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AbstractBackgroundExtended first‐line therapy (1LT) has improved clinical outcomes in newly diagnosed multiple myeloma (NDMM). This retrospective study of NDMM patients evaluated the relationship between dose‐attenuation of 1LT and duration of therapy (DOT) and DOT on outcomes.MethodsAdults with NDMM not undergoing stem cell transplant (SCT) from January 1, 2012 toMarch 31, 2018 from the Integrated Oncology Network were included; 300 were randomly selected for chart review. 1LT DOT, time to next treatment (TTNT), progression‐free survival (PFS), and overall survival (OS) were estimated using Kaplan–Meier analysis. Marginal structural models evaluated relationships between DOT and TTNT, PFS, and OS at 2 years accounting for confounders and survival bias from the time‐dependent nature of DOT.ResultsOf 300 chart‐reviewed patients, 93 were excluded for incomplete data or meeting exclusion criteria. Among 207 NDMM patients, median age was 74 years; 146 (70.5%) did not receive dose‐attenuation during 1LT. Patients with short DOT were older, frailer, with a higher comorbidity burden, and a significantly lower proportion had an Eastern Cooperative Oncology Group PS = 0. As DOT increased, more patients underwent dose‐attenuation (p < 0.0001). The median 1LT DOT was 20.9 (95% confidence interval [CI]: 13.9, 26.4) versus 4.2 months (95% CI: 3.2, 4.9) for patients receiving versus not receiving dose‐attenuation, respectively (p < 0.0001). After accounting for survival bias, confounder‐adjusted TTNT was prolonged with each additional month of 1LT (odds ratio [OR]: 0.76 [95% CI: 0.75, 0.78]); likelihoods of risks of disease progression (OR: 0.87 [95% CI: 0.86, 0.88]) and death at 2 years (OR: 0.72 [95% CI: 0.70, 0.74]) were reduced with each month of 1LT (p < 0.0001 for all outcomes).ConclusionsDose‐attenuated 1LT was associated with longer DOT among patients with non‐SCT NDMM. Each additional month of 1LT was associated with a reduced adjusted likelihood of disease progression and death at 2 years. Dose‐attenuation of 1LT can extend DOT; longer DOT may improve clinical outcomes.

Summary: The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continuing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article discusses the principles that can enable the rational and effective development of therapeutic approaches for high-risk multiple myeloma.

Abstract Introduction: Belantamab mafodotin (belamaf) is a B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate approved in the United States (US) and Europe as a monotherapy for triple-class refractory adult patients with relapsed or refractory multiple myeloma (RRMM). This hypothesis-generating post-hoc analysis of DREAMM-2 trial (NCT03525678) data examined relationships between corneal exam findings (superficial punctate keratopathy and/or microcyst like epithelial changes), best-corrected visual acuity (BCVA), and direct patient-reported ocular symptoms per the Ocular Surface Disease Index (OSDI) questionnaire. This approach could provide insight into the relationship between corneal exam findings, BCVA, and ocular symptoms and their impact on quality of life to help determine if BCVA decline and symptoms could guide dosing. Currently, in the US, eye exams with eye-care professionals (ECPs) are required for each belamaf treatment, which can add to patients' therapy-related burden. Identifying a surrogate marker for results from corneal exam findings would help providers determine if dosing adjustments are necessary. Methods: Eye exams (including a corneal exam and BCVA assessment using the Snellen chart) were performed on all patients receiving single-agent belamaf (2.5 mg/kg) by ECPs at baseline (BL) and before each dose, administered q3w. Corneal exam findings (keratopathy) and BCVA were assessed per protocol-defined criteria, and grade (GR) assessment was based on the worst finding in the worse eye. BCVA and keratopathy grading were relative to BL. Patient-reported ocular symptoms and vision-related functioning, as per the OSDI, were used to evaluate the impact of treatment-related ocular toxicity. The OSDI is a patient-reported outcome questionnaire that assesses eye symptoms and effects on vision-related function in the past week and was performed in all patients before each belamaf dose. Items 1-5 address the frequency of eye-related symptoms (eg, painful or sore eyes, blurred vision) while items 6-9 address the frequency of functional limitations (eg, driving at night or reading). OSDI was considered positive, clinically meaningful, and potentially associated with treatment when at least one question 1-5 (ie, sensitivity to light, gritty or painful eyes, blurred or poor vision) was reported as experienced "all of the time" and at least one question 6-9 (ie, driving