ABBV-383 Plus Daratumumab-Dexamethasone in Relapsed or Refractory Multiple Myeloma: A Phase 1b Dose-Escalation and Safety Expansion Study

Introduction

ABBV-383 is a fully human bispecific antibody that targets B-cell maturation antigen (BCMA) and CD3 on the surface of multiple myeloma (MM) cells and T cells, respectively, resulting in T-cell activation and selective destruction of BCMA-positive MM cells. ABBV-383 is composed of a bivalent BCMA-binding domain with high avidity, a low-affinity CD3-binding domain designed to mitigate cytokine release with potential for minimal T-cell exhaustion, and a present but silenced Fc tail resulting in an extended half-life and convenient dosing interval (every 4 weeks [Q4W]). These characteristics potentially result in a manageable safety profile and robust efficacy. ABBV-383 monotherapy showed promising results in heavily pretreated patients (pts) with relapsed or refractory MM in a phase 1 first-in-human dose-escalation study (NCT03933735; Rodriguez et al. JCO 2024;42[suppl 16]:7531). Daratumumab could add beneficial immunomodulatory effects to treatment with ABBV-383, by eliminating immunosuppressor cells and reducing T-cell exhaustion. The current study (Kilimanjaro; NCT05259839) evaluates the hypothesis that combining ABBV-383 with daratumumab and dexamethasone (Dd) may be tolerable and result in enhanced antitumor activity in heavily pretreated pts with MM.

Methods

This open-label, multicenter, phase 1b, dose-escalation and -expansion study is evaluating safety, preliminary efficacy, pharmacokinetics, and the RP2D of ABBV-383 in different combination regimens; here we report on ABBV-383 plus Dd. The study is being conducted at 47 centers in 7 countries globally. Enrolled pts are adults (≥18 years) who have an ECOG performance status ≤2, MM progression during or after the last treatment, and received ≥3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory drug. Prior anti-CD38 monoclonal antibody (mAb) exposure was allowed (>90 days of first dose of study drug). Pts received 20 mg, 40 mg, or 60 mg intravenous ABBV-383 Q4W. For the first ABBV-383 dose, pts were hospitalized for a minimum of 24 hours; subsequent doses were administered in an outpatient setting until progressive disease. The daratumumab dose was 1800 mg, weekly for cycles 1-2 and then at standard reduced frequency; the dexamethasone dose was 40 mg weekly. Responses were investigator assessed per IMWG 2016 criteria.

Results

As of May 15, 2024, 74 pts were enrolled and treated across 3 dose levels of ABBV-383 plus Dd. Median age was 69 years (range 39-89) and 45 (61%) pts were male. The majority of pts were White (n=65, 88%), 6 (8%) were Asian, and 3 (4%) were Black or African American. R-ISS at study entry was I in 18 (25%) pts, II in 26 (36%), and III in 15 (21%). Pts had received a median of 4 (range 3-9) prior lines of therapy; 70% were exposed to prior anti-CD38 mAb therapy. Forty-two (57%) pts were refractory to prior anti-CD38 mAb therapy, 34 (46%) were refractory to the most recent MM therapy, and 32 (43%) were triple-class refractory. After a median follow-up of 5 months (range 0-14), 48 (65%) pts remained on therapy; the majority of study drug discontinuations were due to progressive disease (n=14, 19%). Cytokine release syndrome (CRS) occurred in 20 (27%) pts. The majority of CRS events were grade 1 (n=8, 11%) or 2 (n=9, 12%); 3 (4%) pts had grade 3 events. Other most common treatment-emergent adverse events (AEs) included (any grade/grade 3-4) neutropenia (39%/38%), anemia (24%/18%), fatigue (22%/0%), and thrombocytopenia (30%/18%). Immune effector cell-associated neurotoxicity syndrome was reported in 2 (3%) pts total. Most common serious AEs were CRS (20%), COVID-19 pneumonia (7%), and pneumonia (5%). Twelve deaths occurred during the study to date; the most common cause was disease progression (n=5, 7%). At the time of data cutoff, 60 pts were evaluable for disease assessment. The aggregate overall response rate (ORR) for the total evaluable population was 70% (42/60). ORRs were 50% (7/14) in the 20-mg Q4W ABBV-383 cohort at a median follow-up of 1 month (range 0-14), 74% (26/35) in the 40-mg cohort at a median follow-up of 4.4 months (1-10), and 82% (9/11) in the 60-mg cohort at a median follow-up of 5.6 months (1-6). Median progression-free survival was not reached at time of analysis.

Conclusion

Preliminary data suggest ABBV-383 in combination with Dd is tolerable. Overall rates of CRS were low and early response rates were promising in the investigated population of heavily pretreated pts with MM.

