Continued Success of Venetoclax in t(11;14) Multiple Myeloma Despite Negative Trials

The June Hot Topics focuses on the challenges venetoclax regimens have faced in multiple myeloma trials.

Multiple myeloma (MM) is a plasma cell neoplasm that remains incurable despite significant recent advances in novel and immune-based therapies.¹ Although cytogenetic assessment has improved disease classification and prognostication,² there are no currently approved mutation-targeted agents for myeloma. The t(11;14) chromosomal translocation between the IGH locus and CCND1 represents the most common primary translocation in plasma cell disorders, found in 16% to 24% of patients with MM and approximately 50% of patients with light chain amyloidosis.3 Patients with t(11;14) disease have increased dependence on B-cell lymphoma 2 (BCL-2) for cellular survival, which represents a rational therapeutic target for relapsed/refractory MM (RRMM).³ However, despite efficacy in early models, venetoclax (Venclexta)–based therapy has yielded 2 negative phase 3 trials with an increased mortality signal and incidence of severe infections,^4,5 and it was not approved for use in MM by the FDA. Nonetheless, venetoclax remains in the National Comprehensive Cancer Network guidelines as a therapeutic option for patients with RRMM with t(11;14) and continues to be widely used off-label.^6,7 We here review the mechanism of venetoclax activity in t(11;14) disease, the rationale for off-label use, and ongoing trials of novel venetoclax combination therapies.

BCL-2 Inhibition in t(11;14) Disease

The BCL-2 family regulates cellular apoptosis and survival through interactions between antiapoptotic (BCL-2, BCL-xL, and MCL-1) and proapoptotic proteins (eg, BIM, NOXA), which modulate mitochondrial pore formation via the activity of BAX and BAK.8 Both normal plasma cells and typical MM cells depend primarily on MCL-1 for survival.^9,10 However, a subset of myeloma cells have instead shown increased reliance on and higher expression of BCL-2 compared with other antiapoptotic proteins,^11,12 creating a mechanistic basis for BCL-2 inhibition in these patients.

Venetoclax and other BCL-2 inhibitors, such as navitoclax, have shown efficacy in multiple preclinical models in the subset of MM cells with high BCL-2:MCL-1 ratio or with preferential binding of the proapoptotic protein BIM to BCL-2 instead of MCL-1.^13-16 Notably, this BCL-2–dependent phenotype is enriched in patients carrying t(11;14),11-13,15,16 making this cytogenetic abnormality a more easily accessible biomarker than BCL-2 expression alone for venetoclax sensitivity. Further, transcriptional and epigenetic evaluation of t(11;14) MM cells has shown enrichment of a B-cell–like signature with increased BCL-2 dependence; in addition, acquired venetoclax resistance is associated with loss of the B-cell–like transcriptional pattern or copy number gains of MCL1.^12,17

Venetoclax additionally shows synergistic efficacy with multiple other MM agents. The corticosteroid dexamethasone increases BIM expression and causes preferential binding to BCL-2, increasing sensitivity to BCL-2 inhibition.^18-20 The proteasome inhibitors bortezomib (Velcade) and carfilzomib (Kyprolis) upregulate the proapoptotic protein NOXA, which neutralizes MCL-1 and increases BCL-2 dependence.^14,21-24 Despite lower surface expression of CD38 in t(11;14) cells due to their B-cell–like phenotype,²⁵ the addition of venetoclax to monoclonal antibodies such as daratumumab (Darzalex) augments antibody-dependent phagocytosis of tumor cells.²⁶ These data provide a physiologic basis for clinical trials of venetoclax-based combinations in t(11;14) RRMM.

Venetoclax Monotherapy or in Combination With Dexamethasone

Venetoclax was initially evaluated as monotherapy for RRMM regardless of cytogenetics. In a phase 1 study, 66 patients—30 with t(11;14)—with a median of 5 prior lines of therapy were treated with venetoclax doses up to 1200 mg daily and showed an overall response rate (ORR) of 21%, including a 40% ORR in patients with t(11;14).²⁷ Response additionally correlated with high BCL2:MCL1 and BCL2:BCL2L1 mRNA expression ratios. The most common grade 3 or higher toxicities were cytopenias, including thrombocytopenia (26%), neutropenia (21%), and anemia (14%), with serious infectious adverse effects (AEs) including pneumonia (8%) and sepsis (5%).27 Investigators in another study found a similar ORR of 44% in 25 patients with t(11;14) RRMM and AL amyloid using a lower dose of venetoclax 400 mg daily.²⁸