at night, reading, working with PC, or watching TV) was reported as experienced "most of the time." Results: Overall, GR 3-4 (severe) keratopathy was observed only 5% of the time in patients who did not report frequent ocular symptoms as measured by the OSDI questionnaire (no items 1-9 ≥ "most of the time"). A further breakdown of the questions revealed that, in patients who reported no items 1-5 "all of the time" AND no items 6-9 ≥ "most of the time" (OSDI negative), GR 3-4 keratopathy was observed only 6% of the time (Table). When considering individual OSDI items, in patients who reported "no deterioration from BL" for any of the OSDI eye-related symptoms or functional limitations, GR 3-4 keratopathy was observed ~3%-7% of the time while GR 0-2 (mild) keratopathy was observed ~23%-34% of the time. Similar results were observed in patients with BCVA ≤20/30 at BL who reported "no deterioration from BL" for any eye-related adverse events (AEs) or functional limitations (GR 3-4 keratopathy: ~2%-6% of the time; GR 0-2 keratopathy: ~19%-28% of the time); patients with worse visual acuity at BL (BCVA &gt;20/30) who reported "no deterioration" for items 1-9 had lower incidence of GR 3-4 and GR 0-2 keratopathy (~0%-1% and ~3%-8%, respectively). Conclusions: The results from this hypothesis-generating post-hoc analysis suggest that hematologists/oncologists may be able to use clinical indicators/tools (eg, ocular symptoms, the OSDI tool) as potential surrogate markers for eye exam results to help determine whether dosing changes are needed. This approach will be explored in trials with other belamaf dose regimens that are currently under evaluation. If the results are validated, it may be possible for hematologists/oncologists to manage belamaf dose modifications, due to ocular AEs, without a confirmatory eye exam by the ECP, reducing the patient burden. Funding Source: GSK (205678). Drug linker technology licensed from Seagen; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Figure 1 Figure 1. Disclosures Popat: Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria; Abbvie, Takeda, Janssen, and Celgene: Consultancy; Janssen and BMS: Other: travel expenses. Badros: GlaxoSmithKline: Research Funding; BMS: Research Funding; Janssen: Research Funding; J&J: Research Funding. Kumar: 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; Tenebio: Research Funding; Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; BMS: Consultancy, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Oncopeptides: Consultancy; Astra-Zeneca: 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; Novartis: Research Funding; Merck: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Rodríguez-Otero: Regeneron: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: 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; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and other expenses. Cohen: BMS: Research Funding; GlaxoSmithKline: Other: Personal fees and other association with, Research Funding; Novartis: Research Funding; Celgene: Honoraria, Other: Personal fees and other association with; Janssen: Honoraria; Kite Pharma: Honoraria; Oncopeptides: Honoraria; Seattle Genetics: Honoraria; Takeda: Honoraria. Manier: Regeneron: Consultancy, Research Funding; Oncopeptides: 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; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Celgene - Bristol Myers Squibb: Consultancy, 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, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Voorhees: Secura Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: 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; BMS: 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; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: 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; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gay: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria. Rifkin: Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Fresenius-Kabi: Membership on an entity's Board of Directors or advisory committees; Coherus: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb (Celgene): Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; McKesson: Current Employment, Current equity holder in publicly-traded company; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Martin: Janssen: Research Funding; Sanofi: Research Funding; Oncopeptides: Consultancy; Amgen: Research Funding; GlaxoSmithKline: Consultancy. Chari: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: 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; Novartis: Consultancy, Research Funding; Pharmacyclics: Research Funding; Millenium/Takeda: Consultancy, Research Funding; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weisel: Bristol Myers Squibb: 