Sanofi: Research Funding; Tenebio: Other, Research Funding.

Background: The combination of a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and dexamethasone is the current standard induction therapy for myeloma. Daratumumab (Dara), a monoclonal antibody directed against CD38, is highly effective in treating myeloma and improves response rates and progression free survival (PFS) when added to PI or IMiD. Ixazomib, lenalidomide and dexamethasone (IRd) is an effective, all oral, induction regimen that has been studied in phase 2 and 3 trials. We designed this trial to examine the feasibility and efficacy of adding daratumumab to the IRd regimen as well as early discontinuation of dexamethasone in two sequential cohorts of patients. Patients and Methods: Patients with previously untreated MM who had measurable disease and adequate organ function were enrolled, irrespective of their autologous stem cell transplant eligibility. The primary objective was to determine the rate of complete response to IRD-Dara combination. A one-stage binomial design was utilized in each cohort independently to test the null hypothesis that the complete response rate is at most 25% against the alternative hypothesis that it is at least 45%, with 89% power and 9% type I error. Treatment involved 28-day cycles consisting of ixazomib 4 mg days 1, 8, 15; lenalidomide 25 mg days 1-21, dexamethasone 40 mg, weekly and Dara 16 mg/kg, weekly for two cycles, every other week during cycles 3-6 and then every 4 weeks thereafter during induction (12-cyles) followed by Dara-ixazomib maintenance (maximum 24 cycles). Cohorts A (n=38) and B (N=40) comprised the study population, with dexamethasone discontinued after two cycles in Cohort B. Results: Baseline demographics and patient disposition are outlined in the table. Among those who have gone off study, 9 and 5 patients, respectively in Cohort A and B went off for progression, while 11 and 8 patients in the respective arms discontinued treatment for an alternative therapy, most frequently a transplant. Responses were rapid and deepened over the duration of treatment as shown in the figure; 32% of patients in Cohort A and 28% of patients in Cohort B achieved a complete response; 29% and 23%, respectively, achieved a marrow minimal residual disease (MRD) negative status. After a median follow up was 31.4 months for Cohort A and 18.2 months for Cohort B, median PFS has not been reached in either cohort. A grade 3 or higher adverse event at least possibly attributed to the study drugs was seen in 58% of patients in Cohort A (hematologic in 47% and non-hematologic in 26%) and 50% of patients in Cohort B (hematologic 43%, non-hematologic 20%). The most common toxicities included fatigue, neutropenia, lymphopenia, peripheral neuropathy and nausea. Stem cells were collected in 30 and 31 patients in Cohorts A and B respectively; median (range) of CD34 cells/kg were 8.5 (2.8, 15.9) x 106and 7.0 (2.9, 12.1) x 106, with plerixafor used in 83% and 94% of patients, respectively, in Cohorts A and B as per our standard of care "on-demand" approach based on blood CD34 count. Conclusion: Dara-IRd is an active regimen in newly diagnosed MM, with high overall rates of response and deep responses that improved over time with therapy. Early discontinuation of dexamethasone does not appear to impact the depth, rate or kinetics of response. The toxicities were manageable, with dose modifications. All patients were able to collect stem cells when required, though majority needed plerixafor. Disclosures Kumar: Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Kite Pharma: Consultancy, Research Funding; Carsgen: Other, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; Dr. Reddy's Laboratories: Honoraria; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Tenebio: Other, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; Sanofi: Research Funding; Novartis: Research Funding; MedImmune: Research Funding; Karyopharm: Consultancy; BMS: Consultancy, Research Funding. Kapoor:GlaxoSmithKline: Research Funding; Celgene: Honoraria; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy. Dingli:Apellis: Consultancy; Karyopharm Therapeutics: Research Funding; Janssen: Consultancy; Bristol Myers Squibb: Research Funding; Alexion: Consultancy; Rigel: Consultancy; Millenium: Consultancy; Sanofi-Genzyme: Consultancy. Dispenzieri:Pfizer: Research Funding; Takeda: Research Funding; Alnylam: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Intellia: Research Funding. Gertz:Abbvie: Other; Sanofi: Other; Celgene: Other; Research to Practice: Other; Physicians Education Resource: Other: personal fee; Amgen: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau; Appellis: Other: personal fee; Annexon: Other: personal fee; Alnylam: Other: personal fee; Spectrum: Other: personal fee, Research Funding; Janssen: Other: personal fee; Teva: Speakers Bureau; Aurora Bio: Other; Springer Publishing: Patents & Royalties; Proclara: Other; DAVA oncology: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Ionis/Akcea: Other: personal fee; Prothena: Other: personal fee.

