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Introduction: Cardiac involvement is one of the main predictors for survival in patients with light chain (AL) amyloidosis. Biomarkers such as Troponin T and N-terminal pro b-type natriuretic peptide (NT-proBNP) are used routinely for detecting cardiac involvement. In addition echocardiogram (ECHO) is used to determine septal and left ventricular wall thickness and strain. Most patients with AL present with preserved ejection fraction (EF) however, the outcomes of AL patients undergoing autologous stem cell transplantation (ASCT) with decreased EF are not very well described. Methods: We retrospectively reviewed patients who had a diagnosis of AL amyloidosis and received ASCT between March 1996 and September 2017. All patients had an ECHO done before ASCT and the EF was documented. In our practice, the threshold for performing ASCT is an EF >40%. We evaluated the outcomes of patients who had an EF <55% compared to patients with an EF ≥55%. The baseline characteristics were compared between patients with high and low EF. 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, bone marrow plasma cell percentage (BMPC) ≥ 10% vs. <10%, organs involved >2 vs. ≤2, melphalan conditioning 200mg/m2 vs. 140 mg/m2 ,ASCT year >2010 vs. ≤2010, and EF <55% vs. ≥55%. Results: We identified 716 patients and 69 (10%) had an EF<55%, with most (n=63, 91%)having cardiac involvement . Compared to patients with EF ≥55%, patients with EF <55% were more likely to have Mayo 2012 stage 3/4 (58% vs. 22%, P<0.0001) and more likely to have thicker interventricular septum (median 14 vs. 12 mm, P<0.0001). The day 100 transplant related mortality (TRM) was higher in patients with EF <55% compared to EF ≥55% (19% vs. 6%, P=0.0006). In patients with Mayo 2012 stage 3/4, the day 100 TRM was higher in patients with an EF<55% compared to EF ≥55% (27% vs. 7%, P=0.004). Overall, PFS and OS were significantly shorter in patients with EF <55% compared to patients with EF ≥55% (Figure 1 A,B). Evaluating PFS and OS according to EF specifically in Mayo 2012 stage 3/4 patients is displayed in Figure 1 (C,D). Predictors for PFS included Mayo 2012 stage 3/4 vs. 1/2 (hazard ratio (HR): 1.4, P=0.006), BMPC ≥ 10% vs. <10% (HR: 1.5,P=0.0005), melphalan conditioning 200mg/m2 vs. 140 mg/m2 (HR:0.7, P=0.01), ASCT year >2010 vs. ≤2010 (HR: 0.7, P=0.01), and EF <55% vs. ≥55% (HR: 1.5, P=0.02). For OS, age >65 vs. ≤65 years (HR:1.4, P=0.04), Mayo 2012 stage 3/4 vs. 1/2 (HR: 1.96, P<0.0001), melphalan conditioning 200mg/m2 vs. 140 mg/m2 (HR:0.5, P<0.0001), BMPC ≥ 10% vs. <10% (HR: 1.8, P=0.03), ASCT year >2010 vs. ≤2010 (HR: 0.5, P<0.0001), and EF <55% vs. ≥55%(HR:1.9, P=0.003) were predictive. Conclusion: Having an EF <55% is associated with a higher day 100 TRM and is an independent predictor for PFS and OS in patients with AL amyloidosis undergoing ASCT. Disclosures Sidiqi: Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Other: Travel grant. Dingli:Alexion: Consultancy; Apellis: Consultancy; Sanofi-Genzyme: Consultancy; Millenium: Consultancy; Bristol Myers Squibb: Research Funding; Karyopharm Therapeutics: Research Funding; Janssen: Consultancy; Rigel: Consultancy. Kapoor:Janssen: Research Funding; GlaxoSmithKline: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Takeda: Honoraria, Research Funding; Amgen: Research Funding. Dispenzieri:Janssen: Research Funding; Pfizer: Research Funding; Alnylam: Research Funding; Intellia: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Kumar: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; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Celgene/BMS: 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; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding; Novartis: Research Funding; Sanofi: Research Funding; MedImmune: Research Funding; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Tenebio: Other, Research Funding; Genecentrix: Consultancy; Cellectar: Other; Carsgen: Other, Research Funding. Gertz:Spectrum: Other: personal fee, Research Funding; Janssen: Other: personal fee; Sanofi: Other; Research to Practice: Other; Celgene: Other; Medscape: Other: personal fee, Speakers Bureau; Proclara: Other; DAVA oncology: Speakers Bureau; Alnylam: Other: personal fee; Johnson and Johnson: Speakers Bureau; Physicians Education Resource: Other: personal fee; Teva: Speakers Bureau; Ionis/Akcea: Other: personal fee; Amgen: Other: personal fee; Springer Publishing: Patents & Royalties; Aurora Bio: Other; Appellis: Other: personal fee; Abbvie: Other; Annexon: Other: personal fee; Prothena: Other: personal fee.

