Outcomes of Venetoclax-Based Treatment Combinations in Relapsed/Refractory Multiple Myeloma: Real-World Practice Patterns and Impact of Cytogenetics on Outcomes

Background: Venetoclax (Ven), a BCL2 inhibitor, has shown promising responses in multiple myeloma (MM) patients with t(11;14) and/or BCL2 expression. However, consistent benefit in clinical trials remain elusive. This report evaluates the efficacy and safety of Ven combination therapies, including in the non-t(11;14) subgroup, and examines the impact of secondary cytogenetic abnormalities (SGA) on outcomes.

Methods: This retrospective study included multiple myeloma (MM) patients without concurrent AL amyloidosis treated with Ven-based combinations at Mayo Clinic sites from January 2015 to December 2023. FISH data was collected at diagnosis and before venetoclax initiation to assess SGAs. Refractoriness was defined by progression on or within 60 days of stopping treatment. Patients refractory to at least one proteasome inhibitor (PI), immunomodulatory drug (ImiD), and anti-CD38 antibody were considered triple-class refractory (TCR). Ven combinations were grouped as: Daratumumab/CD38 antibody (Dara)-Ven based if received Dara ± other drugs, PI-Ven-based without Dara, Ven-dexamethasone (Ven-d), and other combinations (Ven-Misc). BCL2 expression in patients without t(11;14) was determined by immunohistochemistry (IHC). Progression-free survival (PFS) was calculated from treatment initiation to disease progression or last follow-up.

Results: We included 232 patients in this study. The median age at diagnosis of MM was 62 years (range 32-87), and the median age at initiation was 68 years (range 35-89). The median time from diagnosis of MM to initiation of Ven was 55 months (95% CI 28, 89 months), and the median follow-up from initiation of Ven-based treatment was 17.2 months (95% CI: 14, 22). Patients had received a median of 3 lines (IQR 4-6); 65% (n=152) of patients were TCR, 71% (n=163) had received autologous stem cell transplant and 7% (n=16) patients had received prior immune effector therapy prior to initiation of Ven-based therapy. The majority (83%, n=190) of the patients harbored a t(11;14); in the patients without t(11;14), a BCL2 expression by IHC was tested in 18 patients and positive in 17 patients. The most common Ven-based combinations included: Dara-Ven-d (19%, n=44), PI-Ven-d (30.2%, n=70), Ven-d (48.3%, n=112), Ven-misc (2.6%, n=6).

The overall response rate for the entire cohort was 57% [64% for t(11;14) and 26% for non t(11;14), p<0.0001]. The median PFS for the entire cohort was 9.5 months (95% CI 8.5,13), and the duration of response was 18 months (95% CI 15.2-23.3). The median PFS was 11.8 months (95% CI 9.5-16.7) for patients harboring a t(11;14) compared to 2.9 months (95% CI 1.8, 8.4) for patients without a t(11;14), p<0.0001. Among the non-t(11;14) cohort with BCL2 expression, the median PFS was 1.8 months (95% CI: 1.2-4.2). Among the 190 patients with t(11;14), 18% (34/190) harbored deletion 17p and 32% (60/193) harbored a 1q gain/amplification (referred hereforth as 1q21+) at initiation of Ven-based therapy. In the cohort of patients with t(11;14), the presence of either del17p or 1q21+ (n=85/190) was associated with a significantly inferior PFS [median PFS 8.2 months (95% CI: 5.5,13)] vs. 15.1 months (95% CI: 11.6, 22), p=0.03.

At the last follow-up,42 patients had ongoing treatment with ven-based combination. Most common reasons for discontinuation were progression (77% N=140), adverse effect (12%, n=22), patient/provider preference(9%, n=17); 2% (n=4) patients died without progression (3 infection, 1 unclear). The most commonly utilized maximum dose of venetoclax was 400 mg (42%); 15% (n=35) of patients required a dose reduction, and 23% (n=54) received a ramp-up. Tumor lysis syndrome was not noted in any patient. Infectious complications were noted in 23% (n=52). The estimated median OS from initiation of ven-based Rx was 34 months (95%CI 25-47). The estimated median OS for patients without a t(11;14) was 6.2 months (95% CI: 3.3-11.3) compared to 46 months (31.4-54.1), p<0.0001. In the t(11;14) subgroup, the 18-month OS rate was 79% for patients without 1q21+/del17p vs. 50% for patients with a 1q21+/del17p (p=0.002).

