Sonrotoclax Combo Shows Safety, Promising Efficacy in R/R Multiple Myeloma

An all-oral combination consisting of sonrotoclax and dexamethasone demonstrated a manageable safety profile and early efficacy among patients with relapsed/refractory multiple myeloma harboring t(11;14), according to findings from the phase 1b/2 BGB-11417-105 study (NCT04973605) presented at the 22nd Annual International Myeloma Society Meeting and Exposition.¹

Among 55 evaluable patients, the combination therapy produced an overall response rate (ORR) of 78.2%, which included a partial response (PR) rate of 29.1%, a very good PR (VGPR) rate of 27.3%, a complete response (CR) rate of 18.2%, and a stringent CR (sCR) rate of 3.6%. In those who received sonrotoclax at 320 mg (n = 19), these respective values were 73.7%, 36.8%, 21.1%, and 15.8%; no sCRs occurred in this group. Additionally, sonrotoclax at 640 mg (n = 36) produced respective rates of 80.6%, 25.0%, 30.6%, 19.4%, and 5.6%.

Data showed a median time to response of 0.7 months for each cohort. The median duration of response (DOR) was not reached (range, 1.8-not evaluable [NE]) with sonrotoclax at 320 mg compared with 12.2 months (range, 8.3-18.9) with the agent at 640 mg.

After a median follow-up of 12.0 months (range, 0.1-36.4), data showed a median progression-free survival (PFS) of 12.9 months (95% CI, 9.0-19.6) with sonrotoclax at 640 mg; the investigators noted that patients in this cohort had heavily pretreated disease. Among patients who received the agent at 320 mg, the median PFS was 6.6 months (95% CI, 2.9-NE).

“The all-oral combination of sonrotoclax [plus] dexamethasone continued to show a tolerable safety profile, with low rates of grade [3 or higher] infection and hematologic toxicity. Efficacy was promising, with an ORR of 81% and a VGPR or better rate of 56% in the 640-mg cohort, in patients with heavily pretreated, t(11;14)–positive relapsed/refractory [multiple myeloma],” presenting study author Binod Dhakal, MD, MS, an associate professor of medicine in the Division of Hematology at Medical College of Wisconsin, wrote with coauthors in the presentation.¹ “Enrollment in BGB-11417-105 is ongoing; additional treatment combinations with sonrotoclax are being investigated.”

Although BCL2 inhibitors have demonstrated clinical activity in patients with multiple myeloma, the study investigators noted that no BCL2-directed agents have received approval in this patient population. They highlighted that sonrotoclax, a next-generation BCL2 investigator, may be more selective and pharmacologically potent compared with venetoclax (Venclexta) while exhibiting a shorter half-life and no drug accumulation.

Investigators of the ongoing, open-label, phase 1b/2 BGB-11417-105 study are assessing sonrotoclax alone or in combination with other agents for patients with t(11;14)–positive relapsed/refractory multiple myeloma. Following a dose-escalation portion in part 1 of the trial, investigators proceeded to administer sonrotoclax at 320 mg or 640 mg plus dexamethasone as part of the safety-expansion portion in part 2.

The primary end points of part 2 of the trial include investigator-assessed ORR, the VGPR or better rate, and the CR or sCR rate.² Secondary end points in part 2 include time to response, DOR, PFS, and overall survival.

Patients 18 years and older with documented relapsed or progressive multiple myeloma, positivity for t(11;14) translocation, and measurable disease were eligible for enrollment on the trial. Other eligibility criteria included having an ECOG performance status of 0 to 2 and adequate organ function.

Across the overall population, the median age was 70 years (range, 44-86), 49.1% of patients were male, and 92.7% had an ECOG performance status of 0 or 1. Of note, 65.5% of patients had 3 or more prior lines of systemic therapy, and 72.7% had prior exposure to at least 1 proteasome inhibitor, at least 1 immunomodulatory drug, and at least 1 CD38-directed antibody. Additionally, 40.0% of patients had refractory disease following treatment with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody.

Treatment-emergent adverse effects (TEAEs) of any grade affected 98.2% of the overall population, with 45.5% experiencing grade 3 or higher toxicities. For sonrotoclaxand dexamethasone, respectively, data showed TEAEs resulting in dose interruption (38.2% vs 27.3%), dose reduction (5.5% vs 38.2%), and treatment discontinuation (9.1% vs 20.0%). Investigators noted that 7.3% of patients had TEAEs leading to death, none of which were considered associated with study treatment.

Among all patients, the most common any-grade TEAEs included insomnia (38.2%), fatigue (30.9%), diarrhea (25.5%), and upper respiratory tract infections (21.8%). Grade 3 or higher TEAEs in this group included neutrophil count decreases (9.1%), insomnia (3.6%), and fatigue (3.6%). Any-grade and grade 3 or higher hematologic TEAEs affected 33% and 20% of patients, respectively; these rates were 56% and 14.5% for infection TEAEs.

References

1. Dhakal B, Hultcrantz M, Nathwani N, et al. Updated interim results of sonrotoclax + dexamethasone in patients with t(11;14)-positive relapsed/refractory multiple myeloma (R/R MM): an all-oral treatment. Presented at the 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-60.
2. A Phase 1b/​2 study of sonrotoclax (BGB-11417) as monotherapy and in various combinations with dexamethasone plus carfilzomib, dexamethasone plus daratumumab, and dexamethasone plus pomalidomide in multiple myeloma. ClinicalTrials.gov. Updated September 15, 2025. https://tinyurl.com/4j67wk4x