Introduction: VRD (bortezomib, lenalidomide, dexamethasone) and VCD (bortezomib, cyclophosphamide, dexamethasone) are the two most commonly used triplet induction regimens in transplant eligible patients with multiple myeloma (MM). VCD is commonly used in patients with renal dysfunction at diagnosis. Given the variable results seen in head to head comparison of these (or similar) regimens to date, no definitive conclusion can be made on whether they are equivalent. This large CIBMTR registry study compares the outcomes with VRD vs. VCD induction therapy in patients undergoing upfront autologous stem cell transplant (ASCT). Methods: Patients were included if they underwent upfront ASCT for MM from January 2013 to December 2018 within 6 months of diagnosis, received VRD or VCD induction therapy and achieved at least a partial response pre-transplant. Of 1,135 patients, 914 patients received VRD and 221 received VCD therapy. Cox proportional hazards models were created for progression-free survival (PFS) and overall survival (OS). The following covariates were adjusted in the models: induction regimen (main effect), age, sex, race, performance score, hematopoietic cell transplant-comorbidity index (HCT-CI), estimated glomerular filtration rate (eGFR) at diagnosis, immunoglobulin subtype, cytogenetics, ISS stage, response status at transplant, melphalan dose, and maintenance therapy. Results: As shown in Table 1, patients in the VRD and VCD cohorts had similar age at transplant, adjusted HCT-CI scores, and distribution of high-risk cytogenetics. Patients in the VCD group were more likely to have renal impairment and ISS stage III disease. An eGFR (mL/min/1.73m2) at diagnosis < 60 was seen in 26% of VRD patients vs. 48% of VCD patients. ISS stage III was seen in 17% vs. 34% of patients, respectively. Treatment and Response: Pre-transplant response in the VRD cohort was: complete response (CR)- 17%, very good partial response (VGPR)- 48% and partial response (PR)- 35%. Response in the VCD cohort was: CR- 17%, VGPR- 42% and PR- 41%. Conditioning dose was melphalan 200 mg/m2 in 80% of patients receiving VRD vs. 69% in the VCD group. Post-transplant response was at least VGPR in 74% vs. 75% of patients, respectively. Maintenance in the VRD group was: lenalidomide based (+/- bortezomib)- 80%, bortezomib based- 5%, other-3% and none- 12% of patients. In the VCD group, maintenance was: lenalidomide based- 63%, bortezomib based- 11%, other- 1% and none- 24%. Survival: Patients receiving VRD induction had superior outcomes compared to VCD induction with median PFS from transplant of 44.6 (38.0-55.8) months vs 34.1 (25.8-44.7) months, p 0.004 respectively. Median OS was not reached for either group, with 5-year OS 79 (74-83)% for VRD and 60 (50-69)% for VCD, p <0.001. Univariate PFS and OS outcomes by induction regimen and eGFR at diagnosis are shown in Table 2 and Figure 1. Multivariate analysis is shown in Table 3. After adjusting for prognostic factors, there was no statistically significant difference between the two induction regimens, with hazard ratio (HR) for PFS in the VCD vs VRD group being 1.22 (95% CI: 0.96-1.55, p=0.10). ISS stage, cytogenetics, disease status prior to transplant, and maintenance were independent prognostic factors for PFS. Similarly, on multivariate analysis for OS, there was no statistically significant difference in the two groups, with HR for OS in VCD vs VRD group being 1.33 (95% CI: 0.93-1.92, p=0.12). ISS stage, cytogenetics, disease status prior to transplant, and maintenance were independent prognostic factors for OS. Conclusions: In patients with MM undergoing upfront transplant after VRD or VCD induction, no difference in outcomes was seen based on the induction therapy received after adjusting for other prognostic factors. As several MM patients with renal dysfunction are started on VCD, it is reassuring to see that VCD was not associated with inferior PFS, likely due to the eventual transition to maintenance therapy in the majority due to subsequent improvement of renal function. The use of maintenance treatment was uniformly associated with superior outcomes. Disclosures Sidana: Janssen: Consultancy. Kumar:Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding; Genentech/Roche: 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; 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; 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; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Sanofi: Research Funding; MedImmune: Research Funding; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Tenebio: Other, Research Funding; Genecentrix: Consultancy; Carsgen: Other, Research Funding; Cellectar: Other; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy. Giralt:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Actinuum: Other: Advisory board, Research Funding; Amgen: Other: Advisory Board, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; OMEROS: Research Funding; SPECTRUM Pharma: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: 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, Research Funding; PFIZER: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jensenn: Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Research Funding; MILTENYI: Research Funding; JAZZ Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Qazilbash:Janssen: Research Funding; Bioclinica: Consultancy; Amgen: Research Funding; Angiocrine: Research Funding; Bioline: Research Funding. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. D'Souza:Janssen: Consultancy; Akcea: Consultancy; Imbrium: Consultancy; Merck: Research Funding; Pfizer: Consultancy; Teneobio: Research Funding; Amgen: Research Funding.

