ABBV-383 Plus Daratumumab-Dexamethasone in Relapsed or Refractory Multiple Myeloma: A Phase 1b Dose-Escalation and Safety Expansion Study
Authors: Rodriguez Cesar , Mielnik Michal , Kazandjian Dickran , Janowski Wojt , Low Michael S.Y. , Pianko Matthew , Yuda Junichiro , Van Der Weyden Carrie , Anderson Larry D , Banerjee Rahul , Rosinol Dachs Laura , Cerchione Claudio , Hultcrantz Malin , D'Souza Anita , Godara Amandeep , Grajales-Cruz Ariel , Jin Ziyi , Polepally Akshanth R , Ahsan Aarif , Lee Shane , D'Amico Kristin , Bueno Orlando , Talati Chetasi , Svensson Anders Erik , Fleming Leanne , Weisel Katja C. , Hus Marek , Voorhees Peter M. 
Published: December 2024

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 (&gt;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.