Venetoclax-based treatment combinations in relapsed/refractory multiple myeloma: practice patterns and impact of secondary cytogenetic abnormalities on outcomes - Report - MDSpire
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Venetoclax-based treatment combinations in relapsed/refractory multiple myeloma: practice patterns and impact of secondary cytogenetic abnormalities on outcomes
Venetoclax Combination Therapies in Relapsed/Refractory Multiple Myeloma and Cytogenetic Impact
Overview
This retrospective study of 232 patients with relapsed/refractory multiple myeloma (RRMM) treated with venetoclax-based combinations highlights high response rates, especially in patients with t(11;14) translocation. The presence of secondary cytogenetic abnormalities (SCAs) influenced progression-free survival and overall outcomes, underscoring the importance of cytogenetic profiling in guiding venetoclax therapy.
Background
Multiple myeloma remains incurable despite advances in therapy, with BCL-2 overexpression present in up to 20% of patients, particularly those harboring the t(11;14) translocation. Venetoclax, a BCL-2 inhibitor, exploits this dependency to induce apoptosis in myeloma cells. Prior studies demonstrated promising efficacy of venetoclax combinations in RRMM, especially in t(11;14) patients, but the impact of secondary cytogenetic abnormalities on treatment outcomes has not been well characterized.
Response rates in t(11;14) subgroup (prior studies)
40-50%
Phase 2 VenKd study PFS in t(11;14)
24.8 months
Phase 2 VenKd study PFS in non-t(11;14)
22.8 months
Phase I VenDd and VenDVd ≥VGPR rates
96% and 79%, respectively
18-month PFS in VenDd and VenDVd
90.5% and 66.7%, respectively
Key Findings
Venetoclax-based combinations yield high overall response rates in RRMM, particularly in patients with t(11;14) translocation.
Secondary cytogenetic abnormalities negatively impact progression-free survival and overall outcomes with venetoclax therapy.
Combination regimens including daratumumab or proteasome inhibitors with venetoclax demonstrate enhanced efficacy compared to venetoclax monotherapy or dexamethasone combinations.
Prior clinical trials showed improved PFS but raised concerns about overall survival and infection risks, highlighting the need for careful patient selection.
Triple-class and penta-drug refractory status were defined to characterize heavily pretreated patient populations in this study.
Immunohistochemistry for BCL-2 expression was performed in non-t(11;14) patients to further stratify venetoclax candidacy.
Clinical Implications
Cytogenetic profiling, including assessment for t(11;14) and secondary abnormalities, is critical to identify RRMM patients most likely to benefit from venetoclax-based therapies. Combination regimens incorporating daratumumab or proteasome inhibitors may optimize response rates. Clinicians should remain vigilant for infectious complications and consider prior treatment refractoriness when selecting venetoclax-containing regimens.
Conclusion
Venetoclax-based combination therapies offer promising efficacy in RRMM, especially in t(11;14) patients, but secondary cytogenetic abnormalities significantly influence outcomes. Personalized treatment strategies guided by cytogenetic and molecular profiling are essential to maximize benefit and minimize risks.
References
Gagnon et al. 2023 -- FISH Cytogenetic Analysis in Multiple Myeloma
International Myeloma Working Group 2016/2017 -- Response Criteria for Multiple Myeloma
BELLINI Trial 2020 -- Venetoclax in Relapsed/Refractory Multiple Myeloma
CANOVA Study 2023 -- Venetoclax-Dexamethasone vs Pomalidomide-Dexamethasone
Phase 2 VenKd Study 2021 -- Venetoclax, Carfilzomib, and Dexamethasone in RRMM
Phase I VenDd and VenDVd Study 2022 -- Venetoclax Combinations in RRMM
by Abiola Bolarinwa, Madhu Nagaraj, Saurabh Zanwar, Nadine Abdallah, P. Leif Bergsagel, Moritz Binder, Francis Buadi, Saurabh Chhabra, Joselle Cook, David Dingli, Angela Dispenzieri, Morie A. Gertz, Wilson Gonsalves, Suzanne Hayman, Prashant Kapoor, Taxiarchis Kourelis, Nelson Leung, Yi Lin, Eli Muchtar, Ricardo Parrondo, Vivek Roy, Taimur Sher, Mustaqeem Siddiqui, Rahma Warsame, Amie Fonder, Miriam Hobbs, Yi Lisa Hwa, Michelle Rogers, Udit Yadav, J. Erin Wiedmeier-Nutor, Linda B. Baughn, S. Vincent Rajkumar, Rafael Fonseca, Sikander Ailawadhi, Shaji Kumar