Background: Bortezomib, a proteasome inhibitor, has shown efficacy in the treatment of newly diagnosed and relapsed light chain (AL) amyloidosis, and the combination of bortezomib, cyclophosphamide and dexamethasone is a commonly used regimen in AL. Ixazomib is the first oral proteasome inhibitor to be approved, and the combination of ixazomib with cyclophosphamide and dexamethasone is an all oral effective regimen for the treatment of multiple myeloma. This phase 2 trial was designed to evaluate the efficacy of this regimen in patients with AL, who have not received any therapy. Patients and methods: Newly diagnosed patients with biopsy proven AL amyloidosis, with organ involvement requiring therapy, were enrolled if they had measurable disease (Serum immunoglobulin free light chain ≥5 mg/dL AND abnormal serum free light chain ratio) and adequate organ function. Patients with severe organ involvement were excluded (Alkaline phosphatase >750 U/L, creatinine clearance <30 mL/min or NT-ProBNP ≥ 7500 ng/dL). Treatment consisted of ixazomib 4 mg days 1, 8, 15; cyclophosphamide 500 mg PO weekly and dexamethasone 40 mg, weekly for twelve 28-day cycles, followed by ixazomib maintenance (days 1, 8, 15) at the last tolerated dose till progression. The primary objective was to determine the hematologic response rate of ixazomib, used in combination with cyclophosphamide and dexamethasone in patients with previously untreated AL. A one-stage binomial design was utilized to test the null hypothesis that the hematologic response rate is at most 30% against the alternative hypothesis that it is at least 50%, with 85% power and 9% type I error. Results: Thirty-five patients were enrolled, median age was 67 (range 38-78) years; 69% were male. Organ involvement included cardiac in 23 (65.7%), renal in 19 (54.3%), and nervous system involvement in 5 (14.3%). At data cutoff 8 patients still remain on study with a median follow up of 4.4 months for those who are alive. Across the trial a median of 4 cycles (range 0-23) of treatment have been completed; the most common reason for going off study was institution of alternate therapy in 17 patients (63%). The overall hematologic response was 57% (20/35) and included amyloid CR in 5 (14%), VGPR in 9 (26%) and a PR in 6 (17%) patients. Confirmed organ responses have been observed in 5 patients so far, 2 each for cardiac and renal and 1 hepatic. The median PFS and OS have not been reached; 4 patients had hematological progression; 6 patients (17%) have died. Across 193 cycles of treatment administered, dose modification was required in 5, 3, and 10 patients, respectively, for ixazomib, cyclophosphamide and dexamethasone. A grade 3 or higher adverse event (AE), at least possibly attributed to the study drugs, was observed in 41% of patients. The figure shows the maximum grade of adverse events for individual patients seen in more than one patient across the study. Conclusions: The all-oral regimen of ixazomib, cyclophosphamide, and dexamethasone is active in patients with previously untreated AL amyloidosis with hematologic responses observed in 57% of patients, including complete responses. Organ response has been observed but will likely need longer follow up for accurate assessment, given the delay in organ responses in this disease. Further evaluation of this combination is warranted. Disclosures Gertz: Alnylam: Consultancy; Ionis/Akcea: 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; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; NCI SPORE MM: Research Funding; Prothena: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy. Kapoor:Celgene: Honoraria; GlaxoSmithKline: Research Funding; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy. Larsen:Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dingli:Apellis: Consultancy; Janssen: Consultancy; Sanofi-Genzyme: Consultancy; Rigel: Consultancy; Bristol Myers Squibb: Research Funding; Karyopharm Therapeutics: Research Funding; Alexion: Consultancy; Millenium: Consultancy. Dispenzieri:Janssen: Research Funding; Intellia: Research Funding; Alnylam: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Takeda: Research Funding. Kumar:Adaptive Biotechnologies: Consultancy; Carsgen: Other, Research Funding; 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; Genecentrix: Consultancy; Dr. Reddy's Laboratories: Honoraria; Tenebio: Other, Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Kite Pharma: Consultancy, Research Funding; Karyopharm: Consultancy; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; 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; Genentech/Roche: 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; Cellectar: Other; MedImmune: Research Funding.

