Vermeulen, Jessica

Abstract Introduction: Multiple myeloma (MM) is a chronic hematologic malignancy with a high symptom burden that can have a substantial negative impact on patients' (pts) health-related quality of life (HRQoL). The introduction of novel triplet regimens for newly diagnosed MM (NDMM) has extended progression-free survival (PFS) and overall survival (OS); however, adverse events and demanding administration and monitoring schedules have a further negative effect on HRQoL, especially among pts who are transplant ineligible (TIE) due to older age and/or frailty. Optimizing initial treatment is particularly important in older pts, many of whom receive only 1 line of therapy. The phase 3 MAIA trial compared daratumumab, lenalidomide, and dexamethasone (D-Rd) vs lenalidomide and dexamethasone (Rd) in TIE pts with NDMM. At a median follow-up of 28 months, D-Rd significantly prolonged PFS and was associated with faster and sustained clinically meaningful improvements in patient-reported outcomes (PROs) vs Rd. Results of an updated analysis with longer follow-up recently confirmed a significant benefit in OS with D-Rd vs Rd as well as a continued significant PFS benefit and higher rates of complete response or better and very good partial response or better. Here we present an update of the HRQoL analysis with additional follow-up. Methods: MAIA (NCT02252172) is a randomized, open-label, active controlled, multicenter, phase 3 study of TIE pts with NDMM who were randomly assigned 1:1 to receive D-Rd or Rd until disease progression (PD) or unacceptable toxicity. PROs were recorded using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and the EQ-5D-5L visual analog scale. EORTC QLQ-C30 has 30 items comprising 5 functional scales (physical, role, emotional, cognitive, and social functioning), 1 global health status (GHS) scale, 3 symptom scales (fatigue, nausea and vomiting, and pain) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Questionnaires were completed at baseline, on day 1 of cycles 3, 6, 9, and 12 for year 1, and every 6 months thereafter until PD. Analyses were conducted on all pts with a baseline and ≥1 post-baseline PRO assessment. Pts were censored at PD or discontinuation of study treatment. Thresholds for meaningful improvement and worsening were defined a priori based on published literature (≥10-point change). Treatment effect was analyzed using a mixed-effects model for repeated measurements including baseline value, visit, treatment, visit by treatment interaction, and randomization stratification factors as fixed effects and individual subject as random effect. Results: At a median follow-up of 56.2 months, discontinuation rates were lower with D-Rd than Rd (56.8% vs 80.8%). For GHS, physical functioning, fatigue, pain, and dyspnea, PROs that are particularly relevant to pts with MM, a numerically greater proportion of pts achieved a meaningful improvement with D-Rd vs Rd (Table 1). Differences were significant for physical functioning, fatigue, and dyspnea. The proportion of pts achieving a meaningful worsening on therapy was similar in both treatment groups (Table 1). The median time to improvement was numerically shorter with D-Rd vs Rd for physical functioning and pain and with Rd vs D-Rd for GHS and fatigue; differences were not significant (Table 2). The median time to worsening of fatigue was similar between groups, numerically longer for D-Rd vs Rd for GHS, and significantly longer with D-Rd than Rd for physical functioning, pain, and dyspnea (Table 2). Median time to worsening of pain with D-Rd vs Rd was 39.43 vs 17.97 months, reflective of an additional ~21 months without worsening pain among pts treated with D-Rd. Between-group differences for least squares mean change from baseline for these 5 PROs favored D-Rd vs Rd at all assessment time points except cycle 3 for physical functioning and cycle 6 for fatigue; differences were significant at ≥1 timepoint for each scale. Conclusions: These updated PRO analyses from the MAIA study demonstrate sustained and clinically meaningful improvements in HRQoL with D-Rd vs Rd with almost 5 years of follow-up. These results are consistent with the clinical benefits of superior PFS, OS, and deep responses observed with D-Rd compared with Rd and support the use of D-Rd in older pts. Figure 1 Figure 1. Disclosures Perrot: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kumar: Roche-Genentech: Consultancy, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Bluebird Bio: Consultancy; Tenebio: Research Funding; Adaptive: 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; Carsgen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Antengene: Consultancy, Honoraria; Oncopeptides: Consultancy; Beigene: Consultancy; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Plesner: Takeda: Research Funding; Oncopeptides: Other: Advisor, Research Funding; Genentech: Other: Advisor, Research Funding; CSL Behring: Other: Advisor; AbbVie: Other: Advisor, Research Funding; Celgene: Other: Advisor, Research Funding; Janssen: Other: Advisor, Research Funding; Genmab: Research Funding. Orlowski: Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees. Moreau: Oncopeptides: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Celgene BMS: Honoraria; Amgen: Honoraria; Abbvie: Honoraria. Bahlis: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Nahi: XNK Therapeutics AB: Consultancy. Hulin: Takeda: Honoraria; Sanofi: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; abbvie: Honoraria. Quach: CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: 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; Bristol Myers Squibb: Consultancy, 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; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Goldschmidt: Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Incyte: Research Funding; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grant; Molecular Partners: Research Funding; MSD: Research Funding; Mundipharma: Research Funding; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; GSK: Honoraria; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding. O'Dwyer: ONK Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Bristol Myers Squibb: Research Funding. Venner: BMS: Honoraria; Amgen: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Weisel: Celgene: 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; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Macro: Sanofi: Honoraria; GSK: Honoraria; Takeda: Honoraria, Other: Travel accomodation, Research Funding; Janssen: Honoraria, Other: Travel accomodation, Research Funding; Celgen/BMS: Honoraria. Leleu: Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria. Liu: Janssen: Current Employment, Current equity holder in publicly-traded company. Fastenau: Janssen: Current Employment, Current equity holder in publicly-traded company. Gries: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Ho: DRG Abacus: Consultancy; Janssen: Consultancy; Emalex Biosciences: Consultancy. Mistry: Janssen: Current Employment, Current equity holder in publicly-traded company. Tromp: Janssen: Current Employment, Current equity holder in publicly-traded company. Delioukina: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Usmani: Abbvie: Consultancy; Array BioPharma: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Research Funding; EdoPharma: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau.

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<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<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: In oncology clinical trials, overall survival (OS) is considered the gold standard efficacy endpoint. However, in multiple myeloma, the prolonged survival times and availability of multiple salvage therapies render it difficult to rely on OS as a primary endpoint. Instead, progression-free survival (PFS) or clinical response can be a relevant biomarker. At the same time, some health technology assessment bodies will only consider evidence based on patient-relevant endpoints, such as morbidity, mortality, and health-related quality of life (HRQoL), within their benefit assessments. Patient-reported outcomes (PROs) provide insights into how a treatment affects HRQoL, including symptoms and functioning. In the phase 3 MAIA trial, daratumumab, lenalidomide, and dexamethasone (D-Rd) demonstrated a significantly prolonged PFS and rapid and sustained improvements in PROs compared with lenalidomide and dexamethasone (Rd) alone at a median follow-up of 28 months. Updated results with longer follow-up confirmed a continued PFS benefit, deepening best clinical responses, and a significant OS benefit with D-Rd. Here, we report the results of analyses exploring the relationship between clinical efficacy endpoints and PROs in the MAIA trial. Methods: In MAIA (NCT02252172), TIE patients with NDMM were randomized to D-Rd or Rd until disease progression (PD) or unacceptable side effects. Clinical response and PD were defined per the International Myeloma Working Group uniform response criteria. PROs were assessed at baseline, on day 1 of cycles 3, 6, 9, and 12 for year 1, every 6 months thereafter until PD, or at end of treatment and at 8 and 16 weeks post-progression using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30). The current analyses were conducted on patients with a baseline PRO assessment and ≥1 post-baseline PRO assessment using a clinical cutoff date of February 19, 2021. Patients from both treatment groups were pooled and stratified by best clinical response. For PROs, the threshold for clinically meaningful change from baseline was defined a priori as ≥10 points based on published