Conclusion: Venetoclax-based regimens represent an important treatment option for patients harboring a t(11;14). The PFS in patients with BCL2 expression without t(11;14) was poor suggesting lack of efficacy of venetoclax-based regimens for that subgroup. Presence of concurrent del17p and/or 1q21+ with t(11;14) portends an inferior PFS.

Bergsagel:Novartis: Research Funding; Omeros: Consultancy; Oncopeptides: Consultancy; BMS/Celgene: Research Funding; Pfizer: Research Funding; Cellcentric: Consultancy; Janssen: Consultancy; Sanofi: Research Funding. Chhabra:GlaxoSmithKline, Sanofi: Honoraria; Omeros: Speakers Bureau; Bristol Myers Squibb, Amgen, Janssen, Novartis, Syndax, Ionis, Sanofi, and GlaxoSmithKline: Research Funding. Cook:Geron Corp: Other: Held $600 Geron Stock for one week and sold without profit . Dingli:Apellis: Consultancy, Honoraria, Research Funding; K36 Therapeutics: Research Funding; Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sorrento: Consultancy, Honoraria; Genentech: Consultancy; Janssen: Consultancy, Honoraria; Alexion: Consultancy, Honoraria. Dispenzieri:BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; HaemaloiX: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Alnylam: Research Funding; Alexion: Consultancy, Research Funding. Gertz:Astra Zeneca: Honoraria; Alexion: Honoraria; Abbvie: Other: personal fees for Data Safety Monitoring board ; Prothena: Other: personal fees; Sanofi: Other: personal fees; Ionis/Akcea: Honoraria; Alnylym: Honoraria; Johnson & Johnson: Other: personal fees; Medscape: Honoraria; Janssen: Other: personal fees; Dava Oncology: Honoraria. Kapoor:Janssen: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Loxo Pharmaceuticals: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; X4 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Regeneron: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ichnos: Research Funding; Karyopharm: Research Funding; Angitia Bio: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mustang Bio: Membership on an entity's Board of Directors or advisory committees; CVS Caremark: Consultancy; Keosys: Consultancy. Kourelis:Novartis: Research Funding; Pfizer: Research Funding. Leung:AbbVie: Current holder of stock options in a privately-held company; Checkpoint Therapeutics: Current holder of stock options in a privately-held company. Lin:Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Caribou: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; NexImmune: Membership on an entity's Board of Directors or advisory committees; Legend: Consultancy; Regeneron: Consultancy; Genentech: Consultancy. Muchtar:Protego: Consultancy. Parrondo:Bristol Myers Squibb, GSK: Research Funding; Sanofi Aventis: Honoraria; AstraZeneca: Honoraria. Sher:Caelum pharma: Other; Alpha: Consultancy, Membership on an entity's Board of Directors or advisory committees; 2 Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Prothena: Other. Hwa:GSK: Honoraria; Janssen: Honoraria; Shield Therapeutics: Honoraria; MultiMedia Medical, LLC: Consultancy; Pfizer: Other: Consulting fee located to Mayo Research fund. Baughn:Genentech: Consultancy. Fonseca:AbbVie, Adaptive, Amgen, Apple, Bayer, BMS/Celgene, Gilead, GSK, Janssen, Kite, Karyopharm, Merck Sharp & Dohme, Juno Therapeutics, Takeda, Arduro Biotech, Oncotracker, Oncopeptides, Pharmacyclics, Pfizer, RA Capital, Regeneron, Sanofi: Consultancy; Patent for FISH in MM - ~$2000/year: Patents & Royalties: Patent for FISH in MM - ~$2000/year; Antengene: Membership on an entity's Board of Directors or advisory committees; Celgene, Bristol Myers Squibb, Bayer, Amgen, Janssen, Kite, a Gilead company, Merck Sharp & Dohme, Juno Therapeutics, Takeda, AbbVie, Aduro Biotech, Sanofi, OncoTracker: Honoraria. Ailawadhi:Xencor: Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cellectar: Consultancy, Honoraria, Research Funding; Abbvie: Research Funding; Ascentage: Research Funding; GSK: Consultancy, Research Funding; Sanofi: Consultancy; BMS: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Regeneron: Consultancy; Beigene: Consultancy; Takeda: Consultancy; Pharmacuclics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Kumar:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune/AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Sanofi: Research Funding; Oncopeptides: Other: Independent review committee participation.