Background: Multiple myeloma (MM) is a heterogeneous disease that may be evaluated by a broad array of imaging and laboratory techniques to measure disease activity and predict prognosis. FDG PET/CT has been shown to be predictive of patient outcomes throughout the disease course, with several studies demonstrating that PET/CT is an independent prognostic factor for progression free survival and overall survival (OS). We sought to corroborate these findings by specifically examining the prognostic impact of PET/CT in the post-transplant setting. We retrospectively analyzed PET/CT in MM patients after consolidation therapy with autologous stem cell transplant (ASCT) and correlated these findings with time to progression (TTP) and OS to assess the impact of day 100 PET/CT findings as an independent prognostic factor. Methods: A retrospective cohort study was conducted on 231 myeloma patients who underwent ASCT between 2003-2016 and had a FDG PET/CT exam available for analysis at an average of day 104 post-transplant. We recorded the findings on PET/CT prior to transplant, where available. PET/CT without evidence of active/residual disease (PET-) was defined per IMWG guidelines (disappearance of every area of increased tracer uptake found on preceding PET/CT, or uptake < mediastinal blood pool, or decrease < surrounding normal tissue). PET/CT indicating active disease (PET+) was defined as any abnormal uptake or incompletely resolved uptake from previous exam. A Kaplan-Meier model was used to estimate median TTP and OS and the 2-sided log-rank test to compare groups. TTP and OS were calculated from the date of ASCT to the date of confirmed disease progression or death, respectively. Outcomes were then compared among patients with a PET/CT versus those without a PET/CT post-ASCT to assess for the presence of selection bias. A proportional hazards fit model was used for multivariate analysis. Results: The median length of follow-up for the entire cohort was 49 months (range: 43-58 mo), median TTP was 18.5 months (95% CI; 15.4-21.8), and median OS was 61.5 months (95% CI; 49-75). Among the entire cohort (n=231), 150 (65%) patients had a positive PET/CT exam at day 100 post-ASCT while 81 (35%) had a negative PET exam. There were 195 (84%) patients with a PET/CT exam prior to ASCT available for comparison, of which 161 (85%) were PET+ and 29 (15%) were PET-. Median time between PET/CT exams was 4.1 months (range 1.4-55). Median TTP among PET+ patients near day 100 was 12.4 months vs. 24 months PET- patients (p<.0001, Fig 1, panel A). Median OS in the PET+ group was 46 months compared to 99 months in the PET- group (p<.0001, Fig 1, panel B). Among patients with a prior PET/CT (195, 84%), median TTP was longer in patients with both exams negative compared to those who were day 100 PET- and previously PET+ (42.6 mo vs. 21.1 mo respectively; p<.0001). TTP was shorter in those who were day 100 PET+ and previously PET- compared to those with persistently PET+ on both exams (4.5 vs. 12.3 mo; p<.0001, Figure 2). Since PET/CT was not routinely ordered post ASCT, we also compared the outcomes between patients getting a PET/CT (n=231) and remaining patients undergoing ASCT (n=1764). Among patients with a day 100 PET/CT vs. those without a PET/CT exam, there was a slightly longer median TTP and OS in the group who did not have a post-ASCT PET/CT. Hazard ratios (HR) after adjusting for disease response (CR at day 100 vs. non-CR) were as follows: TTP PET+ HR 1.76 (1.2-2.4; p=0.003), OS PET+ HR 1.8 (1.2-2.6; p=.0016). Conclusions: MM is a heterogeneous disease that relies on different assessments for determining response, activity, and prognosis. Among these, PET/CT has shown promise in predicting prognosis, independent of disease state and conventional prognostic factors. Our study confirms these findings, demonstrating that an abnormal PET/CT near day 100 post-transplant is predictive of shorter TTP and OS. This prognostic significance remained even after adjusting for disease response (CR vs. non-CR), which could be explained by the sometimes patchy distribution of myeloma in the bone marrow, and identification of extramedullary disease by PET/CT. Taken together, these results demonstrate a possible role for incorporating PET/CT in the post-transplant setting