literature. Analyses were conducted for the global health status (GHS), fatigue, and pain scales of the EORTC QLQ-C30. The proportions of patients with clinically meaningful improvement in these PROs from baseline at any time while on treatment were calculated for and compared across best clinical response subgroups. For this analysis, patients were censored at the time of PD or discontinuation of therapy. Results were summarized with odds ratios and 95% confidence intervals. Additionally, the proportions of patients with clinically meaningful worsening in PROs from baseline at the time of and post-progression were also calculated for those who had PD. No adjustments were made for multiplicity. Nominal P-values are presented. Results: Best clinical response at a median follow-up of 56.2 months for the 710 patients included in this analysis is shown in the Table. For GHS, fatigue, and pain, the proportion of patients who reported clinically meaningful improvement from baseline increased with increasing depth of best clinical response. Odds ratios comparing best clinical response vs stable disease reflect this relationship and are shown in the Figure. Of the 264 patients who experienced PD and had PRO data at the time of or post-progression, 38.6%, 54.9%, and 39.4% reported meaningful worsening of GHS, pain, and fatigue, respectively, at the time of or post-progression. Conclusions: Patients with deeper best clinical response were more likely to report meaningful improvements in PROs. Patients who experienced PD reported worsening of GHS and symptoms at the time of or following progression. These analyses provide evidence of the association between key clinical efficacy endpoints and PROs and demonstrate the patient relevance of these clinical endpoints. Figure 1 Figure 1. Disclosures Perrot: Abbvie: Honoraria; BMS Celgene: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kumar: Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Antengene: Consultancy, Honoraria; Oncopeptides: Consultancy; Beigene: Consultancy; Tenebio: Research Funding; Takeda: Consultancy, 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; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Plesner: Takeda: Research Funding; Genentech: Other: Advisor, Research Funding; Oncopeptides: Other: Advisor, Research Funding; AbbVie: Other: Advisor, Research Funding; CSL Behring: Other: Advisor; Janssen: Other: Advisor, Research Funding; Celgene: Other: Advisor, Research Funding; Genmab: Research Funding. Orlowski: Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees. Moreau: Abbvie: Honoraria; Oncopeptides: Honoraria; Celgene BMS: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Bahlis: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Honoraria. Nahi: XNK Therapeutics AB: Consultancy. Hulin: abbvie: Honoraria; Celgene/BMS: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Quach: Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: 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; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goldschmidt: GSK: Honoraria; Incyte: Research Funding; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding; Johns Hopkins University: Other: Grant; Mundipharma: Research Funding; MSD: Research Funding; Molecular Partners: Research Funding. O'Dwyer: Bristol Myers Squibb: Research Funding; ONK Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Venner: Amgen: Research Funding; Celgene: Research Funding; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; BMS: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Weisel: Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Macro: Takeda: Honoraria, Other: Travel accomodation, Research Funding; Janssen: Honoraria, Other: Travel accomodation, Research Funding; GSK: Honoraria; Celgen/BMS: Honoraria; Sanofi: Honoraria. Leleu: Sanofi: Honoraria; Roche: Honoraria; Pierre Fabre: Honoraria; Oncopeptides: Honoraria; Novartis: Honoraria; Mundipharma: Honoraria; Merck: Honoraria; Karyopharm Therapeutics: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support. Liu: Janssen: Current Employment, Current equity holder in publicly-traded company. Fastenau: Janssen: Current Employment, Current equity holder in publicly-traded company. Gries: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Ho: DRG Abacus: Consultancy; Emalex Biosciences: Consultancy; Janssen: Consultancy. Mistry: Janssen: Current Employment, Current equity holder in publicly-traded company. Tromp: Janssen: Current Employment, Current equity holder in publicly-traded company. Delioukina: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Usmani: Amgen: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy; Array BioPharma: Consultancy, Research Funding; GSK: Consultancy, Research Funding; EdoPharma: Consultancy; SkylineDX: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding.