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; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Janssen: 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; Takeda: 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; Karyopharm: 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; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Farooq: Five Prime Therapeutics/Amgen: Consultancy; GlaxoSmithKline: Consultancy. Jeng: OysterPoint: Consultancy; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Eyegate: Current equity holder in publicly-traded company. Chng: Abbvie: Consultancy; GlaxoSmithKline: Consultancy; Takeda: Consultancy; BMS/Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Novartis: Research Funding; Johnson & Johnson: Consultancy, Research Funding; Amgen: Consultancy; Antengene: Consultancy; Pfizer: Consultancy; Aslan: Research Funding. Lee: Takeda Pharmaceuticals: Consultancy, Research Funding; Oncopetides: Consultancy; Sanofi: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Legend Biotech: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy, Research Funding; Genentech: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding; Regeneron: Research Funding. Berdeja: BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Celularity: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Kite Pharma: Consultancy; Legend Biotech: Consultancy; SecuraBio: Consultancy; EMD Serono: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Research Funding; Ichnos Sciences: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Poseida: Research Funding; Bluebird bio: Consultancy, Research Funding; Astex Pharmaceuticals: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Takeda: Consultancy; Sanofi: Research Funding; Acetylon: Research Funding; Teva: Research Funding; Lilly: Research Funding. Jadhav: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Tosolini: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Eliason: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Palumbo: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Dimopoulos: Beigene: Honoraria; BMS: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Lonial: Merck: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Trudel: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Amgen Canada: Honoraria; Sanofi: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Janssen: Honoraria, Research Funding; Genentech: Research Funding; Karyopharm: Honoraria. Richardson: Sanofi: Consultancy; Celgene/BMS: Consultancy, Research Funding; Protocol Intelligence: Consultancy; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Oncopeptides: Consultancy, Research Funding; Regeneron: Consultancy; AstraZeneca: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Terpos: Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding.

Background Panobinostat (Pano), a pan-histone deacetylase inhibitor, is approved for the treatment of relapsed or relapsed/refractory multiple myeloma (RRMM) in combination with bortezomib and dexamethasone (FVd) in patients who have received ≥2 prior lines of therapy, including bortezomib and an immunomodulatory agent (IMiD). The pivotal phase 3 PANORAMA 1 trial, which used intravenous (i.v.) bortezomib, demonstrated significant progression-free survival benefit with FVd compared with placebo-Vd; however, adverse events (AEs) were also more frequent (San-Miguel J. et al., Lancet Oncol. 2014). The randomized phase 2 PANORAMA 3 study was conducted to optimize FVd by comparing three regimens with varying dose and schedule of Pano and by incorporating subcutaneous (s.c.) bortezomib. Methods PANORAMA 3 (NCT02654990) was a randomized, open-label, international, multicenter phase 2 study conducted in compliance with the Declaration of Helsinki. Eligible patients were ≥18 years old with 1‒4 prior lines of therapy, including an IMiD. Patients refractory to bortezomib were excluded. Patients were randomized 1:1:1 to Pano 20 mg three times weekly (TIW; the currently approved dosing regimen; Days 1, 3, 5, 8, 10, 12), Pano 20 mg twice weekly (BIW; Days 1, 4, 8, 11), or Pano 10 mg TIW (Days 1, 3, 5, 8, 10, 12), all administered in 21-day cycles. Randomization was stratified by number of prior treatment lines (1 vs 2 vs 3 or 4) and by age at screening (≤75 vs &gt;75 years). For Cycles 1-4, all patients ≤75 years old received s.c. bortezomib 1.3 mg/m2 BIW (Days 1, 4, 8, 11) and oral dexamethasone 20 mg (Days 1, 2, 4, 5, 8, 9, 11, 12). Patients aged ≤75 years from Cycle 5 onwards, and patients &gt;75 years for all cycles, received bortezomib 1.3 mg/m2 weekly (Days 1 and 8) and dexamethasone 20 mg on Days 1, 2, 8, and 9. Patients were treated until progressive disease or death, or until discontinuation due to toxicity or withdrawal of consent. The primary endpoint was overall response rate (ORR; IMWG 