Sanchorawala, Vaishali

PURPOSE Binary cardiac response assessment using cardiac biomarkers is prognostic in light chain amyloidosis. Previous studies suggested four-level cardiac responses using N-terminal prohormone of brain natiuretic peptide improves prognostic prediction. This study was designed to validate graded cardiac response criteria using N-terminal prohormone of brain natiuretic peptide/brain natiuretic peptide. PATIENTS AND METHODS This retrospective, multicenter study included patients with light chain amyloidosis who achieved at least a hematologic partial response (PR) and were evaluable for cardiac response. Four response criteria were tested on the basis of natriuretic peptide response depth: cardiac complete response (CarCR), cardiac very good partial response (CarVGPR), cardiac PR (CarPR), and cardiac no response (CarNR). Response was classified as best response and at fixed time points (6, 12, and 24 months from therapy initiation). The study primary outcome was overall survival. RESULTS 651 patients were included. Best CarCR, CarVGPR, CarPR, and CarNR were achieved in 16%, 26.4%, 22.9%, and 34.7% of patients, respectively. Patients in cardiac stage II were more likely to achieve CarCR than patients in cardiac stage IIIA and IIIB (22% v 13.5% v 3.2%; P < .001). A deeper cardiac response was associated with a longer survival (5-year overall survival 93%, 79%, 65%, and 33% for CarCR, CarVGPR, CarPR, and CarNR, respectively; P < .001). Fixed time-point analyses and time-varying covariates Cox regression analysis, to minimize survivorship bias, affirmed the independent survival advantage of deeper cardiac responses. Four-level response performed better than two-level response as early as 12 months from therapy initiation. CONCLUSION Graded cardiac response criteria allow better assessment of cardiac improvement compared with the traditional binary response system. The study re-emphasizes the importance of early diagnosis, which increases the likelihood of deep cardiac responses.

TPS8076 Background: Light chain (AL) amyloidosis is a progressive and typically fatal disorder caused by misfolded AL protein produced by plasma cells. Birtamimab is a monoclonal antibody designed to neutralize circulating soluble and deposited insoluble amyloid, thus promoting phagocytic clearance. In 2018, the phase 3 VITAL study in newly diagnosed, treatment-naive patients was terminated based on futility analysis of the primary endpoint (time to all-cause mortality [ACM] or time to cardiac hospitalization > 90 days after first study drug infusion); the final hazard ratio (HR) numerically favored birtamimab + standard of care (SOC) over placebo + SOC (0.835 [95% CI: 0.5799, 1.2011]; p = 0.330). Post-hoc analysis of ACM over 9 months revealed a substantial survival benefit (HR = 0.413 [95% CI: 0.191, 0.895]; p = 0.025) in patients at high risk for early death (Mayo Stage IV). Post-hoc analyses of secondary endpoints in this subgroup indicated meaningful improvements in health-related quality of life (assessed with 36-Item Short Form Health Survey version 2; SF-36v2) and 6-minute walk test (6MWT) distance with birtamimab + SOC (p < 0.05) at 9 months. Methods: The phase 3, double-blind, placebo-controlled AFFIRM-AL study (NCT04973137) will enroll up to 150 Mayo Stage IV patients with newly diagnosed, untreated AL amyloidosis. Patients will be randomized (2:1) to 24 mg/kg intravenous birtamimab or placebo every 28 days. Both arms will receive concomitant chemotherapy with a first-line bortezomib-containing regimen, with or without daratumumab (D), at the discretion of the investigator. Patients will be stratified at randomization based on their 6MWT distance ( < 300 vs ≥300 meters) and initiation of D. The primary efficacy endpoint is time to ACM. Secondary endpoints are change from baseline to month 9 in the physical component summary of the SF-36v2 and 6MWT distance. This trial is powered at a significance level of 0.1 under a Special Protocol Assessment (SPA) with the U.S. Food and Drug Administration (FDA). Given the > 50% relative risk reduction for ACM observed in the post-hoc analysis of VITAL for patients with Mayo Stage IV disease, the AFFIRM-AL study is designed to confirm this effect of birtamimab. Approximately 130 global sites are planned; site initiation and patient randomization are underway. Conclusion: Treatments that improve survival in AL amyloidosis are needed, particularly for patients with advanced cardiac involvement, as median overall survival for those with Mayo Stage IV disease is ̃6–9 months. The AFFIRM-AL study is designed to confirm the survival benefit observed in the VITAL study in patients with Mayo Stage IV AL amyloidosis. Clinical trial information: NCT04973137.