Background: Light chain (AL) amyloidosis is a rare disease in which deposits of insoluble amyloid derived from immunoglobulin light chains accumulate and cause dysfunction of organs including the heart and kidneys. In order to reverse organ damage and improve overall survival, treatment must provide rapid, deep, and sustained hematologic responses. Although therapies approved for the treatment of multiple myeloma have demonstrated some efficacy, there are currently no health authority-approved treatments for AL amyloidosis. A retrospective observational study was undertaken to characterize patients and describe treatment patterns in patients with AL amyloidosis from real-world data in the US. Methods: Data were extracted from Optum Electronic Health Records (EHR) and Optum Clinformatics Data Mart (claims) databases. Eligible patients had (1) a diagnosis of AL amyloidosis (ICD-10 code E85.81) on or after January 1, 2008 or (2) a diagnosis of amyloidosis (ICD-9 codes 277.30, 277.39; ICD-10 codes E85.89, E85.9) on or after January 1, 2008 and at least one line of therapy (LOT) comprising one or more of the following treatments: bendamustine bortezomib, carfilzomib, cyclophosphamide, daratumumab, dexamethasone, doxorubicin, elotuzumab, etoposide, interferon alfa-2a, interferon alfa-2b, ixazomib, lenalidomide, melphalan, panobinostat, pomalidomide, prednisone/prednisolone, thalidomide, vincristine, or autologous stem cell transplant. Patients were required to have continuous medical enrollment during the 365 days prior to the index amyloidosis diagnosis date (claims data) or have first active date at least 365 days prior to index amyloidosis date (EHR data), must not have had prior cancer in the 365-day period prior to the index amyloidosis diagnosis date, and must have been age ≥18 years at time of amyloidosis diagnosis. Patients treated with dexamethasone only or dexamethasone and prednisolone only for ≤90 days and those treated with prednisone/prednisolone only irrespective of duration were excluded. LOTs were defined by a start date, an end date, and a distinct regimen made up of ≥1 drugs. Patients may have multiple sequential LOTs during the available follow-up period. Comorbidities were scored according to the Charlson Comorbidity Index (CCI). A score of 0 reflects no comorbidities; higher scores reflect increased mortality risk and the maximum score is 24. Descriptive statistics are provided for patient characteristics at index diagnosis date for patients who had ≥1 LOT, distribution of regimens in each LOT, treatment attrition, and duration of treatment in each line of therapy and by regimen. Results: Data from 1688 patients (Optum claims, n=624; Optum EHR, n=1064) were included in the analysis (Figure). Median age at diagnosis was 67 years and 55.7% of patients were male. Almost 70% of patients had an index diagnosis date between 2013 and 2019. The median CCI score at index diagnosis date (based on comorbidities in the 365-day pre-index diagnosis period) was 1 and 10.9% of patients had a stem cell transplant on or after the index diagnosis date. The three most common comorbidities were hypertension (50.8%), renal failure (26.2%), and congestive heart failure (24.6%). Median follow-up period was 28 months. Treatment information for regimens used by ≥5% of patients for LOT1 is summarized in the Table. The most common treatment regimen for LOT1 was a proteasome inhibitor (PI), an alkylating agent, and a steroid (n=392, 23.2%); this combination was used for an average of 111 days. Of patients treated with this combination, the most common regimen was bortezomib, cyclophosphamide, and dexamethasone (VCd), used by 358 patients. Steroid only (dexamethasone for ≥90 days) regimens accounted for 16.4% and a PI ± steroid for 13.2% of LOT1. A limitation of the study is that assumptions were used to classify AL amyloidosis vs other types of amyloidosis. Conclusions: VCd is the most commonly used regimen in patients with newly-diagnosed AL amyloidosis. This is consistent with clinical guidelines and real world data from Europe (Palladini et al, EHA 2020), supporting this regimen as the current standard of care for treatment of patients with newly-diagnosed AL amyloidosis. Disclosures Dispenzieri: Celgene: Research Funding; Pfizer: Research Funding; Alnylam: Research Funding; Intellia: Research Funding; Janssen: Research Funding; Takeda: Research Funding. Zonder:Intellia, Amgen, Takeda, Janssen, Regeneron, Alnylam, Caelum, Oncopeptides: Consultancy; BMS, Celgene: Research Funding. Hoffman:Loxo: Current equity holder in publicly-traded company; Celgene: Honoraria, Speakers Bureau. Wong:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Fortis: Research Funding; Roche: Research Funding; GSK: Research Funding; Amgen: Consultancy; Bristol Myers Squibb: Research Funding. Liedtke:Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Abonour:BMS: Consultancy, Research Funding; Takeda: Consultancy; Janssen: Honoraria, Research Funding; Celgene: Consultancy. D'Souza:Amgen, Merck, TenoBio: Research Funding; Akcea, Imbrium, Janssen, Pfizer: Consultancy. Lee:Janssen: Current Employment. Nair:Janssen: Current Employment. Potluri:SmartAnalyst Inc.: Current Employment. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Lam:Janssen: Current Employment. Mehra:Janssen: Current Employment.

