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. 2025 Apr 4;15(1):57.
doi: 10.1038/s41408-025-01264-2.

Venetoclax-based treatment combinations in relapsed/refractory multiple myeloma: practice patterns and impact of secondary cytogenetic abnormalities on outcomes

Abiola Bolarinwa  1 , Madhu Nagaraj  1 , Saurabh Zanwar  1 , Nadine Abdallah  1 , P Leif Bergsagel  2 , Moritz Binder  1 , Francis Buadi  1 , Saurabh Chhabra  2 , Joselle Cook  1 , David Dingli  1 , Angela Dispenzieri  1 , Morie A Gertz  1 , Wilson Gonsalves  1 , Suzanne Hayman  1 , Prashant Kapoor  1 , Taxiarchis Kourelis  1 , Nelson Leung  1 , Yi Lin  1 , Eli Muchtar  1 , Ricardo Parrondo  3 , Vivek Roy  3 , Taimur Sher  3 , Mustaqeem Siddiqui  1 , Rahma Warsame  1 , Amie Fonder  1 , Miriam Hobbs  1 , Yi Lisa Hwa  1 , Michelle Rogers  1 , Udit Yadav  2 , J Erin Wiedmeier-Nutor  2 , Linda B Baughn  4 , S Vincent Rajkumar  1 , Rafael Fonseca  2 , Sikander Ailawadhi  3 , Shaji Kumar  5
Affiliations

Venetoclax-based treatment combinations in relapsed/refractory multiple myeloma: practice patterns and impact of secondary cytogenetic abnormalities on outcomes

Abiola Bolarinwa et al. Blood Cancer J. .

Abstract

Venetoclax (Ven), a BCL-2 inhibitor, has demonstrated efficacy in patients with relapsed/refractory multiple myeloma (RRMM) harboring a t(11;14) and/or elevated BCL-2 expression. However, data from clinical trial remain inconclusive. This retrospective study evaluated the efficacy and safety of Ven-based therapies in 232 MM patients without concurrent AL amyloidosis treated at Mayo Clinic sites between Jan 2015 and Dec 2023. The median age was 62 years, with a median of 3 prior lines of therapy. Among the cohort, 82% had t(11;14), and elevated BCL-2 expression was identified in 17 of 18 non-t(11;14) patients tested. Ven combinations included Ven-Dex (VenD; 48.3%), Proteasome Inhibitor-Ven (30.2%), and Daratumumab-Ven (19%) with other combinations making up the rest. The overall response rate was 57%; 64% for t(11;14) patients and 26% for non-t(11;14) patients. Median progression-free survival (PFS) was 9.4 months overall; 11.8 months for t(11;14) patients and 2.9 months for those without (p < 0.001). Among t(11;14) patients, the presence of del(17p) or 1q gain/amplification significantly reduced PFS to 7.7 months. Venetoclax-based regimens remain an important option for t(11;14) patients, but efficacy is limited in patients without a t(11;14). The presence of secondary high-risk cytogenetics imparts an inferior PFS.

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Conflict of interest statement

Competing interests: The authors report to conflicts of interest pertaining to the submitted work. PLB: Novartis: Research Funding; Omeros: Consultancy; Oncopeptides: Consultancy; BMS/Celgene: Research Funding; Pfizer: Research Funding; Cellcentric: Consultancy; Janssen: Consultancy; Sanofi: Research Funding. SC: GlaxoSmithKline, Sanofi: Honoraria; Omeros: Speakers Bureau; Bristol Myers Squibb, Amgen, Janssen, Novartis, Syndax, Ionis, Sanofi, and GlaxoSmithKline: Research Funding. JC: Geron Corp: Other: Held $600 Geron Stock for 1 week and sold without profit. DD: 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. AD: Alexion: Consultancy, Research Funding; Janssen: Research Funding; HaemaloiX: Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Alnylam: Research Funding; Pfizer: Research Funding. MAG: 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. PK: AbbVie: 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; Ichnos: Research Funding; Mustang Bio: Membership on an entity’s Board of Directors or advisory committees; Keosys: Consultancy; Loxo Pharmaceuticals: Research Funding; Angitia Bio: Membership on an entity’s Board of Directors or advisory committees; Oncopeptides: Membership on an entity’s Board of Directors or advisory committees; CVS Caremark: Consultancy; Janssen: Membership on an entity’s Board of Directors or advisory committees; Karyopharm: Research Funding; X4 Pharmaceuticals: 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; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; BeiGene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Regeneron: Research Funding; Amgen: Research Funding. TK: Novartis: Research Funding; Pfizer: Research Funding. NL: AbbVie: Current holder of stock options in a privately-held company; Checkpoint Therapeutics: Current holder of stock options in a privately-held company. YL: 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. EM: Protego: Consultancy. RP: Bristol Myers Squibb, GSK: Research Funding; Sanofi Aventis: Honoraria; AstraZeneca: Honoraria. TS: 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. YLH: GSK: Honoraria; Janssen: Honoraria; Shield Therapeutics: Honoraria; MultiMedia Medical, LLC: Consultancy; Pfizer: Other: Consulting fee located to Mayo Research fund. LBB: Genentech: Consultancy. RF: 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. SA: 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. SK: 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.

Figures

Fig. 1
Fig. 1
Progression Free Survival in patients with t(11;14) vs non-t(11;14): Patients with t(11;14) demonstrated a significantly better median PFS of 11.8 months for t(11;14) patients and 2.9 months for those without t(11;14), p < 0.0001.
Fig. 2
Fig. 2
Impact of Secondary cytogenetic abnormalities in t(11;14): In patients with t(11;14), presence of 1q gain/amplification/ del(17p) is associated with inferior progression free survival (PFS), median PFS 7.7 months vs. 15.1 months, p = 0.013.
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