Abstract Introduction: Light chain (AL) amyloidosis is a plasma cell disease characterized by the deposition of insoluble amyloid fibrils into organs leading to organ dysfunction and death. The analysis at 6 and 12 months of the ANDROMEDA study (NCT03201965) showed that the addition of subcutaneous (SC) daratumumab to the standard of care combination of bortezomib, cyclophosphamide, and dexamethasone (VCd) was superior to VCd alone, with higher rates of hematologic complete response (CR) and an acceptable safety profile. Based on these findings daratumumab with VCd (D-VCd) was approved for newly diagnosed AL amyloidosis in January 2021 in the US and June 2021 in the EU. Here, we present data from the analysis at 18 months of the ANDROMEDA study. Methods: ANDROMEDA is a randomized, open-label, active-controlled phase 3 study including patients with newly diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage I-IIIA, estimated glomerular filtration rate ≥20 mL/min, and absence of symptomatic multiple myeloma. Patients were randomized (1:1) to D-VCd or VCd for 6 28-day cycles. Bortezomib (1.3 mg/m 2), cyclophosphamide (300 mg/m 2 up to 500 mg per week), and dexamethasone (20-40 mg) were administered weekly. SC daratumumab (1800 mg co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was administered once weekly in cycles 1 and 2 and every 2 weeks in cycles 3 to 6. Patients in the D-VCd arm received only SC daratumumab after cycle 6, every 4 weeks (up to a total of 24 cycles from first dose). The primary endpoint was overall (ie, at any time) hematologic CR rate, defined here as normalization of free light chain (FLC) levels and ratio (FLCr) and negative serum and urine immunofixation, confirmed at a subsequent visit; normalization of uninvolved FLC level and FLCr were not required if involved FLC was lower than the upper limit of normal. Secondary endpoints included major organ deterioration progression-free survival (PFS), organ response rate, time to hematologic response, overall survival (OS), and safety. Results: A total of 388 patients were randomized to receive D-VCd (N=195) or VCd alone (N=193). At the May 2021 clinical cutoff, the median duration of treatment for D-VCd and VCd arms was 21.3 and 5.3 months, respectively. In the D-VCd arm, 149 patients (77.2%) received daratumumab monotherapy after completing 6 cycles of D-VCd; of those, 17 (11.4%) were still receiving treatment. The rates of deep hematological responses favored the D-VCd treatment arm (Table). At a median follow-up of 25.8 months, the rate of hematologic CR was significantly higher in the D-VCd arm vs the VCd arm (59.5% vs 19.2%; odds ratio [95% confidence interval (CI)], 6.03 [3.80-9.58]; P&lt;0.0001). Similarly, more patients achieved a very good partial response or better (≥VGPR) (D-VCd vs VCd, 79.0% vs 50.3%; odds ratio [95% CI], 3.74 [2.39-5.86]; P&lt;0.0001). Among patients who responded, the median time from randomization to ≥VGPR was shorter in the D-VCd arm (0.56 months) vs the VCd arm (0.82 months). Comparable to the cardiac response analysis at 6 months (D-VCd vs VCd, 42% vs 22%), greater cardiac response rates were achieved with D-VCd compared with VCd at 18 months (53% vs 24%). Similarly, renal response rates remained superior with D-VCd vs VCd alone at 18 months (58% vs 26% compared with 6 months [54% vs 27%]). A total of 79 deaths occurred (D-VCd, N=34; VCd, N=45). In the D-VCd arm, only 1 additional grade 3/4 treatment-emergent adverse event occurred over 18 months vs 12 months (119 [61.7%] vs 118 [61.1%] patients) and no additional infusion-related reactions were reported. OS will be analyzed and major organ deterioration PFS will be updated after approximately 200 events have occurred. Conclusions: These results demonstrate the sustained clinical benefits of D-VCd vs VCd in terms of hematologic and organ responses with longer follow-up, although it should be noted that many patients in the D-VCd arm received daratumumab monotherapy following 6 cycles of D-VCd, while patients in the VCd group stopped study treatment. Nevertheless, the