Biomarker Correlates and Clinical Activity of Cevostamab in Patients (pts) with Triple-Class Refractory Multiple Myeloma (MM) Who Have Received ≥1 Prior B-Cell Maturation Antigen (BCMA)-Targeted Bispecific Antibody (BsAb): Results from the Phase I/II CAMMA 2 Study

Background: Proven salvage therapies for pts with triple-class refractory MM who progress on BCMA-targeted therapies are lacking.Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed exclusively in the B-cell lineage. Cevostamab is a FcRH5xCD3 BsAb that facilitates T cell-mediated killing of MM cells. In an initial Phase I study (GO39775), cevostamab monotherapy was clinically active and had manageable toxicity in pts with heavily pretreated relapsed/refractory MM (Trudel et al. ASH 2021). In Cohort A1 of the subsequent Phase I/II CAMMA 2 study (CO43476; NCT05535244), cevostamab was highly active and had manageable safety at the 160mg target-dose (TD) level in pts with triple-class refractory MM who had received a prior BCMA-targeted antibody-drug conjugate (ADC; overall response rate [ORR]: 60%, 6/10 pts) or chimeric antigen receptor T-cell (CAR-T) therapy (ORR: 73%, 8/11 pts) but had not received a prior BCMA-targeted BsAb (Kumar et al. EHA 2024). We present initial results from Cohort A2, which enrolled pts with triple-class refractory MM who had received prior BCMA-targeted therapies, including ≥1 BCMA-targeted BsAb. An exploratory analysis of baseline patient and tumor-related factors is also presented.

Methods: Cevostamab was initiated with step dosing (Cycle [C] 1 Day [D] 1: 0.3mg; C1D2, D3, or D4 depending on the emergence of cytokine release syndrome [CRS] after the initial administration: 3.3mg) and continued at the 160mg TD on C1D8 and on D1 of each subsequent 21-day cycle until disease progression (PD) or unacceptable toxicity. Cytokine, tumor antigen, T-cell function/activation, and inhibitory immune checkpoint expression were assessed in blood and tumor samples collected at baseline and during treatment.

Results: As of February 23, 2024, 21 pts (median age: 64 years, range: 46-84) had been enrolled into Cohort A2. Seven pts (33%) had extramedullary disease and 5/12 pts (42%) with a conclusive assay result had high-risk cytogenetics (t(4;14), t(14;16), or del(17p)). All pts were heavily pretreated (median prior lines of therapy: 8, range: 5-14); 62% had received ≥2 prior BCMA-targeted therapies (median time since last: 122 days, range: 68-558) and 33% had received ≥2 prior BsAbs (median time since last: 139 days, range: 68-782). Most pts (86%) were refractory to their last line of therapy; 62% were penta-drug refractory. Median follow-up was 173 days (range: 20-360).

Grade (Gr) 3-4 adverse events (AEs) occurred in 71% of pts (15/21). Gr 3-4 AEs in >3 pts were neutropenia, anemia, thrombocytopenia (38% each), and infections (29%). CRS occurred in 76% of pts (16/21) and was mainly Gr 1 (43%) or Gr 2 (29%); 1 patient had Gr 3 CRS. One treatment-related Gr 5 (fatal) AE of pneumonia was reported in the context of PD. No treatment-related AEs leading to cevostamab discontinuation occurred.

Objective responses (partial response [PR] or better) were observed in 2/21 pts (ORR: 10%). Both pts achieved a very good PR and had ongoing responses at cut-off. Stable disease was observed in 10 pts (48%).

Pts in the prior BsAb group had received more prior lines of therapy than those in the prior ADC and CAR-T groups (median 8 vs 5 and 6, respectively) and more prior BCMA-targeted therapies (median 2 vs 1 and 1). The percentage of pts with low levels (<4.5 ng/mL) of soluble BCMA in plasma was also higher in the prior BsAb group (47% vs 0% and 18%). At baseline, inhibitory immune checkpoint expression across T-cell subsets was more common in the prior BsAb group. Notably, the median frequency of PD1+CD8+Tnaive and TIGIT+CD8+Tnaive cells in blood was higher in the prior BsAb group (21% and 29%, respectively) than in the prior ADC (3% and 6%) and CAR-T groups (4% each). Peak median IL-6 and IFN-γ levels were delayed until the first TD in the prior BsAb group, suggesting a different pharmacodynamic profile.