Background: Newly diagnosed patients with AL Amyloidosis are a heterogeneous population, ranging from incidentally found nephrotic syndrome to delayed advanced cardiac disease. For the purposes of trials, patients with the highest-risk disease are often excluded from trial participation. An NT-proBNP of 8500 or higher is the criterion most often used for exclusion from clinical trials due to high rates of early death. It is well documented that overall survival is improving over time, in part due to earlier diagnosis and in part due to more effective therapies. It is our aim to describe outcomes of patients with very high (NT-proBNP >=8500) and advanced stage amyloidosis excluding very high (VH) NT-proBNP. Methods: To address this need, we examined the outcomes of AL patients diagnosed between 1/2012 and 7/2020 and seen at our institution within 90 days of diagnosis. Of the 1290 patients, 291 were seen beyond the 90 day threshold and were thus excluded. Another 170 patients were excluded due to missing biomarkers to calculate stage, leaving 829 patients for our analysis. Thresholds for troponins and BNPs were used according to Muchtar Blood 133(7):2019 to correct for assay used. The vast majority of patients had troponin T measured, and for them the 0.025 mcg/L and the 0.035 mcg/L cut-points were used for the 2012 and 2004 staging systems. A minority of patients did not have troponin T, but rather high sensitivity troponin T (n=129) or troponin I (n=23). For patients with high sensitivity troponin T, cut-points of 41 and 50 ng/L were used, respectively, for the 2012 and 2004 systems, and for patients with troponin I only, a cut-point of 0.1 mcg/L was used for both systems. In the 3 patients with no NT-proBNP but with BNP, 400 and 81 ng/L were used respectively for the 2012 and 2004 systems; otherwise, the 1800 ng/L and 332 ng/L cut-offs were used. A BNP of > 700 ng/L was considered equivalent to NT-proBNP greater than or equal to 8500 ng/L. For the 2012 system, the dFLC of 18 mg/dL was used as a cut-off. Survival estimates were done using the method of Kaplan-Meier, and differences in survival were by determined by Log-Rank. Results: The median age of patients was 65 (range 29, 89), and 65% were male. 148 (17%) of these newly diagnosed patients had a VH (>=8500) NT-proBNP. Patients with VH NT-proBNP were older (67 versus 64 years, p=0.004). Only 4% of the VH NT-proBNP patients received an ASCT in contrast to 34% without VH NT-proBNP. With a median follow-up of 30 months for surviving patients, median OS for VH NT-proBNP patients was 3.3 months in contrast to patients without VH NT-proBNP at 68.4 months (Figure). Breakdown of early death for patients with VH NT-proBNP by stage is shown in Table. Of Mayo 2012 patients staged I, II, III, and IV, the percent of patients with VH NT-proBNP was 0, 3, 20, and 45%. In contrast, for the European modification of the Mayo 2004 system, the percent with VH NT-proBNP by stage was 0, 6, 0, 100 for stages I, II, IIIa, and IIIb, respectively. Among the VH NT-proBNP patients, there was stage discrimination using the Mayo 2012 system (6-month death rates were 17, 45, and 66% for patients with stages II, III, and IV, respectively, p=0.02). In contrast, using the Mayo 2004 system in the patients with VH NT-proBNP, 6-month death rates were 45 and 60% for stage II and IIIb patients, respectively (p= 0.12). Among patients without VH NT-proBNP, rates of death in the first year were 21% including stage I patients whose death rates were well under 10%. Patients without VH NT-proBNP but Mayo 2012 Stage III and IV had 1-year mortalities of 28 and 43% respectively. Using the modified Mayo 2004 system, excluding the VH NT-proBNP 1-year mortality was 19 and 37% for patients with stage II and IIIa, respectively. Discussion: Establishing expected outcomes for the sickest AL amyloidosis patients is a means by which trials can be designed for these patients with an unmet need. Patients with VH NT-proBNP should be considered for specially designed trials, and patients without VH NT-proBNP and advanced stage should be included in trials for newly diagnosed patients regardless of stage as long as there is appropriate stratification. Disclosures Dispenzieri: Janssen: Research Funding; Pfizer: Research Funding; Intellia: Research Funding; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Kumar:AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; Sanofi: Research Funding; Carsgen: Other, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Adaptive Biotechnologies: Consultancy; Dr. Reddy's Laboratories: Honoraria; Novartis: Research Funding; MedImmune: Research Funding; Genecentrix: Consultancy; Kite Pharma: Consultancy, Research Funding; Cellectar: Other; Karyopharm: Consultancy; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments. Dingli:Karyopharm Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Millenium: Consultancy; Janssen: Consultancy; Alexion: Consultancy; Rigel: Consultancy; Apellis: Consultancy; Sanofi-Genzyme: Consultancy. Kapoor:Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding. Lin:Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy. Gertz:Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; NCI SPORE MM: Research Funding; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Prothena: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Consultancy.