study continues to support the use of D-VCd over VCd alone in patients with newly diagnosed AL amyloidosis. Following its recent approval, D-VCd represents a new SOC for patients with AL amyloidosis. Figure 1 Figure 1. Disclosures Comenzo: Prothena Biosciences: Consultancy, Research Funding; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Caelum: Consultancy, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Patents & Royalties: WO2016187546A1, Research Funding. Palladini: Pfizer: Honoraria; Siemens: Honoraria; Janssen Global Services: Honoraria, Other: advisory board fees. Kastritis: Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria. Minnema: Janssen: Consultancy; BMS: Consultancy; Kite/Gilead: Consultancy; Celgene: Other: Travel expenses; Alnylam: Consultancy; Cilag: Consultancy. Wechalekar: Amgen: Research Funding; Janssen: Consultancy; Takeda: Honoraria; Celgene: Honoraria; Caelum Biosciences: Other: Clinical Trial Funding; Alexion, AstraZeneca Rare Disease: Consultancy. Jaccard: Pfizer: Honoraria; Abbvie: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees. Dispenzieri: Janssen: Consultancy, Research Funding; Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Alnylam: Research Funding; Pfizer: Research Funding; Takeda: Research Funding. Lee: Karyopharm: Consultancy; Celgene: Consultancy; Takeda Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Sanofi: Consultancy; Genentech: Consultancy; Legend Biotech: Consultancy; Janssen: Consultancy, Research Funding; Oncopetides: Consultancy; Bristol Myers Squibb: Consultancy; Regeneron: Research Funding. Sanchorawala: Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Pfizer: Honoraria; Proclara: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Prothena: 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, Research Funding; Takeda: Research Funding; Celgene: Research Funding. Gibbs: AbbVie: Consultancy; Janssen, Celgene, Amgen, Takeda, BMS and Pfizer: Consultancy, Honoraria. Mollee: Janssen, Pfizer: Research Funding; Amgen, BMS, Janssen, Caelum, EUSA, Pfizer, SkylineDx, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: No personal fees received. Venner: BMS: Honoraria; Amgen: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Schönland: Janssen: Honoraria, Other: Travel grants, Research Funding; Pfizer: Honoraria; Takeda: Honoraria, Other: Travel grants; Prothena: Honoraria, Other: Travel grants; Sanofi: Research Funding. Suzuki: Abie: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; ONO: Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Kim: BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Cibeira: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akcea: Honoraria, Membership on an entity's Board of Directors or advisory committees. Beksac: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Libby: Genentech: Research Funding; BMS: Research Funding; GSK: Research Funding; Janssen: Consultancy, Research Funding. Valent: Caelum Biosciences: Other: Clinical Trial Funding; Celgene Corporation: Speakers Bureau; Takeda Pharmaceuticals: Speakers Bureau; Amgen: Speakers Bureau. Hungria: Amgen, BMS, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/travel ; Abbvie: Honoraria; Sanofi: Honoraria, Other: Support for attending meetings/travel ; Takeda: Honoraria. Wong: Amgen: Consultancy; Genentech: Research Funding; Fortis: Research Funding; Janssen: Research Funding; GloxoSmithKlein: Research Funding; Dren Biosciences: Consultancy; Caelum: Research Funding; BMS: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosenzweig: Janssen: Consultancy, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Akcea: Speakers Bureau; Takeda: Speakers Bureau; Onocopeptides: Speakers Bureau. Bumma: Amgen, Sanofi: Speakers Bureau; Janssen, Oncopeptides, Sanofi: Consultancy. Tran: Janssen: Current Employment, Current equity holder in publicly-traded company. Qin: Janssen: Current Employment. Khaled: Jazz: Honoraria; Astellas: Honoraria; Alexion: Honoraria, Speakers Bureau; Omeros: Honoraria; Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company.