Conclusions: Cevostamab has manageable safety in pts with triple-class refractory MM who have received prior BCMA-targeted therapies, including ≥1 BCMA-targeted BsAb. Clinical responses were less frequent in the prior BsAb group than in the prior ADC and CAR-T groups, which could be explained by the higher number of prior lines of therapy and T-cell exhaustion due to multiple prior exposures to BsAbs. Notably, the high frequency of CD8+ T-cell subsets expressing inhibitory immune checkpoints in the prior BsAb group suggests a level of T-cell dysfunction that could prevent effective T-cell activation.

Delforge:Roche: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; University Hospital Leuven: Consultancy, Honoraria; Amgen, BMS, GSJ, Janssen, Sanofi, Pfizer, Roche: Honoraria; Amgen, BMS, GSJ, Janssen, Sanofi, Pfizer, F. Hoffmann-La Roche Ltd: Consultancy. Richter:Johnson & Johnson - Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Pfizer: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy, Speakers Bureau; Takeda: Consultancy; AbbVie: Consultancy; Regeneron: Consultancy; Adaptive Biotechnologies: Speakers Bureau. Cohen: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, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Johnson and Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen, BMS, GSK, JNJ, Medison, Pfizer, Roche, Sanofi Aventis, Takeda: Consultancy. Corradini:Pfizer: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Roche: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Sanofi: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); SOBI: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Bristol Myers Squibb: Other: Support for travel and accommodations; Takeda: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Amgen: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Incyte: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); GlaxoSmithKline: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Celgene: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Daiichi Sankyo: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Gilead/Kite: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Novartis: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Kyowa Kirin: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Janssen: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; AbbVie: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations. Sborov:Bristol Myers Squibb: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Legend Biotech: Consultancy; Sanofi: Consultancy; Society of Utah Medical Oncology: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Binaytara Foundation: Honoraria; Pfizer: Consultancy, Research Funding; Bioline: Consultancy; Parexel, Keosys: Other: IRC; Arcellx: Consultancy; Abbvie: Consultancy; University of Utah, Huntsman Cancer Institute: Current Employment; AstraZeneca: Consultancy. Lesokhin:Arcellx: Consultancy, Honoraria; Memorial Sloan Kettering Cancer Center: Current Employment; F. Hoffmann-La Roche Ltd, Janssen, SVB Leerink: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Serametrix, Inc.: Patents & Royalties. Berdeja:2 Seventy Bio; AbbVie; Amgen; BMS; C4 Therapeutics; Caribou Biosciences; CARsgen; Cartesian Therapeutics; Celularity; CRISPR Therapeutics; Fate Therapeutics; Genentech; GSK; Ichnos Sciences; Incyte; Janssen; Juno Therapeutics; K36 Therapeutics; Karyopharm: Research Funding; AstraZeneca; BMS; Caribou Biosciences; Galapagos; Janssen; K36 Therapeutics; Kite Pharma; Legend Biotech; Pfizer; Regeneron; Roche; Sanofi-Aventis; Sebia; Takeda: Consultancy; Janssen: Honoraria, Speakers Bureau. Gatt:Hadassah Medical Center Jerusalem: Current Employment. Paris:Menarini Stemline: 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: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodation; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodation; Takeda: Honoraria, Other: Travel, accommodation; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodation. Rosinol Dachs:GSK: Honoraria, Other: Honoraria for lectures; Sanofi: Honoraria, Other: Honoraria for lectures; Amgen: Honoraria, Other: Educational lectures; Janssen Pharmaceutica: Honoraria, Other: Honoraria for lectures and meeting travel support; Janssen, BMS, Takeda, Menarini, Pfizer: Honoraria. Quach:Roche: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; GSK: Consultancy, Research Funding; AbbVie: Research Funding; Johnson & Johnson: Consultancy. Kanwar:Roche Products Ltd: Current Employment; Viatris: Ended employment in the past 24 months. Catalani:F. Hoffmann-La Roche Ltd: Current Employment. Sewpaul:Roche Products Ltd: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Wassner-Fritsch:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Mishra:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd, Apple, Amazon, Mobil, Meta, Google, Nividia, JP Morgan chase, Applied materials, Netflix: Current equity holder in publicly-traded company. Trunzer:F. 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