Health-Related Quality of Life (HRQoL) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplantation and Treated with Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone (Isa-VRd) Vs. Vrd Alone: Results from the Imroz Study

Introduction. Multiple myeloma (MM) is an incurable hematologic malignancy typically affecting older adults. Adding isatuximab (Isa) to bortezomib, lenalidomide and dexamethasone (Isa-VRd) significantly reduced risk of progression or death by 40.4% vs. VRd while providing deep and sustained responses in patients with NDMM who are ineligible for transplantation in the phase III IMROZ study (NCT03319667). The analysis reported here evaluated the effect of Isa-VRd vs. VRd on HRQoL, where four, 6-week induction cycles with Isa-VRd were followed by 4-week cycles of Isa-Rd in the Isa-VRd arm (VRd arm: VRd followed by Rd).

Methods. The European Organization for Research and Treatment of Cancer core questionnaire (EORTC QLQ-C30) and the multiple myeloma module (MY20) were administered on day 1 of every treatment cycle (C), at the end of treatment (EOT), and at one follow-up visit after EOT. Longitudinal analyses of change from baseline (BL) using mixed models for repeated measures were conducted through C63, with a threshold of 5 points for interpreting differences between treatment arms. Time to first deterioration (TTFD) and time to confirmed deterioration (TTCD) were assessed using Kaplan-Meier estimates and Cox models. All analyses were prespecified and conducted in the intent-to-treat (ITT) population. No adjustment for multiplicity was made and all reported p-values are nominal.

Results. A total of 446 patients were randomized 3:2 to Isa-VRd (n=265) or VRd (n=181). Completion rates were >90% at BL and remained high during treatment (approximately 70% at EOT) in both arms. At BL, patient reported functioning and symptom burden were similar in both arms. During a median follow-up of ~5 years (59.73 months [mo]), improvement from BL was observed in the Isa-VRd arm in most HRQoL symptom scales and functional domains. The overall positive impact of Isa-VRd on HRQoL was reflected in global health status/QoL (GHS/QoL) scores. GHS/QoL improved until C19 and then remained stable in both treatment arms at all time points thereafter (overall LS mean change [95% CI]: 3.45 [1.51, 5.40] in Isa-VRd, 2.41 [0.24, 4.59] in VRd; p=0.3587). Additionally, patients receiving Isa-VRd reported clinically meaningful better physical functioning vs. VRd (overall LS mean difference [95% CI]: 5.92 [2.76, 9.08]; p=0.0003). The median TTFD in physical functioning trended to be longer in the Isa-VRd arm vs. VRd (median TTFD [95% CI]: 5.78 [4.27, 7.43] mo in Isa-VRd, 4.27 [3.06, 5.75] mo in VRd; p=0.0720) with a similar trend observed for TTCD (median TTCD [95% CI]: 34.23 [26.55, 54.14] mo in Isa-VRd, 22.47 [11.24, 59.60] mo in VRd; p=0.1599). Cognitive functioning declined over time in both arms (p>0.05).

Improvements in certain disease-related symptoms such as pain and dyspnea were also observed in the Isa-VRd arm. Despite relatively low pain levels at BL, patients in both arms reported reduction in pain as early as C2 which was sustained throughout the study. Pain reduction showed a trend towards being numerically greater with Isa-VRd vs. VRd (overall LS mean difference: -2.78, 95% CI [-6.36, 0.80]; p=0.1281). Isa-VRd significantly delayed TTFD in the pain subscale (median TTFD [95% CI]: 6.51 [4.76, 8.41] mo in Isa-VRd vs. 4.24 [2.92, 5.59] mo in VRd; HR [95% CI]: 0.75 [0.59, 0.94]; p=0.0146). Median TTCD in pain was also numerically longer in the Isa-VRd arm (p>0.05). Notably greater improvement in dyspnea was reported by patients in the Isa-VRd arm vs. those in VRd arm (overall LS mean difference: -3.20, 95% CI [-6.33, -0.08]; p=0.0447). Moreover, Isa-VRd delayed TTFD and TTCD in dyspnea vs VRd (p<0.05).

While patients in both arms reported a modest worsening in side effects of treatment as measured by MY20, the magnitude of change was numerically lower with Isa-VRd suggesting no additional toxicity with the addition of Isa to VRd (overall LS mean change [95% CI]: 2.75 [0.90, 4.59] in Isa-VRd, 4.76 [2.71, 6.81] in VRd; p=0.0680). Median TTCD in side effects of treatment was longer in Isa-VRd arm (p>0.05).

Conclusions. Isa-VRd was associated with faster and durable improvement in HRQoL vs. VRd, including physical functioning, pain, and dyspnea, throughout a follow-up period of ~5 years. The improved efficacy reported previously for Isa-VRd, together with this evidence of maintained or improved HRQoL supports the overall benefit of Isa-VRd for patients with NDMM who are ineligible for transplantation.

