Enduring Responses after 1-Year, Fixed-Duration Cevostamab Therapy in Patients with Relapsed/Refractory Multiple Myeloma: Early Experience from a Phase I Study

Background: Relapsed/refractory multiple myeloma (RRMM) remains an incurable disease, with most treatment regimens continued until disease progression (PD). New treatments that are efficacious when given for a fixed duration and offer the potential for an extended treatment-free period may also decrease cumulative toxicities and reduce the burden of treatment on both patients and healthcare systems. Cevostamab is an FcRH5xCD3 T-cell engaging bispecific monoclonal antibody that facilitates T-cell directed killing of myeloma cells and has demonstrated clinically meaningful activity and a favorable toxicity profile when given Q3W for up to 17 cycles (approximately 1 year) in an ongoing Phase I trial (GO39775; NCT03275103) in patients with heavily pre-treated RRMM (Trudel et al. ASH 2021). Here, we report early duration of response data for patients in GO39775 who completed 17 cycles of cevostamab and stopped treatment.

Methods: All patients were aged ≥18 years and had RRMM for which no established therapy was available, appropriate, or tolerable, and an ECOG performance status of 0-1. Cevostamab was administered by intravenous infusion in 21-day cycles with step-up dosing in Cycle (C) 1 for cytokine release syndrome mitigation. Treatment was continued for 17 cycles (approximately 1 year) unless PD or unacceptable toxicity occurred. Patients who achieved a partial response (PR) or better by C17 and maintained a response through C17 were included in the analysis.

Results: At data cut-off (March 8, 2022), a total of 16 patients (median age: 66.5 years; range: 45-80) completed C17 of cevostamab treatment and were eligible for analysis. Patients had received a median of 6 prior lines of therapy (range: 2-11), with 12 patients having received ≥5 prior therapies. Thirteen patients were triple-class refractory and 11 were penta-refractory. Fifteen patients were refractory to their last prior therapy. Five patients had received prior anti-B-cell maturation antigen (BCMA) targeted therapies, 4 of whom were refractory to anti-BCMA treatment.

Patients received cevostamab target doses ranging from 40-160mg and received a median of 17 cycles of treatment (range: 16-17). Among the 16 patients analyzed, the best overall response (BOR) achieved was: stringent complete response (sCR) in 7 patients, CR in 3 patients, very good partial response (VGPR) in 5 patients, and PR in 1 patient. At data cut-off, 13 of the 16 patients remained in remission, with 8 patients (BOR: 5 sCR, 1 CR, 2 VGPR) maintaining a response ≥6 months after completion of therapy and 3 patients (BOR: 2 sCR, 1 CR) maintaining a response ≥12 months after completion of therapy. Eight patients had <6 months of follow-up. None of the patients (0/10) who completed C17 and attained a sCR or CR had relapsed. Only 3 of the 16 patients (BOR: 2 VGPR, 1 PR) had PD after the completion of C17 of cevostamab. Time to progression following completion of therapy for the 2 patients who achieved a VGPR was 7.8 months and 12.9 months. For the patient who achieved a PR, time to progression was 1.3 months.

Due to its mechanism of action, treatment with cevostamab may be associated with an increased risk of infection. Infections occurred in 2 patients after the completion of C17 of cevostamab therapy. Pneumonia was reported in both patients, with onset after the last dose of 1.3 months and 3.8 months. Both events resolved and both patients have remained on study.

Conclusions: Early data from this Phase I study suggest that patients can maintain durable responses (≥6 months) after completion of 17 cycles of cevostamab treatment, highlighting the potential for an extended treatment-free period following fixed-duration therapy. Further data are needed to confirm the duration of response and associated correlates following completion of treatment.

Additional data on responding patients with premature discontinuation of treatment (i.e. prior to completion of C17) and patients retreated with cevostamab will be presented.