as an independent prognostic variable in stratifying disease risk. Disclosures Dingli: Apellis: Consultancy; Janssen: Consultancy; Rigel: Consultancy; Millenium: Consultancy; Karyopharm Therapeutics: Research Funding; Sanofi-Genzyme: Consultancy; Bristol Myers Squibb: Research Funding; Alexion: Consultancy. Gertz:NCI SPORE MM: Research Funding; International Waldenstrom Foundation: Research Funding; Amyloidosis Foundation: Research Funding; Springer Publishing: Patents & Royalties; i3Health: Consultancy; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; DAVA oncology: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Celgene: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; Physicians Education Resource: Consultancy; Medscape: Consultancy, Speakers Bureau; Amgen: Consultancy; Appellis: Consultancy; Annexon: Consultancy; Spectrum: Consultancy, Research Funding; Janssen: Consultancy; Sanofi: Consultancy; Prothena: Consultancy; Alnylam: Consultancy; Ionis/Akcea: Consultancy. Dispenzieri:Janssen: Research Funding; Celgene: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Intellia: Research Funding; Takeda: Research Funding. Kapoor:Takeda: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Celgene: Honoraria; Cellectar: Consultancy; GlaxoSmithKline: Research Funding. Lin:Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy; 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; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Kumar:Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Merck: 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; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Novartis: Research Funding; Kite Pharma: Consultancy, Research Funding; Karyopharm: Consultancy; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; 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; Cellectar: Other; Tenebio: Other, Research Funding; Sanofi: Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Carsgen: Other, Research Funding; Genecentrix: Consultancy; MedImmune: Research Funding; BMS: Consultancy, Research Funding.

Background: Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by a complex genomic landscape with molecular and clinical heterogeneity. Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor currently under investigation as a potential targeted therapy for the treatment of relapsed/refractory (RR) MM. Using a next-generation sequencing (NGS)-based approach, the mutational landscape and gene expression profile (GEP) of patients (pts) with RRMM in BELLINI was evaluated for potential impact on observed clinical outcomes in key biomarker subgroups. Methods: BELLINI (NCT02755597) is a randomized, double-blind, multicenter Phase 3 study of bortezomib + dexamethasone (Bd) + either Ven or placebo (Pbo) in pts with RRMM who received 1-3 prior therapies and were sensitive or naïve to proteasome inhibitors. Pts were randomized 2:1 to receive Ven 800 mg/d or Pbo + Bd. The following biomarker analyses were performed by central laboratory assessments of CD138-enriched bone marrow mononuclear cells collected at baseline: BCL2 gene expression by quantitative PCR (qPCR), cytogenetic abnormalities by interphase fluorescence in situ hybridization (FISH), identification of somatic mutations by whole-exome sequencing (WES), and transcriptomic analysis by RNA sequencing (RNAseq). Correlation between mutational status, BCL2high status (Harrison et al. Blood. 2019:134 suppl:142), cytogenetics, GEP, and survival outcomes were examined by pairwise t-test and by hazard ratio (HR) from Cox proportional hazard model. Results: As of the data cutoff (13 Sep 2019), 291 pts were randomized (194 to Ven and 97 to Pbo); 262 pts (90.0%) were evaluable by FISH, 257 pts (88.3%) by qPCR, 197 pts (67.7%) by WES, and 184 pts (63.2%) by RNAseq. The mutational landscape of evaluable pts was highly heterogeneous (Figure 1A). MAPK pathway mutations were the most prevalent (62/197 pts; 31.5%); however, recurrent mutations in the NF-kB pathway (TRAF3 or CYLD) were also observed (12/197 pts; 6.1%). Within the MAPK pathway, the most frequently mutated genes were KRAS (39/197 pts; 19.8%), NRAS (8/197 pts; 4.1%), BRAF (8/197 pts; 4.1%), and NF1 (12/197 pts; 6.1%). Although a higher rate of pts with a MAPK mutation was observed in the t(11;14) and BCL2high