2011 criteria) after up to 8 treatment cycles by Independent Review Committee assessment. Secondary endpoints included best response, time to response (TTR), duration of response (DOR) and safety. Results In total, 248 patients were randomized (Pano: 20 mg TIW, N=82; 20 mg BIW, N=83; 10 mg TIW, N=83) and 241 patients received treatment (Pano: 20 mg TIW, N=79; 20 mg BIW, N=82; 10 mg TIW, N=80). Mean (SD) age was 65 (9) years; 55% of patients were male. Overall, patients had a median (range) time since diagnosis of 49 months (7‒242) and a median (range) of 2 (1-4) prior lines of therapy; 17% and 2% of patients were refractory to lenalidomide and pomalidomide, respectively. In total, 68% of patients had relapsed and 32% had relapsed/refractory disease. High-risk molecular findings were present in 15% of patients, with either del(17p) or t (4;14) at screening by fluorescence in situ hybridization. For the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, median (range) number of treatment cycles completed was 9 (1; 50), 8 (1; 40) and 7 (1; 39); ORR (95% CI) after up to 8 treatment cycles was 62% (51; 73), 65% (54; 75), and 51% (39; 62); median TTR was 1, 2, and 3 months, with a median (95% CI) DOR of 22 (14, not estimable), 12 (9, 21), and 11 (6, 14.5) months. Best responses are presented in Table 1. In the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, treatment-related AEs Grade ≥3 were reported in 78%, 72%, and 54% of patients; serious AEs were reported in 54%, 48%, and 44% of patients; and discontinuations due to AEs occurred in 29.5%, 28%, and 15% of patients, respectively. Most common treatment-emergent AEs (≥20% patients) are presented in Table 2. Grade ≥3 diarrhea occurred in 11.5%, 10%, and 5% of patients, respectively. There were 14 (6%) on-treatment deaths during the study (20 mg TIW, n=5; 20 mg BIW, n=3; 10 mg TIW, n=6), with none causally related to therapy and with 12 of 14 directly attributable to progressive disease. Conclusion In patients with RRMM, the 20 mg TIW and 20 mg BIW dosing regimens provided favorable outcomes, with most durable and deepest responses observed in the 20 mg TIW arm. The rate of AEs, including diarrhea, with Pano 20 mg TIW was lower than those observed with the same dosing regimen in PANORAMA 1, suggesting s.c. administration of bortezomib improves tolerability compared with i.v. administration. Moreover, all three regimens of FVd proved generally manageable; Pano 20 mg TIW had greatest efficacy, while 10mg TIW proved best tolerated. Disclosures Schjesvold: Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Lech-Marańda:Roche, Amgen, Gilead: Speakers Bureau; Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Oncopeptides: Consultancy. Wróbel:Roche: Honoraria, Research Funding; Takeda, Celgene, Janssen, Amgen, AbbVie, Teva, Sandoz: Consultancy, Honoraria. Sureda Balari:Takeda: Consultancy, Honoraria, Speakers Bureau; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Roche: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Beksac:Janssen&janssen: 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; Sanofi: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goncalves:Janssen, Takeda, Amgen, Bayer, Novartis, Merck, Bayer, Celgene, GSK, BMS: Research Funding; Janssen: Consultancy, Speakers Bureau. Bladé Creixenti:Celgene: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Chari:Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Novartis: Honoraria; Oncopeptides: Consultancy; Takeda: Consultancy, Research Funding; Antengene: Consultancy; Sanofi Genzyme: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Adaptive Biotechnology: Honoraria; Array BioPharma: Honoraria; Karyopharm: Consultancy; Glaxo Smith Kline: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; The Binding Site: Honoraria. Lonial:JUNO Therapeutics: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; GSK: Consultancy, Honoraria, Other: Personal fees; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal fees; Onyx: Honoraria; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria. Spencer:Haemalogix: Consultancy, Honoraria, Other: Grant/Research Support; Secura Bio: Consultancy, Honoraria; Pharmamar: Other; Abbvie: Consultancy, Honoraria, Other: Grant/Research Support; Janssen: Consultancy, Honoraria, Other: Grant/Research Support, Speakers Bureau; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; TheraMyc: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Grant/Research Support; BMS: Honoraria, Other: Grant/Research Support, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Other: Grant/Research Support; Takeda: Honoraria, Other, Speakers Bureau; Antegene: Consultancy, Honoraria. Maison-Blanche:Chiesi Pharmaceutical, Sanofi, Novartis: Honoraria. Moreau:Novartis: Honoraria; Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees.