Abstract Introduction: Renal light chain (AL) amyloidosis typically manifests as proteinuria with or without renal failure and is associated with a risk of progression to renal replacement therapy (RRT). A significant reduction in circulating amyloidogenic light chain is needed to achieve a renal response. Current renal response criteria are binary defining a renal response as &gt;30% reduction in 24-h proteinuria without worsening estimated glomerular filtration rate (eGFR). Several studies suggest that greater reduction in proteinuria following successful therapy improves renal and overall survival. Methods: AL amyloidosis patients diagnosed between 2010 to 2015, achieving at least hematological partial response (hemPR) to therapy and with renal involvement (defined as 24-h non-selective proteinuria &gt;0.5 g/24-h) were included. Four predefined renal response categories were formulated based on reduction level in pretreatment 24-h proteinuria in the absence of renal progression (≥25% decrease in eGFR): renal complete response (renCR, 24-h proteinuria ≤200 mg/24-h); renal very good partial response (renVGPR, &gt;60% reduction in 24-h proteinuria); renal partial response (renPR, 31-60% reduction in 24-proteinuria); and renal no response (renNR, 30% or less reduction). Renal response was assessed at landmark (6-, 12-, and 24 months from treatment initiation) and as best renal response. Graded renal responses were assessed as predictors for time from diagnosis to RRT and overall survival. Results: Seven hundred and thirty-seven patients were included. The median age was 63. The breakdown of renal stage was: I, 34%; II, 52%; and III, 14%. Eighty percent of patients received 1 line of therapy within 12 months of their diagnosis. Bortezomib-based therapy was given to 60% of the patients; 28% received autologous stem cell transplantation (ASCT) as their first line therapy. Hematological CR was achieved in 44% of patients, followed by hematological very good partial response (38%) and hemPR (18%). RRT was required during follow-up in 15% of patients (n=108) with a median time from diagnosis to RRT of 18 (IQR 6-43) months. Twenty-eight percent of the patients died. The median follow-up of the surviving patients was 69 months (IQR 56-86). Reduction in 24-h proteinuria from baseline improved over time with a median reduction of 34%, 50% and 71% at 6-month, 12-month, and 24-months, respectively. At best response, renCR, renVGPR, renPR and renNR were achieved in 27% (n=199), 34% (n=247), 15% (n=112) and 24% (n=179) of patients, respectively. The median time to best renal response among renal responders was 17 (IQR 8-31) months, longer for renCR (23 months, IQR 10-40) compared to renVGPR (16 months, IQR 9-27) or renPR (11 months, IQR 6-19). A renal response as early as 6 months after therapy initiation was able to predict time to RRT with an increase in RRT risk with lower level of renal response at that time point (5-year RRT risk 0%, 3%, 9% and 16% for renCR, renVGPR, renPR and renNR, respectively, P&lt;0.001, Figure 1A). Prediction of risk for RRT based on renal response depth improved at 12- and 24-months (Figure 1B-C) and at best renal response (Figure 1D). Overall survival discrimination based on renal response depth was noted as early as 12 months from therapy initiation and improved with time. Renal response criteria as best response were tested in a univariate analysis and multivariable proportional hazard models for time to RRT and OS. The graded renal response criteria demonstrated an independent prognostic role for time to RRT and OS. Along with renal stage, graded renal responses were the strongest predictors for time to RRT. Conclusions: We validated new graded renal response criteria based on reduction in 24-h proteinuria. These 4-level renal response criteria highlight the importance of achieving a deep renal response to improve renal and overall survival. These findings will allow clinicians to make decisions on therapy changes or augmentation based on response depth as early as 6-months, before irreversible renal failure develops. Figure 1 Figure 1. Disclosures Palladini: Janssen Global Services: Honoraria, Other: advisory board fees; Siemens: Honoraria; Pfizer: Honoraria. Milani: Celgene: Other: Travel support; Janssen-Cilag: Honoraria. Schönland: Sanofi: Research Funding; Prothena: Honoraria, Other: Travel grants; Janssen: Honoraria, Other: Travel grants, Research Funding; Takeda: Honoraria, Other: Travel grants; Pfizer: Honoraria. Hegenbart: Akcea: Honoraria; Alnylam: Honoraria; Janssen: Consultancy, Research Funding; Prothena: Research Funding; Pfizer: Consultancy, Honoraria. Dispenzieri: Oncopeptides: Consultancy; Alnylam: Research Funding; Sorrento Therapeutics: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. Kumar: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Carsgen: Research Funding; Beigene: Consultancy; Novartis: Research Funding; Bluebird Bio: Consultancy; Amgen: Consultancy, Research Funding; Roche-Genentech: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Antengene: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Kastritis: Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding. Dimopoulos: Takeda: Honoraria; Janssen: Honoraria; Beigene: Honoraria; BMS: Honoraria; Amgen: Honoraria. Liedtke: Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Alnylam: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Witteles: Pfizer: Honoraria, Research Funding; Alnylam: Honoraria, Research Funding; Eidos: Research Funding. Sanchorawala: Pfizer: Honoraria; Takeda: Research Funding; Celgene: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding. Landau: Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genzyme: Honoraria. Cibeira: Celgene: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akcea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wechalekar: Caelum Biosciences: Other: Clinical Trial Funding; Amgen: Research Funding; Janssen: Consultancy; Celgene: Honoraria; Takeda: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy. Gertz: Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria.