subgroup compared to pts without these biomarkers (39/101 pts [38.6%] vs 23/95 pts [24.2%]; P=.04), improvement in progression-free survival (PFS) with Ven+Bd was observed in pts with (HR=0.08; 95% CI, 0.02-0.31; P<.001) or without (HR, 0.31 [95% CI, 0.16-0.63]; P=.001) a MAPK pathway mutation. High somatic mutation loads are associated with increased genomic instability, resistance to therapy, and decreased overall survival (OS) in MM. High tumor mutation burden (TMB), defined as ≥20 mutations/megabase of sequenced DNA, was observed in 12/197 pts (6.1%). Although there were a limited number of high TMB pts, reduced PFS (HR, 4.55 [95% CI, 2.33-8.88]; P<.001) and OS (HR, 3.89 [95% CI, 1.76-8.56]; P<.001) compared to low TMB pts was observed regardless of treatment arm. WES detected a recurrent BCL2 mutation (Ala43Thr) in 15/197 pts (7.6%). This BCL2 mutation has not previously been identified in MM and did not appear to affect survival outcomes among pts in either arm. Supervised clustering of RNAseq data grouped pts into respective MM GEP (Zhan et al. Blood. 2006;108:2020) at the following frequencies: CD-1 (2.7%), CD-2 (8.2%), HY (40.2%), MF (1.6%), MS (10.9%), LB (5.4%), and PR (31.0%). As shown in Figure 1B, 16/20 pts (80%) allocated to the CD-1/CD-2 cluster had a t(11;14) mutation, but 17/20 pts (85%) and 2/3 pts (67%) in MS and MF GEP groups had t(4;14) or t(14;16) mutations, respectively. The HY GEP group was primarily (56/74 pts; 76%) hyperdiploid by FISH. Though a higher rate of pts with a HY GEP (50/98 pts [51.0%] vs 24/86 pts [27.9%]; P<.001) and a lower rate of PR GEP (11/98 pts [11.2%] vs 46/86 pts [53.5%]; P<.001) were observed in the t(11;14) and BCL2high subgroups compared with non-t(11;14) and BCL2low subgroups, respectively, improvement in PFS with Ven+Bd was independent of GEP classification. Conclusion: Using an integrative approach of genomic and transcriptomic profiling, response to Ven+Bd in key biomarker subgroups was shown to be independent of concurrent mutations in key oncogenic signaling pathways and GEPs known to be prognostic in MM; however, high mutation load appears to be a clinically relevant risk factor that negatively affects survival in MM. Disclosures O'Dwyer: Celgene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS: Research Funding; Carrick Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy; ONK Therapeutics: Consultancy, Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Spencer:Roche: Honoraria; Sanofi: Consultancy, Honoraria; Pharmamar: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; HaemaLogiX: Consultancy, Honoraria, Research Funding. Kumar:Janssen Oncology: 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; Takeda: 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; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Genecentrix: Consultancy; Cellectar: Other; MedImmune: Research Funding; Karyopharm: Consultancy; Sanofi: Research Funding; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; 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; Novartis: Research Funding. Popat:AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol Myers Squibb: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy, Honoraria. Moreau:Abbvie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Novartis: Honoraria. Dail:Genentech: Current Employment, Current equity holder in publicly-traded company. Jalaluddin:AbbVie: Current Employment, Other: may hold stock or stock options. Yang:Abbvie: Current Employment, Current equity holder in publicly-traded company. Lu:AbbVie: Current Employment, Current equity holder in publicly-traded company. Zha:Abbvie: Current Employment, Current equity holder in publicly-traded company. Dunbar:Abbvie: Current Employment, Current equity holder in publicly-traded company. Vishwamitra:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Mantis:Abbvie: Current Employment, Current equity holder in publicly-traded company. Melhem-Bertrandt:AbbVie: Current Employment; Astellas: Ended employment in the past 24 months. Ross:AbbVie: Current Employment, Current equity holder in publicly-traded company. Harrison:F. Hoffmann-La Roche: Consultancy, Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Janssen: Honoraria; Haemalogix: Consultancy; BMS: Consultancy, Honoraria.