PURPOSE To evaluate the effects of daratumumab, lenalidomide, and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) on patient-reported outcomes (PROs) in the phase III MAIA study. PATIENTS AND METHODS PROs were assessed on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item and the EuroQol 5-dimensional descriptive system at baseline and every 3 months during treatment. By mixed-effects model, changes from baseline are presented as least squares means with 95% CIs. RESULTS A total of 737 transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma were randomly assigned to D-Rd (n = 368) or Rd (n = 369). Compliance with PRO assessments was high at baseline (> 90%) through month 12 (> 78%) for both groups. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item global health status scores improved from baseline in both groups and were consistently greater with D-Rd at all time points. A global health status benefit was achieved with D-Rd, regardless of age (< 75 and ≥ 75 years), baseline Eastern Cooperative Oncology Group (ECOG) performance status score, or depth of response. D-Rd treatment resulted in significantly greater reduction in pain scores as early as cycle 3 ( P = .0007 v Rd); the magnitude of change was sustained through cycle 12. Reductions in pain with D-Rd were clinically meaningful in patients regardless of age, ECOG status, or depth of response. Similarly, PRO improvements were observed with D-Rd and Rd on the EuroQol 5-dimensional descriptive system visual analog scale score. CONCLUSION D-Rd compared with Rd was associated with faster and sustained clinically meaningful improvements in PROs, including pain, in transplant-ineligible patients with newly diagnosed multiple myeloma regardless of age, baseline ECOG status, or depth of treatment response.

AbstractTriple‐class‐refractory multiple myeloma (MM) describes MM refractory to proteasome inhibitors, immunomodulatory agents, and anti‐CD38 monoclonal antibodies. In the Phase IIb STORM study (NCT02336815), oral selinexor plus low‐dose dexamethasone (Sel‐dex) demonstrated a 26.2% overall response rate in triple‐class‐refractory MM. Here, we compare overall survival (OS) of 122 patients with triple‐class‐refractory MM who received Sel‐dex in STORM Part 2 with that of 64 similar patients treated with other available therapies in a Flatiron Health Analytic Database (FHAD) cohort. OS from the date that the patients’ MM became triple‐class‐refractory was longer in STORM versus FHAD, with an unadjusted hazard ratio (HR) of 0.43 (P = .0002; adjusted HR 0.35 [P = .011]). In a subset analysis of highly resistant patients receiving further therapies after their MM first became at least triple‐class‐refractory (i.e., who received Sel‐dex in STORM,n = 64, and non‐Sel‐dex in FHAD,n = 36), the OS was significantly longer in STORM with an unadjusted HR of 0.52 (P = .0331; adjusted HR 0.33 [P = .041]). Within the limits of this analysis, the OS of patients with at least triple‐class‐refractory MM was significantly better with Sel‐dex versus available therapies, suggesting that Sel‐dex may be associated with a meaningful OS benefit in these patients.