Introduction: Lenalidomide is increasingly used for the treatment of newly diagnosed multiple myeloma. However, most patients experience relapse during treatment or after prolonged exposure to lenalidomide, therefore, there is an emerging unmet need for new, highly efficacious lenalidomide-sparing regimens at relapse. CANDOR is an ongoing phase 3 randomized clinical trial (RCT) that compares the lenalidomide-free KdD regimen with carfilzomib 56mg/m2 twice-weekly with dexamethasone (Kd) in patients with relapsed and/or refractory multiple myeloma (RRMM). Based on the primary analysis, KdD was associated with a 37% reduction in the risk of progression or death compared to Kd (HR: 0.63, p=0.001).(Dimopoulos et al. 2020 Lancet) Besides the trial-based comparator Kd, DVd is considered as an additional relevant comparator. DVd is the most similar lenalidomide-free triplet regimen comprising a proteasome inhibitor, daratumumab, and dexamethasone. DVd was assessed in the phase 3 CASTOR RCT and demonstrated superior PFS versus 8 cycles (24 weeks) of bortezomib in combination with dexamethasone (Vd) (HR: 0.31, p<0.001).(Weisel et al. 2019 ASH) In the absence of a direct head-to-head trial comparing these treatments and an assessment suggesting that network meta-analysis is not feasible, matching-adjusted indirect comparisons (MAIC) were used (Signorovitch et al. 2010) to assess the efficacy of KdD relative to DVd. MAIC leverages all available data and compares outcomes across balanced populations. Method: Baseline characteristics and PFS data from the CANDOR and CASTOR trials were used in the analyses. Outcomes were compared in three steps. First, after aligning patient selection criteria of both trials, KdD patients in CANDOR were matched to the average characteristics of DVd patients in CASTOR using matching-adjusted indirect treatment comparisons methodology. The matching variables reflected tumor stage, disease burden, and treatment history, and were generally consistent with validated prognostic markers used in stratifying patients into different risk groups. Second, the published Kaplan-Meier PFS curves for DVd were digitized to generate virtual patient-level data that reconstructed the curves. Third, Cox regression models were fitted to the matched CANDOR data and the reconstructed virtual patient-level CASTOR data to estimate the efficacy of KdD versus DVd. The outcome measure was the hazard ratio (HR) for PFS. Outcomes were also compared for the first 24 weeks and for the period beyond 24 weeks to assess the impact of stopping Vd in DVd after 24 weeks on the HRs. Scenario and subgroup analyses were conducted to assess the robustness of results. Results: KdD patients in the CANDOR trial who were proteasome inhibitor-refractory (n=102) were removed from the data so that the KdD population was aligned with that of DVd in the CASTOR trial. Following the matching procedure, the effective sample size for KdD reduced to 82. In matched populations, PFS at 12 months was 73.1% for KdD and 59.9% for DVd. The MAIC results showed that treatment with KdD decreases the risk of progression or death versus DVd, with an overall HR of 0.61 (95% CI: 0.45-0.82). The time-dependent analysis demonstrated similar PFS for the two treatments for the first 24 weeks and a larger benefit for KdD over DVd after 24 weeks. Similar results were obtained in scenario analyses; in bortezomib-exposed patients the overall HR was 0.46 (95% CI: 0.33-0.64). Conclusions: After adjusting for cross-trial differences, KdD was associated with a significant reduction in the risk of progression or death compared with DVd. Although based on an approach in agreement with methods guide, the results are associated with inherent limitations due to the decreased sample size for KdD, and due to known (longer follow-up for DVd, different duration of proteasome inhibition) or unobserved differences in the trials (potential unobserved heterogeneity in patient characteristics). A comparison of overall survival was not considered due to immature data in CANDOR. The results are in line with those of the head-to-head ENDEAVOR trial that directly compared carfilzomib with bortezomib (HR for PFS for Kd vs Vd 0.53; 95% CI: 0.44-0.65) supporting the clinical validity of this study. The present analysis suggests that KdD improves outcomes compared with DVd in patients with RRMM and may provide a rationale for a preferential treatment. Disclosures Weisel: Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Adaptive: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Nooka:Sanofi: Consultancy, Honoraria; Spectrum Pharmaceuticals: Consultancy; Oncopeptides: Consultancy, Honoraria; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Adaptive Technologies: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Terpos:Janssen: Honoraria, Research Funding; Genesis pharma SA: Honoraria, Other: travel expenses , Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Sanofi: Honoraria; BMS: Honoraria. Spencer:AbbVie, Amgen, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Honoraria; AbbVie, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Consultancy; Amgen, Celgene, Haemalogix, Janssen, Servier and Takeda: Research Funding; Celgene, Janssen and Takeda: Speakers Bureau. Goldschmidt:Merck Sharp and Dohme (MSD): Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Molecular Partners: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Incyte: Research Funding; Mundipharma GmbH: Research Funding. Majer:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company. DeCosta:Amgen Ltd: Current Employment, Current equity holder in publicly-traded company. Medhekar:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Yusuf:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Kumar:Karyopharm: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Sanofi: Research Funding; Carsgen: Other, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Cellectar: Other; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; MedImmune: Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Tenebio: Other, Research Funding.

Introduction: The bone marrow plasma cell (BMPC) clone burden is typically low in light chain (AL) amyloidosis and some patients do not have a detectable serum monoclonal spike (M-spike). Increased BMPC% and serum free light chain (FLC) are associated with poorer outcomes. However, the outcomes of patients with AL amyloidosis based on the presence or an absence of a measurable serum M-spike before autologous stem cell transplantation (ASCT) has not been explored. Methods: This was a retrospective review of patients who had a diagnosis of AL amyloidosis and received ASCT between March 1996 and September 2017. The serum M-spike was recorded before ASCT and patients were divided according to the presence or absence of a measurable serum M-spike. Progression-free survival (PFS) was defined as time from ASCT to disease progression, relapse or death of any cause. Overall survival (OS) was calculated from time of ASCT to death of any cause. Univariate and multivariate analysis for PFS and OS were done using the following variables: age>65 vs. ≤65 years, Mayo 2012 stage 3/4 vs. 1/2, BMPC ≥ 10% vs. <10%, organs involved >2 vs. ≤2, melphalan conditioning 200mg/m2 vs. 140 mg/m2 ,ASCT year >2010 vs. ≤2010, and presence vs. absence of a measurable serum M-spike. Results: Seven-hundred and sixteen patients were identified and 521 (73%) had a measurable serum M-spike. Patients who had a measurable serum M-spike were more likely to have BMPC≥ 10% than patients without a measurable serum M-spike (46% vs. 34%, P=0.002) and they were more likely to have a difference in FLC ≥18 mg/dl (47% vs. 29%, P=0.0001). Overall, PFS and OS were significantly shorter in patients who had a measurable serum M-spike compared to patients without a measurable serum M-spike (Figure 1 A,B). The shorter survival was irrespective of the administration of induction therapy before ASCT. We also evaluated the difference in survival in patients with Mayo 2012 stage 3/4 based on the presence or absence of a measurable serum M-spike. The PFS and OS were also significantly different in these patients (Figure 1 C,D). Predictors for PFS included Mayo 2012 stage 3/4 vs. 1/2 (hazard ratio (HR): 1.5, P=0.003), BMPC ≥ 10% vs. <10% (HR: 1.4,P=0.004), melphalan conditioning 200mg/m2 vs. 140 mg/m2 (HR:0.6, P=0.001), ASCT year >2010 vs. ≤2010 (HR: 0.8, P=0.03), and the presence vs. absence of a measurable serum M-spike (HR: 1.82, P<0.0001). For OS, Mayo 2012 stage 3/4 vs. 1/2 (HR: 2, P<0.0001), melphalan conditioning 200mg/m2 vs. 140 mg/m2 (HR:0.4, P<0.0001), ASCT year >2010 vs. ≤2010 (HR: 0.6, P=0.002), and the presence vs. absence of a measurable serum M-spike (HR:1.9, P=0.003) were predictive. Conclusion: The presence of a measurable serum M-spike before ASCT is a negative independent predictor for PFS and OS in AL amyloidosis. Figure 1 Disclosures Sidiqi: Amgen: Honoraria; Celgene: Honoraria, Other: Travel grant; Janssen: Honoraria. Dingli:Karyopharm Therapeutics: Research Funding; Apellis: Consultancy; Alexion: Consultancy; Janssen: Consultancy; Bristol Myers Squibb: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Sanofi-Genzyme: Consultancy. Kapoor:Amgen: Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; GlaxoSmithKline: Research Funding. Dispenzieri:Intellia: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Kumar:Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; Genecentrix: Consultancy; MedImmune: Research Funding; Cellectar: Other; Dr. Reddy's Laboratories: Honoraria; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Novartis: Research Funding; Adaptive Biotechnologies: Consultancy; Kite Pharma: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Carsgen: Other, Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Sanofi: Research Funding. Gertz:Proclara: Other; Abbvie: Other; DAVA oncology: Speakers Bureau; Aurora Bio: Other; Prothena: Other: personal fee; Teva: Speakers Bureau; Physicians Education Resource: Other: personal fee; Annexon: Other: personal fee; Ionis/Akcea: Other: personal fee; Sanofi: Other; Appellis: Other: personal fee; Amgen: Other: personal fee; Janssen: Other: personal fee; Spectrum: Other: personal fee, Research Funding; Medscape: Other: personal fee, Speakers Bureau; Research to Practice: Other; Alnylam: Other: personal fee; Johnson and Johnson: Speakers Bureau; Springer Publishing: Patents & Royalties; Celgene: Other.