Dimopoulos:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee; Menarini: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee; Swixx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee; BeiGene Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Abbvie, Takeda, Beigene, BMS, GSK, Janssen, Menarini, Regeneron, Sanofi: Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Beksac:BMS, Takeda, Janssen, Menarini, Amgen, GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS, Janssen, Takeda, Sanofi: Speakers Bureau. Hajek:Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; BMS: Consultancy, Honoraria, Research Funding; PharmaMar: Consultancy, Honoraria; Novartis: Consultancy, Research Funding. Minarik:Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: 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; 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. Moreau:Celgene, Janssen, Takeda, Amgen, Pfizer, AbbVie, Sanofi: Consultancy; Celgene, Janssen, Takeda, Amgen, Pfizer, AbbVie, Sanofi: Honoraria; Celgene, Janssen, Takeda, Amgen, Pfizer, AbbVie, Sanofi: Other: Participation on a Data Safety Monitoring Board or advisory board . Romejko-Jarosinska:AstraZeneca, Gilead, Roche, Janssen, Celgene, Sanofi, Takeda: Honoraria, Speakers Bureau; Gilead, Roche, Takeda: Other: Support for attending meetings and/or travel; Swixx: Other: Participation on a Data Safety Monitoring Board or advisory board. Špička:Charles University and General University Hospital in Prague, Czech republic: Current Employment; BMS: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria; Takeda: 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; GSK: Honoraria; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Besemer:Takeda: Honoraria; Janssen: Honoraria; Oncopeptides: Honoraria; AMGEN: Honoraria; Pfizer: Honoraria; GlaxoSmithKline: Honoraria. Parmar:Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Other: travel grants. Zamagni:Janssen: 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; Menarini Stemline: 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; Bristol Myers Squibb: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Goldschmidt:Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product; Celgene: Research Funding; GlaxoSmithKline (GSK): Honoraria, Other: Support for attending meetings and/or travel, Research Funding; GlycoMimetics Inc.: Research Funding; Heidelberg Pharma: Research Funding; Hoffmann-La Roche: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product; support for attending meetings and/or travel, Research Funding; Incyte Corporation: Research Funding; Karyopharm: Research Funding; Merck Sharp and Dohme (MSD): Research Funding; Millennium Pharmaceuticals Inc.: Research Funding; Molecular Partners: Research Funding; MorphoSys AG: Research Funding; Novartis: Honoraria, Other: Support for attending meetings and/or travel, Research Funding; Pfizer: Honoraria, Other: Support for attending meetings and/or travel, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product; support for attending meetings and/or travel, Research Funding; Takeda: Research Funding; Array Biopharma/Pfizer: Other: Grants and/or provision of Investigational Medicinal Product; Bristol Myers Squibb/Celgene: Other: Grants and/or provision of Investigational Medicinal Product; Dietmar Hopp Foundation: Other: Grants and/or provision of Investigational Medicinal Product; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; grants and/or provision of Investigational Medicinal Product, Research Funding; Mundipharma GmbH: Other: Grants and/or provision of Investigational Medicinal Product. Martin:Pfizer: Honoraria; Roche: Honoraria; GSK: Honoraria; BMS: Research Funding; Sanofi: Research Funding; Janssen: Research Funding; AMGEN: Research Funding. Manier:Abbvie: Consultancy; Adaptive Biotechnology: Consultancy; Amgen: Consultancy; Celgene/BMS: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Regeneron: Consultancy; Roche: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Mohty:Novartis: Honoraria; Takeda: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria; Pfizer: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Research Funding, Speakers Bureau; GSK: Honoraria; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria; Adaptive: Honoraria; Stemline Menarini: Honoraria; MaaT Pharma: Current equity holder in publicly-traded company. Orlowski:Bristol Myers Squibb, CARsgen Therapeutics, Exelixis Inc, Heidelberg Pharma, Janssen Biotech Inc, Sanofi, Takeda Pharmaceuticals USA Inc; Laboratory Research Funding: Asylia Therapeutics Inc, BioTheryX Inc, Heidelberg Pharma: Research Funding; AbbVie Inc, Adaptive Biotechnologies Corporation, Asylia Therapeutics Inc, BioTheryX Inc, Bristol Myers Squibb, Karyopharm Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Nanjing IASO Biotherapeutics, Neoleukin Therapeutics, Oncopeptides, Pf: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; DEM BioPharma, Inc., Karyopharm Therapeutics, Lytica Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Myeloma 360, Nanjing IASO Biotherapeutics, Neoleukin Corporation, Oncopeptides AB, Pfizer, Inc., Regeneron Pharmaceuticals, Inc., Sporos Bio: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Asylia Therapeutics Inc.: Current equity holder in private company, Patents & Royalties; Sanofi, Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Comerford:Sanofi: Other: Employee of Sanofi and may hold stock/stock options in Sanofi.. Msihid:Sanofi: Other: Employee of Sanofi and may hold stock/stock options in Sanofi.. Lin:Sanofi: Current Employment, Other: Employee of Sanofi and may hold stock/stock options in Sanofi.. Leleu:GSK, Novartis, BMS, Takeda Pharmaceuticals, Abbvie: Honoraria, Other: Consulting Fee, Speakers Bureau; Janssen, Sanofi, Pfizer: Honoraria, Other: Consulting fee, support for attending meetings and travel, Speakers Bureau.