Abstract Introduction: Binary cardiac response assessment using NT-proBNP is prognostic in light chain (AL) amyloidosis. Previous studies suggested that refining the criteria to multi-level cardiac responses improves prognostic prediction. We validate a graded cardiac response assessment tool in AL amyloidosis using NT-proBNP or BNP. Methods: In this retrospective, multicenter study AL amyloidosis patients who were diagnosed between 2010 and 2015, achieving at least a hematological partial response (PR) within 12 months of diagnosis and were evaluable for cardiac response (defined as baseline NT-proBNP &gt;650 pg/mL or BNP &gt;150 pg/mL) were included. The following response criteria were tested: cardiac complete response (carCR, nadir NT-proBNP≤350 pg/mL or BNP≤80 pg/mL); cardiac very good partial response (carVGPR, &gt;60% reduction in NT-proBNP/BNP); Cardiac PR (carPR 31-60% reduction); and cardiac non response (carNR, ≤30% reduction). Response was assessed at fixed time points (6, 12 and 24 months from therapy initiation) and at best response. The primary outcome was overall survival based on depth of cardiac response. Multivariate Cox proportional models were analyzed to determine independent prognostic factors for OS and time to cardiac progression using variables with p-value &lt;0.1 in a univariate analysis. Results: Six hundred and fifty-one patients were included. The median age was 64 years. Mayo 2004 cardiac stage II, IIIA and IIIB was present in 47.5%, 38% and 14.5% of patients, respectively (by definition, patients with Mayo stage I do not have cardiac amyloidosis evaluable for response). Seventy-six percent of patients received only one line of therapy within the initial 12 months of diagnosis. Bortezomib-based therapy was the most common (70.2% of patients) followed by autologous stem cell transplantation (ASCT) in 15.7% of patients. Hematological CR, hematological VGPR and hematological PR as best response was achieved in 38%, 39% and 23% of patients, respectively. Forty-three percent of the patients have died, with 36% of the patients dying within 5-years of diagnosis. The median follow-up of the surviving patients is 70 months (IQR 56-84). Cardiac response was evaluable using NT-proBNP in 494 patients (75.9%), BNP in 109 patients (16.7%) and both NT-proBNP and BNP in 48 patients (7.4%). The latter two were grouped together for further analysis. The median time to best cardiac response among responders was 12 months (IQR 7-21 months; 18 months for carCR, 11.5 months for carVGPR and 9.5 months for carPR). Cardiac response improved over time with a median percentage reduction in NT-proBNP/BNP compared to baseline of 15%, 37% and 54%, at 6, 12 and 24 months respectively. Cardiac responses at 6-, 12- and 24-months are depicted in Figure 1A. At best cardiac response, carCR, carVGPR, carPR and carNR were achieved in 16%, 26%, 23% and 35% of patients, respectively. Patients who achieved a carCR had lower cardiac stage at diagnosis compared to patients who achieved carVGPR or carPR (stage II 65% vs 47% vs 47%, respectively; P&lt;0.001). At least carPR at 6 and 12 months and at least carVGPR at 24-months was associated with better survival compared with a lower depth of response. At best cardiac response, deeper cardiac response was associated with a longer survival (5-year OS 93%, 80%, 62% and 35% for carCR, carVGPR, carPR and carNR, respectively; P&lt;0.001, Figure 1B). A 2-year landmark analysis (excluding early deaths not evaluable for cardiac response depth) confirmed improved survival with a deeper cardiac response (5-year OS 93%, 82%, 70% and 58%, P&lt;0.001; Figure 1C). These cardiac response criteria were independent predictors of survival and time to cardiac progression (&gt;30% rise in NT-proBNP/BNP) in multivariate analysis that included age, type of first line therapy, light chain burden, cardiac stage, and hematological response. Conclusions: We validated the prognostic value of graded cardiac response. These response criteria allow better discrimination of patient populations and assessment of treatment effectiveness in an era of improved therapies for AL amyloidosis. The study emphasizes the importance of early diagnosis which increases the likelihood of deep and