Venetoclax also has been studied as a doublet with dexamethasone. In a phase 1/2 trial of venetoclax 800 mg daily with weekly dexamethasone, 51 patients with t(11;14) RRMM and a median of 3 to 5 prior lines of therapy were treated.²⁹ In the phase 2 cohort, grade 3/4 AEs included lymphopenia (19%), anemia (16%), thrombocytopenia (10%), and sepsis (10%). The ORR was similarly 48% with progression-free survival (PFS) of 10.8 months.29 Based on these data, the randomized phase 3 CANOVA study (NCT03539744) of venetoclax-dexamethasone vs pomalidomide-dexamethasone enrolled 263 patients with early relapsed t(11;14) MM and 2 or more prior lines of therapy. The study did not meet statistical significance for its primary end point of PFS (9.9 vs 5.8 months, respectively; P = .237); however, venetoclax-dexamethasone showed significantly increased ORR (62% vs 35%; P < .0001), deeper responses with a higher rate of at least very good partial response (VGPR) (39% vs 14%; P < .0001), and a trend toward improved median overall survival (OS) (32.4 vs 24.5 months; P = .067).⁵

Venetoclax-Based Triplet Therapy

The phase 3 BELLINI trial (NCT02755597) evaluated a venetoclax triplet regimen in 291 patients with RRMM—35 with t(11;14) —and 1 to 3 prior lines of therapy.4 Patients were randomly assigned 2:1 to receive bortezomib/dexamethasone with venetoclax 800 mg daily or placebo. The study showed promising efficacy with significantly increased median PFS (22.4 vs 11.5 months; P = .01) and rate of VGPR or better (59% vs 36%; P = .00029) in the overall cohort. However, the venetoclax group had increased rates of grade 3 or higher neutropenia (18% vs 7%) and pneumonia (16% vs 9%), and 8 patients developed fatal infections contributing to worse OS (HR, 2.03; 95% CI, 1.04-3.95; P = .034) in the venetoclax group.4 Based on this mortality signal, the FDA briefly placed a clinical hold on all venetoclax-based MM trials and did not approve the drug.

However, there are multiple concerns about BELLINI’s study design that may have contributed to mortality. Specifically, the trial included primarily patients who did not have t(11;14), and patients were given high venetoclax doses without antimicrobial prophylaxis. In the final updated analysis when restricted to patients with t(11;14) disease, median PFS was 36.8 months in the venetoclax group vs 9.3 months in the placebo group (HR, 0.12; 95% CI, 0.03-0.44) with an OS trend that favored the venetoclax group (HR, 0.61; 95% CI, 0.16-2.32),³⁰ suggesting that increased mortality with venetoclax may have been restricted to patients without t(11;14).

Ongoing randomized studies of venetoclax-based triplets have restricted inclusion to patients with t(11;14), included treatment arms with a lower 400-mg dose, and added fluoroquinolone prophylaxis for the first 90 days of therapy as well as for subsequent episodes of severe neutropenia. Based on encouraging early-phase data,³¹ a randomized phase 2 study of carfilzomib-dexamethasone with or without venetoclax 400 mg or 800 mg (NCT02899052) is currently underway in patients with t(11;14) myeloma with 1 to 3 prior lines of therapy. Interim analysis of 58 patients showed increased ORR (92% vs 63%, respectively), depth of response (≥ VGPR, 82% vs 42%), and median PFS (23 months vs 17 months) favoring venetoclax, though with an ongoing signal of increased grade 3/4 infections (28% vs 11%), pneumonia (18% vs 11%), and sepsis (15% vs 0%).³²

After similar phase 1 efficacy with daratumumab,³³ a randomized phase 1/2 study of daratumumab-dexamethasone combined with bortezomib vs venetoclax (400/800 mg) (NCT03314181) was initiated in patients with t(11;14) RRMM with 1 or more prior therapies.³⁴ Preliminary results recently presented from the first 81 patients again showed higher ORR (96% vs 65%, respectively), VGPR or greater (93% vs 38%), minimal residual disease negativity (38% vs 8%, < 10^–5), and median PFS (46.1 months vs 15.5 months) in the venetoclax groups. Significantly, although venetoclax-treated patients had a higher incidence of grade 3/4 neutropenia compared with the bortezomib group (13% vs 0%), only 1 treatment-related death was noted after 49 cycles of therapy.³⁴

Conclusion

Despite its lack of FDA approval and initial safety concerns, venetoclax remains widely used in patients with t(11;14) myeloma due to its established mechanism and clinical efficacy in this disease subgroup. With the evolving therapeutic landscape for RRMM and recent approvals of cellular therapy in early relapse, the future role of venetoclax remains uncertain pending more mature data from ongoing triplet studies. Nonetheless, with careful patient selection and appropriate antimicrobial prophylaxis, it remains an attractive targeted therapy for t(11;14) disease.

Disclosures

ZMA declares no conflicts of interest. JR has consulted for both AbbVie and Genentech.

Corresponding Author

Joshua Richter, MD, FACP

The Tisch Cancer Institute; Icahn School
of Medicine at Mount Sinai

1470 Madison Ave

New York, NY 10029

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