Background: The absence of residual monoclonal protein in the serum and urine by IFE using specific antibodies to individual heavy and light chains has been an important part of response assessment and is required for categorizing patients as in complete response. MASS FIX has been shown to be more sensitive in picking up small amounts of monoclonal protein and represents an advancement in the field. Ongoing studies are examining the clinical significance of this increased sensitivity. We designed the following study using clinically obtained test results to examine this question. Patients and methods: The clinical laboratory at Mayo Clinic changed the process from IFE to MASS FIX in July 2018. We identified patients who had sequential testing before and after this date and collected test results from the last IFE prior to the date of transition and the first MASS FIX after the date of transition. Patients were grouped based on the paired results and outcomes compared between groups. Time to next therapy (TTNT) was defined as the time from the first MASS FIX date to the start of next therapy. Survival was estimated by the Kaplan-Meier method and these curves were compared using log rank test. Results: Overall, 739 patients with MM, who had a MASS FIX within 12 months of the IFE were studied; 380 (51%) patients had a negative IFE prior to implementation of MASS FIX. These patients had a MASS FIX test performed at a median of 3.7 (0.03-12) months from the last available IFE. The gap between IFE and MASS FIX was <6 months and < 3 months in 71% and 54% of the patients. Among the patients with a negative IFE, 130 (34%) tested positive on the subsequent MASS FIX. Limiting the analysis to those with a MASS FIX within 6 and 3 months yielded 32% in each group that turned positive from previous negative IFE. The median TTNT from the MASS FIX date was significantly shorter for those who became positive on MASSFIX; median was not reached for either group (P=0.002) (Figure). We then limited the analysis to those patients with a gap of <6 months and <3 months between the tests. The results were consistent: P= 0.012 for those with a gap of < 6 months and P=0.01 for those with a gap < 3 months. Conclusion: The results suggest that the additional sensitivity offered by MASS FIX have clinical significance in patients with MM, given that patients with residual disease identified by MASS FIX have an earlier relapse. The data supports the use of the more sensitive MASS FIX in the laboratory compared to the conventional IFE approaches. The study has the disadvantage that the samples were not tested simultaneously and some of the samples turning positive may reflect an early evidence of relapse, but the relative consistency of the finding irrespective of the gap between the tests argues against that. Ongoing studies are examining MASS FIX on the samples that were called to be negative by IFE initially. Figure Disclosures Murray: The Binding Site: Patents & Royalties: Patent Use of Mass Spec to identify monoclonal proteins licensed to The Binding Site. Dispenzieri:Takeda: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Intellia: Research Funding; Pfizer: Research Funding; Alnylam: Research Funding. Kapoor:Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Celgene: Honoraria; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Amgen: Research Funding. Gertz:Janssen: Other: personal fee; Spectrum: Other: personal fee, Research Funding; Springer Publishing: Patents & Royalties; Abbvie: Other; Appellis: Other: personal fee; Annexon: Other: personal fee; Celgene: Other; Amgen: Other: personal fee; Physicians Education Resource: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau; Research to Practice: Other; Sanofi: Other; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Proclara: Other; Aurora Bio: Other; Prothena: Other: personal fee; Alnylam: Other: personal fee; Ionis/Akcea: Other: personal fee. Dingli:Karyopharm Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Rigel: Consultancy; Sanofi-Genzyme: Consultancy; Millenium: Consultancy; Alexion: Consultancy; Janssen: Consultancy; Apellis: Consultancy. Lin:Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy. Kumar:Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Carsgen: Other, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Tenebio: Other, Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Adaptive Biotechnologies: Consultancy; Kite Pharma: Consultancy, Research Funding; Sanofi: 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; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; MedImmune: Research Funding; Cellectar: Other; Genecentrix: Consultancy; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Novartis: Research Funding.

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.