Lesokhin:Trillium Therapeutics: Consultancy, Research Funding; Sanofi: Research Funding; BMS: Honoraria; Amgen: Honoraria; Janssen, Pfizer, Iteos, Sanofi, Genmab: Honoraria; Janssen, Pfizer, BMS, Genentech/Roche: Research Funding; Pfizer, Genmab, Sanofi, Iteos, BMS, Janssen: Consultancy; Serametrix, inc: Patents & Royalties; Memorial Sloan Kettering Cancer Center: Current Employment. Richter:Takeda: Consultancy; Oncopeptides: Consultancy, Honoraria; Secura Bio: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trudel:Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria; Forus: Consultancy; Sanofi: Honoraria; Genentech: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding. Cohen:GlaxoSmithKline and Novartis: Research Funding; Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Ichnos, Janssen Oncology, Oncopeptides, Pfizer, Seattle Genetics, Genentech/Roche, AstraZeneca, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Patents & Royalties: CAR T-cells and biomarkers of cytokine-release syndrome. Spencer:Haemalogix: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria. Forsberg:BMS, GSK: Consultancy; Karyopharm: Research Funding; University of Colorado: Current Employment. Laubach:Lignancies: Honoraria. Thomas:Janssen Pharma: Research Funding; X4 Pharma: Research Funding; Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Cellectar Pharma: Research Funding; Ascentage Pharma: Research Funding. Bahlis:AbbVie, Amgen, Bristol Myers Squibb, Celgene, Forus, Janssen, Genentech, GSK, Karyopharm, Novartis, Pfizer, Takeda, Sanofi: Consultancy; Pfizer: Research Funding. Costa:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; AbbVie: Research Funding; Sanofi: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; Genentech: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Rodriguez Otero:Consultant in Hematology Clínica Universidad de Navarra: Current Employment; Oncopeptides: Other: Advisory board participation ; Pfizer: Other: Advisory board participation ; Kite Pharma: Other: Advisory board participation ; AbbVie: Other: Advisory board participation ; Regeneron: Honoraria; Sanofi: Honoraria, Other: Advisory board participation; Amgen: Honoraria; GSK: Honoraria, Other: Advisory board participation ; Janssen: Honoraria, Other: Advisory board participation ; BMS-Celgene: Honoraria, Other: Advisory board participation ; Janssen, BMS, Sanofi, Pfizer, GSK: Consultancy; Amgen, Sanofi, GSK, Janssen, BMS-Celgene, Regeneron: Speakers Bureau. Mateos: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; Bristol Myers Squibb/Celgene: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Berdeja:My institution, Sarah Cannon Research Institute, received consultancy payments for the following: Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; My institution, Sarah Cannon Research Institute, receives research funds in my name for the following: 2Seventy bio, Abbvie, Acetylon, Amgen, Bluebird bio, BMS, C4 Therapeutics, CARsgen, Cartesian Therapeutics, Celgene, Celularity, CRISPR Therapeutics,: Research Funding. Kaedbey:BMS. Janssen: Honoraria; BMS: Honoraria, Other: Advisory boards; Sanofi: Other: Advisory boards; FORUS Therapeutics: Other: Advisory boards; Beigene: Other: Advisory boards; Janssen: Honoraria, Other: Advisory boards; Janssen, BMS, Sanofi, FORUS, Beigene, Pfizer: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Advisory boards; Jewish General Hospital, Montreal, QC, Canada: Current Employment; BMS. Janssen: Honoraria; Janssen, BMS, Sanofi, FORUS, Beigene, Pfizer: Membership on an entity's Board of Directors or advisory committees. Krishnan:Sutro: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Adaptive: Consultancy; Regeneron: Consultancy; Janssen: Consultancy, Research Funding; AstraZeneca: Consultancy; Artiva: Consultancy; BMS, Janssen, Adaptive, GSK, AbbVie, Regeneron, Sanofi, AstraZeneca: Consultancy; BMS: Current equity holder in publicly-traded company; Janssen: Research Funding; Takeda, GSK, BMS: Speakers Bureau; Sutro SAB: Speakers Bureau; Bristol Myers Squibb: Consultancy, Other: Stock Ownership (not including stocks owned in a managed portfolio), Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau. Fonseca:Adaptive Biotechnologies: Divested equity in a private or publicly-traded company in the past 24 months; Genentech, Pfizer, Sanofi: Honoraria, Research Funding; AbbVie, Amgen, Bayer, BMS/Celgene, GSK, H3 Therapeutics, Janssen, Juno, Karyopharm, Kite, Merck, Novartis, Oncopeptides, OncoTracker, Pfizer, Pharmacyclics, Regeneron, Sanofi, Takeda: Consultancy; Adaptive Biotechnologies, Caris Life Sciences, OncoMyx and OncoTracker: Other: Scientific Advisory Board; Adaptive Biotechnologies, Caris Life Sciences, Oncomyx and OncoTracker: Membership on an entity's Board of Directors or advisory committees; Amgen, BMS, Celgene, Takeda, Bayer, Janssen, Novartis, Pharmacyclics, Sanofi, Merck, Juno, Kite, Aduro, OncoTracker, GSK, AbbVie, Pfizer, Karyopharm.: Consultancy; FIH prognostication in myeloma: Patents & Royalties. Choeurng:Genentech: Current Employment, Current equity holder in publicly-traded company. Cooper:Genentech: Current Employment. Sumiyoshi:Genentech: Current Employment, Ended employment in the past 24 months, Research Funding; Roche/Genentech: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Wong:"For Henry": https://www.forhenryahc.org/: Membership on an entity's Board of Directors or advisory committees; CTMX and BMRN: Current equity holder in publicly-traded company; Patents but no royalties: https://patents.justia.com/inventor/chihunt-wong: Patents & Royalties: https://patents.justia.com/inventor/chihunt-wong; Genentech/Roche: Current Employment. Harrison:Haemalogix: Membership on an entity's Board of Directors or advisory committees; Abbvie, Amgen, Celgene/BMS, GSK, Janssen Cilag, Novartis, Roche Genentech, Eusa: Speakers Bureau; Abbvie, Amgen, Celgene/BMS, GSK, Janssen Cilag, Novartis, Roche Genentech, Haemalogix, Eusa, Terumo BCT: Honoraria; Celgene/BMS, GSK, Janssen Cilag, Haemalogix: Research Funding; Abbvie, Amgen, Celgene/BMS, GSK, Janssen Cilag, Novartis, Roche Genentech, Haemalogix, Eusa, Terumo BCT: Consultancy.