Introduction Autologous stem cell transplantation (ASCT) has been used for treating multiple myeloma (MM) for over three decades and is generally reserved for patients younger than 65 years of age. The definition of transplant eligible is ill-defined and different centers have different policies to determine which patients are transplant eligible. Some centers have an age cut-off, others use clinical judgment, and some use various frailty scores (a scoring system based on comorbidities and physical and cognitive assessments) aiming to objectively assess transplant eligibility. There are limited data about outcomes in patients ≥ 75 years. Aim To report on outcomes of ASCT in a cohort of patients with MM aged 75 years or older. Methods Retrospective study of all consecutive MM patients aged ≥ 75 years that underwent ASCT at Mayo Clinic, Rochester, Minnesota. Stem cell transplantation at our center is routinely performed as an outpatient, with patients being hospitalized when deemed clinically necessary upon physician review. Results Between October 2005 and March 2020, 46 patients aged 75 years or older, received an ASCT at Mayo Clinic, Rochester. The median hematopoietic stem cell transplantation specific comorbidity index (HCT-CI) was 0 (range 0-6) with 8 patients having HCT-CI of 5 or 6. Median time from diagnosis to ASCT was 6.45 months (IQR 5.2-10.52) and 54% received reduced intensity conditioning with melphalan 140 mg/m2. All patients except one (that was treated with dexamethasone only) received induction with novel agents (listed in table 1) and 6 patients (13%) received doublet induction. All others received triplet induction. 46% of patients completed the ASCT without requiring hospitalization and 54% (n=25) of patients required hospitalization with a median duration of hospital admission of 9 days (IQR 5-13). Reasons for hospitalization included fever or infection (32%), cardiac arrhythmia (36%) and dehydration (32%). Overall response rate was 100% with a complete response seen in 57% of patients and 16 patients achieving MRD negative sCR. Median overall survival and progression free survival for the cohort were 82 months and 33 months, respectively. One patient died within 100 days of transplant representing a 2% 100-day mortality rate. Univariable cox regression model that evaluated the effect of gender, high risk cytogenetics, hemoglobin, renal function and melphalan dose did not detect any variable that was predictive of OS or PFS (Table 3). Conclusions ASCT is efficacious and can be safely delivered in the outpatient setting in carefully screened patients aged 75 or above. An arbitrary cutoff for age should not be used to exclude patients from ASCT, rather a careful assessment of "physiological age" including performance status and co-morbidities is required by an experienced treating team. Disclosures Kumar: Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Cellectar: Other; Carsgen: Other, Research Funding; Dr. Reddy's Laboratories: Honoraria; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Sanofi: Research Funding; Kite Pharma: Consultancy, Research Funding; Novartis: Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; MedImmune: Research Funding; BMS: Consultancy, Research Funding; Tenebio: Other, Research Funding; Karyopharm: Consultancy; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Adaptive Biotechnologies: Consultancy. Dispenzieri:Pfizer: Research Funding; Janssen: Research Funding; Alnylam: Research Funding; Intellia: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Dingli:Bristol Myers Squibb: Research Funding; Rigel: Consultancy; Janssen: Consultancy; Alexion: Consultancy; Karyopharm Therapeutics: Research Funding; Apellis: Consultancy; Sanofi-Genzyme: Consultancy; Millenium: Consultancy. Kapoor:Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Celgene: Honoraria; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; GlaxoSmithKline: Research Funding. Gertz:Prothena: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau; Appellis: Other: personal fee; Alnylam: Other: personal fee; Ionis/Akcea: Other: personal fee; Janssen: Other: personal fee; Research to Practice: Other; Sanofi: Other; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Proclara: Other; Springer Publishing: Patents & Royalties; Celgene: Other; Physicians Education Resource: Other: personal fee; Aurora Bio: Other; Amgen: Other: personal fee; Annexon: Other: personal fee; Spectrum: Other: personal fee, Research Funding; Abbvie: Other.