Rodriguez:Janssen: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; BMS: Consultancy; AbbVie: Consultancy; Johnson and Johnson: Consultancy; Amgen: Consultancy; Karyopharm Therapeutics: Consultancy. Mielnik:Eli Lilly: Honoraria; Sanofi: Honoraria; MSD: Honoraria; Bristol-Myers Squibb: Honoraria; Bristol-Myers Squibb - Celgene: Honoraria; Novartis: Honoraria; Johnson & Johnson - Janssen: Consultancy, Honoraria, Other: travel; AbbVie: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Kazandjian:MJH Life Sciences: Honoraria; Aptitude Health: Honoraria; NCI/NIH, FDA, MMRF, DoD-PROMETHEUS (Murtha Cancer Center Research Program), Amgen, BMS/Celgene, Janssen,: Research Funding; Dedham Group: Consultancy; Plexus: Honoraria; Alphasights: Consultancy; Curio Science: Honoraria; Karyopharm Therapeutics: Honoraria, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aperture Medical Technologies: Honoraria, Other: served on independent data monitoring committees (IDMC); Arcellx: Honoraria, Other: served on independent data monitoring committees (IDMC); Magnolia: Honoraria; MJH Life Sciences: Honoraria; Bridger Consulting Group: Consultancy; BMS: Honoraria; MMRF: Honoraria. Janowski:Janssen, Pfizer, Beigene: Consultancy. Pianko:Janssen, Karyopharm, Oncopeptides, Pfizer, Sanofi: Honoraria; Janssen, Pfizer: Consultancy; AbbVie, Ascentage, Bristol Myers Squibb, Janssen, Nektar, Pfizer, Regeneron, Sanofi: Research Funding. Yuda:Incyte: Research Funding; Janssen: Research Funding; Mitsubishi Tanabe: Research Funding; Sumitomo: Research Funding; BMS: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Genmab: Research Funding; AbbVie: Research Funding; Amgen: Research Funding; Chugai: Research Funding; Daiichi Sankyo: Research Funding; MSD: Research Funding. Van Der Weyden:Kyowa Kirin: Consultancy. Anderson:Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: 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, Research Funding; Celgene: 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; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectar Biosciences: 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; BMS: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Banerjee:Adaptive; BMS; Caribou Biosciences; Genentech; GSK; JNJ / Janssen; Karyopharm; Legend Biotech; Pfizer; Sanofi; SparkCures: Consultancy; Abbvie; JNJ; Novartis; Pack Health; Prothena; Sanofi: Research Funding. Rosinol Dachs:Sanofi: Honoraria, Other: Honoraria for lectures; Janssen, BMS, Takeda, Menarini, Pfizer: Honoraria; GSK: Honoraria, Other: Honoraria for lectures; Janssen Pharmaceutica: Honoraria, Other: Honoraria for lectures and meeting travel support; Amgen: Honoraria, Other: Educational lectures. Cerchione:Karyopharm: Consultancy; Jazz: Consultancy; Beigene: Consultancy; Astellas: Consultancy; AMGEN: Consultancy; Skyline DX: Consultancy; GSK: Consultancy; Takeda: Consultancy; Curis: Consultancy; Glycomimetics: Consultancy; Immunogen: Consultancy; Janssen: Consultancy; Servier: Consultancy; BMS: Consultancy; Abbvie: Consultancy; GSK: Consultancy, Current holder of stock options in a privately-held company; Sanofi: Consultancy; Pfizer: Consultancy; Oncopeptides: Consultancy; Menarini-Stemline: Consultancy; Karyopharm: Consultancy; Stemline: Consultancy; Abbvie, AMGEN, Astellas, Beigene, BMS, Glycomimetics, GSK, Immunogen, Janssen, Jazz, Karyopharm, Menarini - Stemline, Oncopeptides, Pfizer, Sanofi, Servier, Stemline, Takeda: Other: Advisory board. Hultcrantz:Curio Science LLC, Intellisphere LLC, Janssen, Bristol Myers Squibb, and GlaxoSmithKline: Consultancy, Honoraria; Abbvie, GlaxoSmithKline, SpringWorks Therapeutics, Daiichi Sankyo, Cosette Pharmaceuticals: Research Funding. D'Souza:Kedrion, Pfizer, Janssen, Bristol Myers Squibb, BMS, Janssen, and Prothena.: Consultancy; AbbVie, Sanofi, Novartis, Janssen, Regeneron, Takeda, TeneoBio, Caelum, and Prothena: Research Funding. Godara:Janssen, Sanofi: Consultancy. Grajales-Cruz:Cellectar Biosciences: Honoraria, Other: Data Safety Monitoring/Advisory Board, Research Funding; Janssen: Honoraria, Other: Data Safety Monitoring/Advisory Board; Sanofi: Honoraria, Other: Data Safety Monitoring/Advisory Board; Amgen: Honoraria; Pfizer: Honoraria, Other: Data Safety Monitoring/Advisory Board. Jin:AbbVie Inc.: Current Employment, Current holder of stock options in a privately-held company. Polepally:AbbVie Inc.: Current Employment, Current holder of stock options in a privately-held company. Ahsan:AbbVie Inc.: Current Employment, Current holder of stock options in a privately-held company. Lee:AbbVie Inc.: Current Employment, Current holder of stock options in a privately-held company. D'Amico:AbbVie Inc.: Current Employment, Current holder of stock options in a privately-held company. Bueno:AbbVie Inc.: Current Employment, Current holder of stock options in a privately-held company. Talati:AbbVie Inc.: Current Employment, Current holder of stock options in a privately-held company. Svensson:AbbVie Inc.: Current Employment, Current holder of stock options in a privately-held company. Fleming:AbbVie Inc.: Current Employment, Current holder of stock options in a privately-held company. Weisel:Amgen: Consultancy, Honoraria, Other: Research grant to institution; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Other: Research grant to institution; GlaxoSmithKline: Consultancy, Honoraria, Other: Research grant to institution; Janssen: Consultancy, Honoraria, Other: Research grant to institution; Sanofi: Consultancy, Honoraria, Other: Research grant to institution; Adaptive Biotechnologies: Consultancy, Honoraria; AstraZeneca: Honoraria; BeiGene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Roche Pharma: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Novartis: Honoraria; AbbVie: Other: Research grant to institution; Stemline: Honoraria; Takeda: Consultancy, Honoraria; Regeneron: Consultancy. Hus:AbbVie Inc., Amgen, AstraZeneca, BMS/Celgene, Janssen, GSK, MSD, Novartis, Roche, Oncopeptides, Sanofi, Takeda: Honoraria; Roche: Other: travel expenses; medical writing support; Janssen: Other: travel expenses. Voorhees:Janssen: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Research Funding; AstraZeneca: Consultancy; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: 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; Lava Therapeutics: Consultancy; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.