Background: The extent of cardiac involvement has a major impact on clinical outcomes in patients with newly diagnosed light chain (AL) amyloidosis. Here, we present the hematologic responses, major organ deterioration progression-free survival (MOD-PFS) and event-free survival (MOD-EFS), and organ responses by cardiac stage in patients with newly diagnosed AL amyloidosis treated with cyclophosphamide, bortezomib, and dexamethasone (VCd) with or without daratumumab subcutaneous (DARA SC) in the ANDROMEDA trial (NCT03201965). Methods: Key eligibility criteria included newly diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage I-IIIA (based on the European Modification of the Mayo staging system), eGFR ≥20 mL/min, and absence of symptomatic multiple myeloma. Patients were randomized (1:1) to receive DARA-VCd or VCd alone. All patients received bortezomib (1.3 mg/m2 SC weekly), cyclophosphamide (300 mg/m2 oral [PO] or intravenous [IV] weekly [500 mg maximum]), and dexamethasone (20-40 mg PO or IV weekly) for six 28-day cycles. DARA SC (1800 mg, co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was administered by injection weekly in Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter for up to 24 cycles. Disease evaluations occurred every 4 weeks (Cycles 1-6) and every 8 weeks (after Cycle 7) until major organ deterioration, hematologic progression, death, end of study, or withdrawal. The primary endpoint was overall (ie, at any time) hematologic complete response (CR) rate. Secondary endpoints included MOD-PFS, MOD-EFS, organ response rate, time to hematologic response, survival, and safety. Analyses of hematologic CR and MOD-PFS were performed on the intent-to-treat analysis set; cardiac response analyses were based on patients who were evaluable for cardiac response, defined as patients with baseline NT-ProNBP value ≥650 ng/L or baseline NYHA class 3 or 4 and received at least 1 administration of study treatment. Patients without a baseline assessment or post-baseline assessment were censored at randomization for the MOD-PFS analysis. Descriptive statistics were used to summarize overall CR rate and organ response rate. Hazard ratios and corresponding 95% confidence intervals were estimated based on Cox proportional hazard model. Results: A total of 388 patients were randomized to receive DARA-VCd (n=195) or VCd alone (n=193). Baseline characteristics were well balanced between treatment groups. The median age was 64 years and the proportions of patients with cardiac stage I, II, and III were 23%, 40%, and 37%, respectively. The median duration of treatment was 9.6 months for DARA-VCd and 5.3 months for VCd. Median follow-up was 11.4 months (range, 0.03-21.3+). Baseline characteristics were generally balanced across cardiac stages, except increasing cardiac stage was associated with older age (≥65 years), worse Eastern Cooperative Oncology Group performance status, more advanced renal failure (CrCl ≤30), and functionally worse heart failure (NYHA IIIA). Hematologic CR rates were higher in the DARA-VCd group than in the VCd group in patients with cardiac stages I, II, and III at baseline (Table). Cardiac and renal response rates at 6 months were also higher in the DARA-VCd group regardless of cardiac stage at baseline (Table). The hazard ratios (HRs) for MOD-PFS were 0.33, 0.55 and 0.66 for cardiac stages I, II and III, respectively, favoring DARA-VCd. Corresponding HRs for MOD-EFS were 0.24, 0.39, and 0.48, respectively. Rates of any grade adverse events (AEs) were similar in patients with and without cardiac involvement at baseline. Across both treatment arms, rates of serious treatment-emergent AEs were higher in patients with cardiac involvement at baseline than in those without. Conclusions: The benefit of DARA-VCd was retained over VCd alone across cardiac stages for hematologic CR, MOD-PFS, MOD-EFS, and organ responses. Disclosures Minnema: Kite, a Gilead Company: Speakers Bureau; Celgene: Other: travel support, Research Funding; Amgen: Consultancy; Servier: Consultancy. Dispenzieri:Alnylam: Research Funding; Intellia: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Comenzo:Unum: Consultancy; Prothena: Consultancy, Research Funding; Amgen: Consultancy; Sanofi: Consultancy; Caleum: Consultancy; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Kastritis:Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Wechalekar:Takeda: Honoraria, Other: Travel; Celgene: Honoraria; Janssen: Honoraria, Other: Advisory; Caelum: Other: Advisory. Witteles:Pfizer: Membership on an entity's Board of Directors or advisory committees; Alnylam Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Maurer:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ionis: Research Funding; Eidos: Research Funding; Akcea: Research Funding. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Qin:Janssen: Current Employment. Vasey:Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Tromp:Janssen: Current Employment, Current equity holder in publicly-traded company. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Jaccard:Janssen: Consultancy, Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Janssen., Research Funding; Celgene: Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Celgene., Research Funding.