Introduction: The routine incorporation of proteasome inhibitors, immunomodulatory drugs (IMIDs), and monoclonal antibody drugs (mAbs) in managing multiple myeloma (MM) has improved patients' prognosis. Unfortunately, triple refractory patients continue to do poorly. Immunotherapeutic approaches (mAbs, CAR-T cells) have shown the most promise in these patients. However, the efficacy of these therapies depends on a functional tumor immune microenvironment (iTME), which is extensively reshaped by existing MM therapies and disease evolution. Understanding how the iTME and malignant clone co-evolve over the disease course is crucial to optimize the use of immune-based treatments and understand their mechanisms of action. Methods: Newly diagnosed MM patients (NDMM), MM patients relapsing prior to anti-CD38 antibody exposure (RMM), and triple refractory MM patients (TRMM) were identified from the Mayo Clinic biospecimen database. We performed CyTOF (with a 37 marker lymphoid panel on CD138- bone marrow [BM] mononuclear cell samples) to assess the cellular iTME, Luminex (using BM plasma) to assess the humoral iTME (cytokines and chemokines) and RNAseq analysis (using BM CD138+ cells) to assess the malignant clone transcriptome. Astrolabe was used to identify immune cell clusters. Gene set enrichment analysis (GSEA) was used to identify gene pathways with differential expression across groups. JMP was used to perform unsupervised hierarchical clustering and descriptive statistics. An FDR corrected p value of <0.05 was considered statistically significant for all comparisons. Results: This study included 39 patients (13 NDMM, 11 RMM, and 15 TRMM). Samples were hierarchically clustered by cellular iTME, humoral iTME and malignant cell transcriptome, separately. The cellular iTME best recapitulated known disease biology and was used as the "anchoring" variable for subsequent analyses. Three distinct immune clusters were identified (figure 1): cluster 1, comprised mainly of NDMM and RMM patients; and clusters 2 and 3, comprised primarily of TRMM patients. In cluster 2, 4/5 patient samples were collected immediately after progression on daratumumab-IMID therapy, whereas all 7 TRMM patient samples in cluster 3 were collected at a median of 2.8 (range 0-17.2) months after last daratumumab exposure (table 1). Most naïve T cell subsets (including the TIGIT+ T5 and the C38/CD127+ subsets T1, T2, and T12) were highest in cluster 1 compared to clusters 2 and 3. Several unfavorable T cell subsets were elevated in Cluster 2: 1) CD161+ T6, T7 and T17 subsets, which are thought to be Th17 polarized cells that promote MM growth; 2) T7, T9 CCR5+ subsets, which are thought to represent tumor-specific exhausted (PD-1+) T cell subsets; 3) senescent subsets (T-10, T14, T16,T18, T19); and 4) TCR-gd subsets with features of senescence (KLR, CD57), exhaustion (PD-1, TIGIT) and Th17 polarization (CD161). There were no significant differences in cytokine and chemokine expression based on disease status (NDMM, RMM, or TRMM) or iTME (immune clusters 1, 2, or 3). GSEA was performed to compare clusters 2 and 3 (TRMM enriched) with cluster 1. The most up-regulated gene pathways in clusters 2 and 3 related to cell cycle targets of E2F transcription factors and MYC proliferation pathways. The most down-regulated gene pathways in clusters 2 and 3 were IFN-gamma, IFN-alpha and TNF-alpha response and signalling. Conclusion: Changes in the cellular iTME mirror the disease course better than changes in the malignant clone or humoral iTME. Patients with more refractory MM have a smaller pool of naïve T cells which express TIGIT or CD127 and could be "revived" with anti-TIGIT antibodies or IL-7 prior to manufacturing CART cells or administering BCMA-based therapies. Significant heterogeneity exists within the more refractory subgroups, with some patients having more dysfunctional T cell subsets which may be less responsive to immunotherapeutic approaches. The malignant transcriptome of samples in clusters 2 and 3 parallels the aggressive clinical course, with myc upregulation and