durable cardiac responses. Figure 1 Figure 1. Disclosures Dispenzieri: Oncopeptides: Consultancy; Pfizer: Research Funding; Sorrento Therapeutics: Consultancy; Takeda: Research Funding; Alnylam: Research Funding; Janssen: Consultancy, Research Funding. Palladini: Siemens: Honoraria; Pfizer: Honoraria; Janssen Global Services: Honoraria, Other: advisory board fees. Schönland: Janssen: Honoraria, Other: Travel grants, Research Funding; Takeda: Honoraria, Other: Travel grants; Sanofi: Research Funding; Pfizer: Honoraria; Prothena: Honoraria, Other: Travel grants. Hegenbart: Alnylam: Honoraria; Janssen: Consultancy, Research Funding; Prothena: Research Funding; Pfizer: Consultancy, Honoraria; Akcea: Honoraria. Kumar: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Novartis: Research Funding; Merck: Research Funding; Tenebio: Research Funding; Bluebird Bio: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Antengene: Consultancy, Honoraria; Oncopeptides: Consultancy; Amgen: Consultancy, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Kastritis: Genesis Pharma: Honoraria; Takeda: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Dimopoulos: Beigene: Honoraria; Takeda: Honoraria; BMS: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Liedtke: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees. Witteles: Eidos: Research Funding; Alnylam: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Sanchorawala: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Proclara: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Karyopharm: Research Funding; Oncopeptide: Research Funding; Pfizer: Honoraria; Sorrento: Research Funding. Landau: Genzyme: Honoraria; Takeda: Research Funding; Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees. Cibeira: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akcea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Ionis Pharmaceuticals: Other: Advisory Board; Aurora Biopharma: Other: Stock option.

Abstract Introduction Systemic immunoglobulin light chain (AL) amyloidosis is a rare disease characterized by amyloid fibril deposits, most commonly in the heart and kidneys. Management of the disease relies primarily on off-label use of multiple myeloma therapies. No treatments are approved for AL amyloidosis in the relapsed/refractory setting. In the phase 3, open-label TOURMALINE-AL1 trial (NCT01659658), patients with relapsed/refractory AL amyloidosis were randomized 1:1 to receive either oral ixazomib plus dexamethasone (Id) or physician's choice (CH) in 28-day cycles, and followed until progression or unacceptable toxicity. An interim analysis demonstrated that Id was well tolerated and, although the primary endpoint of hematologic response rate was not met, time-to-event efficacy analyses consistently favored Id. We report an analysis of patient-reported outcome (PRO) data on health-related quality of life (HRQOL) and AL amyloidosis symptoms from TOURMALINE-AL1; such data for AL amyloidosis in general have been limited. Methods Four PRO instruments were used to collect data to support PRO-related secondary endpoints during the treatment period: the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity subscale (FACT/GOG-Ntx), an amyloidosis symptom questionnaire (ASQ), the EuroQoL 5-Dimension 3-Level (EQ-5D-3L), and the Visual Analogue Scale (EQ VAS) were collected at screening, day 1 of each cycle, and end of treatment (EOT), and the 36-item Short Form General Health Survey version 2 (SF-36v2) was collected at screening, day 1 of every third cycle, and EOT. Analysis of PRO data included descriptive summaries of means and change from baseline and a linear mixed model (LMM) for repeated measures for patients in the intent-to-treat (ITT) population with a baseline and at least one postbaseline PRO-specific assessment. No adjustment was made for multiple comparisons. Data cutoff date was 20 February 2019. Results The ITT population included 168 patients (Id: n=85; CH: n=83), who completed up to 58 cycles (Id) and up to 43 cycles (CH); median treatment duration was 11.7 vs 5.0 months, respectively. PRO compliance in the treatment period was high for all instruments (Figure). Baseline HRQOL as measured by the SF-36v2 and EQ VAS was similar between treatment