Venetoclax in Combination With Carfilzomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma Harboring t(11,14)(q13;q32)

Two Case Reports and a Review of the Literature

Khadega A. Abuelgasim; Noha Alherz; Ayman Alhejazi; Moussab Damlaj

Disclosures

J Med Case Reports. 2020;14(54) 

In This Article

Background

Multiple myeloma (MM) has witnessed significant advances over the last two decades with regard to diagnostic methodologies and approval of many novel agents that have significantly prolonged the survival of patients. However, in spite of all these new developments, MM remains an incurable disease with inevitable relapse in the majority of patients.[1] Cytogenetic aberrations are quite common in MM, and they are used as prognostic factors to estimate the outcome of patients. t(11,14)(q13;q32) is a commonly detected aberration; it is found in up to 20% of newly diagnosed patients with MM. Although the presence of t(11,14)(q13;q32) stratifies patients as having standard risk disease, the response rates and overall outcomes in these patients appear to be inferior to those of their other standard risk counterparts.[2–5] Typically, t(11,14)(q13;q32) has been associated with lymphoplasmacytic morphology and increased number of circulating plasma cells (PCs).[6] Furthermore, it results in the upregulation of cyclin D1 and antiapoptotic protein B-cell lymphoma 2 (Bcl-2), thus raising the hypothesis of whether Bcl-2 inhibition could be a potential target in the treatment of t(11,14)(q13;q32) MM.[7]

Venetoclax is the first-in-class selective Bcl-2 inhibitor (Bcl-2-specific BH3 mimetic) that induces cell death in MM cells, particularly in those patients harboring t(11,14)(q13;q32). Venetoclax monotherapy has demonstrated efficacy in the treatment of patients with relapsed/refractory multiple myeloma (RRMM).[8] Venetoclax-containing combinations with dexamethasone with or without bortezomib were found to be of even higher efficacy.[9]

BELLINI (A Study Evaluating Venetoclax [ABT-199] in Multiple Myeloma Subjects Who Are Receiving Bortezomib and Dexamethasone as Standard Therapy) is a phase III, double-blind, multicenter trial investigating bortezomib/dexamethasone (Bd) plus venetoclax (VenBd) vs. Bd placebo in patients with RRMM. Eleven percent of the patients enrolled in the venetoclax arm had t(11,14)(q13;q32), as compared with 16% in the placebo arm. Following a median follow-up of 18.7 months, the overall response rate (ORR) was 82% in the venetoclax arm compared with 68% in the placebo arm. However, the rate of death was 21.1% (41 of 194 patients) in the venetoclax arm compared with 11.3% (11 of 97 patients) in the placebo arm. Eight of the 13 treatment-related deaths in the venetoclax arm were attributed to infection. The median overall survival was not reached (hazard ratio, 2.027; 95% confidence interval, 1.042–3.945). Subgroup analysis of patients with t(11,14)(q13;q32) benefited the most from VenBd without treatment-related toxicity.[10] In March 2018, the U.S. Food and Drug Administration issued a partial clinical hold of enrollment of new patients with MM in venetoclax trials, pending further review of these results.

In a phase II dose escalation study, the combination of venetoclax, carfilzomib, and dexamethasone (VenKd) was tested in 42 patients with RRMM; 19% of them had t(11,14)(q13;q32). The ORR was 78% with very good partial remission (VGPR) or better seen in 56% of the whole cohort. Interestingly, the ORR was 100% with VGPR or better of 88% in the among patients with t(11;14)(q13;q32) with no new safety signals.[11] In this report, we describe two cases of patients with RRMM harboring t(11,14)(q13;q32) who received 7 and 10 total lines of therapy, respectively, with short-lasting response to VenKd.

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