downregulation of cytokine pathways that mediate an antitumor immune response. This study suggests that the MM iTME becomes more dysfunctional with therapy and may explain the differential sensitivity of patients to immunotherapeutic approaches. Disclosures Kumar: MedImmune: Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Tenebio: Other, Research Funding; Genecentrix: Consultancy; Sanofi: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Adaptive Biotechnologies: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Carsgen: Other, Research Funding; Novartis: Research Funding; Cellectar: Other; Kite Pharma: Consultancy, Research Funding; Karyopharm: Consultancy; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments.

Abstract In the phase 3 ENDEAVOR study, carfilzomib-dexamethasone (Kd) improved survival over bortezomib-dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM), regardless of baseline renal function. This real-world study compared renal response in patients with RRMM (1-3 prior lines) and renal impairment (estimated glomerular filtration rate ≤50 mL/min) treated with Kd vs Vd. Electronic medical records data from the Oncology Services Comprehensive Electronic Records database were assessed (from January 2012 through February 2018). Time to renal response (defined according to International Myeloma Working Group criteria) was evaluated using the Kaplan-Meier method and log-rank test. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for renal overall response (ROR) and renal complete response (RCR) using Cox proportional hazard models adjusted for baseline covariates. Included were 543 Kd-treated and 1005 Vd-treated patients. In line 2 (2L), compared with Vd, Kd achieved significantly higher ROR (51.4% vs 39.6%; P < .0001) and RCR (26.6% vs 22.2%; P = .0229). After baseline covariate adjustment, 2L patients receiving Kd vs Vd were 45% more likely to achieve ROR (IRR, 1.45; 95% CI, 1.18-1.78), and 68% were more likely to achieve RCR (IRR, 1.68; 95% CI, 1.24-2.28). The renal response benefit with Kd remained consistent in 2L to line 4 (4L). In a combined analysis of patients receiving Kd and Vd (2L and 2L-4L), renal responders had longer overall survival and time to next treatment than renal nonresponders. These results demonstrate improved real-world effectiveness of Kd over Vd in RRMM renal rescue, and the positive association between renal response and improved survival.

AbstractThree sets of criteria (International Society of Amyloidosis [ISA], Palladini and Kastritis) were independently developed for staging, progression and response criteria to predict renal survival in patients with AL amyloidosis. We evaluated these criteria using a cohort of 495 newly diagnosed AL amyloidosis patients with renal involvement using time to event competing risk analysis at baseline, 3, 6 and 12 months after treatment. Only Palladini and Kastritis had a staging system and both predicted a higher risk of end stage renal disease (ESRD) in the stage III vs stage I patients but only the Palladini model was predictive for stage II patients. At 3 months, risk of ESRD was significantly higher for Palladini and ISA renal progression (hazard ratio [HR] 2.8 [95% CI: 1.5–5.3, p = .001] and 2.5 [CI: 1.4–4.6, p = .004, respectively]), but renal response was not significantly protective; conversely, the risk of ESRD was not significantly higher for the Kastritis renal progression, but was significantly protective for the Kastritis renal responders (HR 0.38 [95% CI: 0.17–0.84], p = .017). Both progression and response with ISA, Palladini and Kastritis criteria were predictive of ESRD at 6 months and 12 months. While the Palladini staging criteria at baseline, and the ISA and Palladini criteria for progression at 3 months performed better than the Kastritis criteria at baseline and 3 months post‐treatment, the Kastritis criteria performed better for response 3 months after treatment. All three sets of criteria performed well at and after 6 months post‐treatment. These differences are important when choosing endpoints for clinical trials.