arms. During the treatment period, SF-36v2 Mental and Physical Component Summary (MCS and PCS) scores remained stable relative to baseline and were similar between arms; the 8 subscale scores were also generally maintained over time, and mostly similar between arms. Least-squares (LS) mean changes from baseline were significantly higher (better HRQoL) for Id compared with CH at several cycles in the SF-36v2 Role Physical and Vitality subscales (p&lt;0.05) (Figure); no subscales demonstrated significant differences favoring CH. Symptom burden as measured by the FACT/GOG-Ntx and ASQ was low at baseline, leaving little room for improvement. FACT/GOG-Ntx scores were generally maintained over time. In the treatment period, there were small but significant differences in LS mean changes from baseline favoring Id over CH at multiple cycles for 7 of the 11 individual items and the neurotoxicity and sensory summary scores; there were small but significant differences favoring CH over Id for 1 individual item (trouble hearing) at a few later cycles. The ASQ total score trended downward slightly (lower burden) during treatment after the first few cycles in both arms. There were significant differences per the LMM favoring Id over CH at cycles 7 and 21 (p&lt;0.05). In both arms, EQ VAS scores trended upward (better HRQoL) during treatment and then declined slightly at EOT. (LMM analyses were not conducted for EQ-5D.) At EOT, a slight deterioration from baseline was observed in actual scores for SF-36v2 domains and summary scales, FACT/GOG-Ntx neurotoxicity and sensory subscales, and ASQ items and total score for both Id and CH. Conclusions Relapsed/refractory AL amyloidosis patients treated with Id experienced HRQOL and symptoms that were similar to or trended better than patients treated with CH. These data suggest that treatment with Id, although with a substantially longer treatment duration, did not have a negative impact on HRQOL in patients with relapsed/refractory AL amyloidosis, a population with currently no approved treatment options. Figure 1 Figure 1. Disclosures Sanchorawala: Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Pfizer: Honoraria; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Prothena: 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, Research Funding; Takeda: Research Funding; Celgene: Research Funding. Wechalekar: Caelum Biosciences: Other: Clinical Trial Funding; Alexion, AstraZeneca Rare Disease: Consultancy; Janssen: Consultancy; Celgene: Honoraria; Amgen: Research Funding; Takeda: Honoraria. Kim: Janssen, BMS: Research Funding. Schönland: Janssen: Honoraria, Other: Travel grants, Research Funding; Takeda: Honoraria, Other: Travel grants; Sanofi: Research Funding; Prothena: Honoraria, Other: Travel grants; Pfizer: Honoraria. Landau: Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genzyme: Honoraria. Fiona: Pfizer: Research Funding. Suzuki: Janssen: Consultancy, Honoraria; Abie: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; ONO: Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Dispenzieri: Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Pfizer: Research Funding; Alnylam: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Comenzo: Karyopharm: Research Funding; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Patents & Royalties: WO2016187546A1, Research Funding; Prothena Biosciences: Consultancy, Research Funding; Caelum: Consultancy, Research Funding. Cherepanov: Takeda: Current Employment, Current equity holder in publicly-traded company. Hayden: Takeda: Current Employment, Current equity holder in publicly-traded company. Kumar: Takeda: Current Employment, Current holder of stock options in a privately-held company. Labotka: Takeda: Current Employment. Faller: Takeda Pharmaceuticals Co.: Current Employment; Viracta Therapeutics, Inc: Current holder of stock options in a privately-held company, Ended employment in the past 24 months, Membership on an entity's Board of Directors or advisory committees; Briacell, Inc: Current holder of stock options in a privately-held company. Kastritis: Amgen, Genesis Pharma, Janssen, Takeda: Consultancy; Amgen, Janssen, Pfizer: Research Funding; Amgen, Genesis Pharma, Janssen, Takeda, Pfizer: Honoraria.

