Sonrotoclax plus dexamethasone is tolerable and demonstrates antimyeloma activity
in patients with relapsed/refractory (R/R) multiple myeloma harboring t(11;14)
Authors: Binod Dhakal,1 Malin Hultcrantz,2 Susan Bal,3 Hun Chuah,4 Jonathan L. Kaufman,5Dickran Kazandjian,6 Nitya Nathwani,7 Gordon Royle,8 Douglas Sborov,9 Christopher P.
Venner,10 Huan Cheng,11 Adam Idoine,11 Rocco Crescenzo,11 Amit Agarwal,11 Hang Quach12
Affiliations: 1Medical College of Wisconsin, Milwaukee, WI, USA; 2Memorial Sloan Kettering
Cancer Centre, New York, NY, USA; 3University of Alabama at Birmingham, Birmingham, AL,USA; 4Royal Perth, Perth, WA, Australia; 5Emory University, Atlanta, GA, USA; 6University ofMiami, Miami, FL, USA; 7City of Hope, Duarte, CA, USA; 8Middlemore Hospital, Auckland,
New Zealand; 9Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT, USA;
10BC Cancer – Vancouver Centre, Vancouver, BC, Canada; 11BeiGene USA, Inc, San Mateo,CA, USA; 12St Vincent's Australia, University of Melbourne, Melbourne, VIC, Australia.
Background: BCL2 is an attractive therapeutic target in multiple myeloma (MM) witht(11;14), in that MM cells are primed for BCL2 and responsive to oral BCL2 inhibitors, suchas venetoclax, a first-generation BCL2 inhibitor. Although BCL2 inhibitors have shown clinicalactivity in patients (pts) with MM, no BCL2-targeted therapies are currently approved for MM.
Sonrotoclax (BGB-11417) is more selective and a more pharmacologically potent inhibitor ofBCL2 than venetoclax in biochemical assays. BGB-11417-105 (NCT04973605) is an ongoing,phase 1b/2 trial evaluating the safety and efficacy of sonrotoclax as monotherapy or as
combination therapy for pts with R/R MM harboring t(11;14).
Aims: To report updated safety and efficacy data from the sonrotoclax plus dexamethasone
cohort in pts with R/R MM treated with 640 mg sonrotoclax.
Methods: Eligible pts have R/R MM harboring centrally-confirmed t(11;14) and had received
a minimum of 3 (dose–finding cohort) or 1 (dose–expansion cohort) prior line(s) of therapy.
Pts received 640 mg sonrotoclax orally, once daily, and 40 mg dexamethasone weekly until
intolerance, disease progression, consent withdrawal, or death. Adverse events (AEs) weregraded per CTCAE v5.0 and disease responses were assessed by the investigator per theInternational Myeloma Working Group response criteria (Kumar et al, 2016).

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Results: As of Jan 8, 2024, 20 pts had been enrolled in the 640 mg dose-escalation (n=10)
and dose-expansion (n=10) cohorts with a median follow-up of 6.2 months (range, 0.3-16.6months). Median age was 70 yrs (range, 48-79 yrs); 50% were male, 85% were White, 5%were Black, and 5% were Hispanic. The median number of prior lines of therapy was 4(range, 1-12), with 70% and 80% of pts refractory to anti-CD38 therapy and IMiDs,respectively. At the data cutoff, 13 pts (65%) were still on study treatment (reasons fordiscontinuation: disease progression [n=3], AE [n=2; hematuria, pancreatic cancer], pt
withdrawal [n=1], and physician decision [n=1]). Nineteen (95%) pts experienced a treatmentemergent AE (TEAE); insomnia (n=6; 30%), diarrhea, fatigue, and nausea (each n=5; 25%)
were the most common. Hematologic TEAEs occurred in 3 pts (thrombocytopenia [n=2;grades 1 and 3], neutropenia [n=1; grade 1]). Serious TEAEs occurred in 3 pts (15%) andgrade ≥3 AEs occurred in 4 pts (20%); none were considered related to sonrotoclax (2 pts
experienced both serious TEAEs and grade ≥3 TEAEs). No pt experienced a dose-limiting
toxicity. Two pts died on study; both deaths were not considered related to study therapy (1TEAE [metastatic pancreatic cancer] and 1 non-TEAE [liver failure due to hepatocellularcarcinoma]). Infections that were observed in >1 pt were COVID-19 (n=2; 10%) and upper
respiratory tract infection (n=2; 10%). Among 15 efficacy-evaluable pts, the ORR was 80%(n=12; 95% CI, 51.9-95.7), with a 40% VGPR or better rate (n=6). The median time toresponse was 0.7 months and median duration of response (DOR) was 8.3 months (95% CI,4.4 to not reached) with a maximum DOR of 15.4 months (ongoing; Figure).
Summary/Conclusion: With longer follow-up, sonrotoclax plus dexamethasone continues todemonstrate a manageable safety profile, with low rates of hematologic toxicities andinfections. The combination provided deep and durable responses in this R/R population. The
study is ongoing, and other combination treatments with sonrotoclax are being investigated.

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Figure. Treatment duration and response assessment in patients with R/R MM
harboring t(11;14)

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