Background: Isatuximab (SAR650984) is an IgG1k monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells in AL amyloidosis. It has been shown to be efficacious and well tolerated in relapsed and refractory multiple myeloma as a single agent and in combination. Here we report on the preliminary results of a prospective multi-center, phase II study of isatuximab in previously treated patients with AL amyloidosis (NCT03499808). Methods: Eligibility included age ≥ 18 years, relapsed or refractory systemic AL amyloidosis, ≥ 1 prior line of therapy, measurable disease (defined as a positive monoclonal serum immunofixation electrophoresis (IFE) or urine IFE, a serum free light chain ratio outside of the normal range (0.25-1.65), and a difference in the involved versus the uninvolved serum free light chain of ≥ 4.5 mg/dL), at least one organ involved, not refractory to daratumumab, ECOG performance status 0-2, creatinine clearance ≥25 mL/min as measured by 24-hour urine collection or as estimated by Cockcroft and Gault formula, and NT-proBNP ≤8500 pg/mL. Patients received isatuximab intravenously 20 mg/kg weekly during the first 28 day cycle and every other week during cycles 2 through 24 for a maximum of 24 cycles. The primary objective was hematologic response with secondary objectives of organ response, safety, progression free survival, and overall survival. Results: At data cut-off (July 24, 2020), 43 patients were registered from March 2018 to September 2019 at 14 institutions. Thirty six patients were eligible with 35 patients receiving at least one dose of isatuximab. Of the eligible patients, the median age was 70 (range 40-81). Prior therapies included proteasome inhibitors in 32 patients (89%), high dose therapy followed by autologous stem cell transplant in 17 patients (47%), immunomodulatory therapy in 9 patients (25%), and anti-CD38 monoclonal antibody therapy in 2 patients (6%). Single organ system involvement was seen in 19 patients (53%), ≥ 2 organ systems in 17 patients (47%), 16 patients (44%) had renal involvement, and 24 (67%) had cardiac involvement. For those with cardiac involvement, 7 patients (29%) had cardiac biomarker stage II and 9 patients (38%) had stage III disease using the Revised Mayo Staging (Kumar S et al., J Clin Oncol, 2012). A total of 17 patients remain on therapy. The median duration on treatment for eligible patients is currently 11.8 months (current range, 0.3-22.1). Of the 19 patients who discontinued treatment, the most common reasons included adverse events in 5 patients (26%), disease progression in 4 patients (21%), sub-optimal response in 2 patients (11%), and concerns related to COVID-19 in 2 patients (11%). The current median follow up is 16.3 months. The most common drug-related AEs were infusion related reactions in 18 patients (50%) with the majority (16/18) being grade I or II, anemia in 9 patients (25%) with the majority (8/9) being grade I, and lymphopenia in 8 patients (22%). Patient characteristics and preliminary safety data were previously presented at the International Symposium on Amyloidosis. The overall hematologic response rate was 77%. Hematological complete response (CR) was observed in 1 of 35 evaluable (completing at least 1 dose) patients (3%), very-good-partial response (VGPR) in 19 patients (54%), and partial response (PR) in 7 patients (20%). Conclusions: Isatuximab demonstrates encouraging efficacy in previously treated patients with AL amyloidosis. The administration of isatuximab in these patients is associated with a good safety profile similar to other monoclonal antibodies against CD38. The data will be updated at the meeting. Disclosures Sanchorawala: Prothena: Research Funding; Caelum: Research Funding; Oncopeptide: Research Funding; Janssen: Research Funding; Regeneron: Other: advisory board; Caleum: Other: advisory board; Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents & Royalties; Takeda: Research Funding; Celgene: Research Funding. Kapoor:Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Research Funding; Takeda: Honoraria, Research Funding. Neparidze:GlaxoSmithKline: Research Funding; Janssen: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Diagnostic committee member . Sarosiek:Spectrum: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Usmani:Incyte: Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Array Biopharma: Research Funding; Pharmacyclics: Research Funding; Celgene: Other; Seattle Genetics: Consultancy, Research Funding; GSK: Consultancy, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Abbvie: Consultancy. Orlowski:Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Isatuximab is FDA approved for relapsed refractory myeloma in combination with pomalidomide and dexamethasone. Isatuximab is not FDA approved for AL amyloidosis.