Natural history of multiple myeloma patients refractory to venetoclax: A single center experience

Maples, Kathryn T.; Nooka, Ajay K.; Gupta, Vikas A.; Joseph, Nisha; Heffner, Leonard T.; Hofmeister, Craig C.; Dhodapkar, Madhav V.; Matulis, Shannon M.; Lonial, Sagar; Boise, Lawrence H.; Kaufman, Jonathan L.

doi:10.1002/ajh.26064

Cited by 9 publications

(12 citation statements)

References 8 publications

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“…The first retrospective study to assess real-world outcomes from the time of venetoclax refractoriness demonstrated a median OS of 31.4 months. These findings support the use of venetoclax early in the treatment of the t(11;14) patient group, challenging the notion that venetoclax resistance results in a more aggressive disease phenotype ( 81 ).…”

Section: Translocation T(11;14) and Precision Intervention In MMmentioning

confidence: 72%

Exploring the current molecular landscape and management of multiple myeloma patients with the t(11;14) translocation

2022

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Multiple myeloma (MM) is a genetically complex disease. The key myeloma-initiating genetic events are hyperdiploidy and translocations involving the immunoglobulin heavy chain (IgH) enhancer on chromosome 14, which leads to the activation of oncogenes (e.g., CCND1, CCND3, MAF, and MMSET). The t(11;14) translocation is the most common in MM (15%–20%) and results in cyclin D1 (CCND1) upregulation, which leads to kinase activation and tumor cell proliferation. Notably, t(11;14) occurs at a higher rate in patients with plasma cell leukemia (40%) and light chain amyloidosis (50%). Patients with myeloma who harbor the t(11;14) translocation have high levels of the anti-apoptotic protein B-cell lymphoma 2 (BCL2). Multiple studies demonstrated that the presence of t(11;14) was predictive of BCL2 dependency, suggesting that BCL2 could be a target in this subtype of myeloma. Venetoclax, an oral BCL2 inhibitor, has shown remarkable activity in treating relapsed/refractory MM patients with t(11;14) and BCL2 overexpression, either as monotherapy or in combination with other anti-myeloma agents. In this review, we describe the molecular defects associated with the t(11;14), bring into question the standard cytogenetic risk of myeloma patients harboring t(11;14), summarize current efficacy and safety data of targeted venetoclax-based therapies, and discuss the future of individualized or precision medicine for this unique myeloma subgroup, which will guide optimal treatment.

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Section: Translocation T(11;14) and Precision Intervention In MMmentioning

confidence: 72%

Exploring the current molecular landscape and management of multiple myeloma patients with the t(11;14) translocation

2022

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“…Furthermore, in a single-institution retrospective analysis of 68 patients selected for venetoclax treatment based on the presence of t(11;14), the ORR was 71% (48.5% VGPR or better) with a median progression-free survival (PFS) of 14.1 months. 53 For patients with less than 3 prior lines of therapy, the PFS was 23.2 months. These promising results have led to an ongoing Phase III study randomizing patients with t(11;14) myeloma to either venetoclax and dexamethasone or pomalidomide and dexamethasone.…”

Section: Clinical Studies Of Venetoclax In Multiple Myelomamentioning

confidence: 99%

“…However, in a retrospective analysis of 38 patients who progressed on venetoclax, 84% went on to receive an additional line of therapy and experienced a median OS of 31.4 months from the time of venetoclax refractoriness, arguing against any inferior outcomes post-venetoclax. 53 The safety concerns from this trial have increased scrutiny of other venetoclax combination trials in myeloma and led to adjustments such as routine antimicrobial prophylaxis and closer infectious monitoring.…”

Section: Dovepressmentioning

confidence: 99%

BCL2 Family Inhibitors in the Biology and Treatment of Multiple Myeloma

Gupta¹,

Ackley²,

Kaufman³

et al. 2021

BLCTT

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Although much progress has been made in the treatment of multiple myeloma, the majority of patients fail to be cured and require numerous lines of therapy. Inhibitors of the BCL2 family represent an exciting new class of drugs with a novel mechanism of action that are likely to have activity as single agents and in combination with existing myeloma therapies. The BCL2 proteins are oncogenes that promote cell survival and are frequently upregulated in multiple myeloma, making them attractive targets. Venetoclax, a BCL2 specific inhibitor, is furthest along in development and has shown promising results in a subset of myeloma characterized by the t(11;14) translocation. Combining venetoclax with proteasome inhibitors and monoclonal antibodies has improved responses in a broader group of patients, but has come at the expense of a toxicity safety signal that requires additional follow-up. MCL1 inhibitors are likely to be effective in a broader range of patients and are currently in early clinical trials. This review will cover much of what is known about the biology of these drugs, biomarkers that predict response, mechanisms of resistance, and unanswered questions as they pertain to multiple myeloma.

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“…A retrospective study, using functional profiling of venetoclax sensitivity and presence of t (11;14) as a selection criteria involving 68 patients, reached ORR of 71%. 9 In an ongoing Phase III study, only t(11;14) RRMM patients will be randomized to venetoclax and dexamethasone or pomalidomide and dexamethasone. 10 In this study, we used low dose venetoclax (400 mg daily) in 25 RRMM or relapsing AL-amyloidosis patients harboring t (11;14), ORR was 44% with manageable AE and no associated deaths.…”

Section: Introductionmentioning

confidence: 99%

“…The ORR in the phase II part of trial was 48%. A retrospective study, using functional profiling of venetoclax sensitivity and presence of t(11;14) as a selection criteria involving 68 patients, reached ORR of 71% 9 . In an ongoing Phase III study, only t(11;14) RRMM patients will be randomized to venetoclax and dexamethasone or pomalidomide and dexamethasone 10 .…”

Section: Introductionmentioning

confidence: 99%

Low dose venetoclax as a single agent treatment of plasma cell malignancies harboring t(11;14)

et al. 2021

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Approximately 20% of newly diagnosed multiple myeloma (NDMM) patients harbor t (11;14), a marker of inferior prognosis, resulting in up-regulation of CCND1. These patients respond to BCL2 inhibitor experimental drug venetoclax. Furthermore, t(11;14) is reported to be associated with increased BCL2/MCL1 ratio. We investigated the use of venetoclax (400 mg daily) in a cohort of 25 multiple myeloma (MM) and ALamyloidosis patients harboring t(11;14) and assessed safety and efficacy. Efficacy was assessed by response rate (RR) and time on treatment. Furthermore, immunohistochemistry (IHC), for BCL2 family member expression was assessed at diagnosis and relapse in the venetoclax-treated group and analyzed for correlation with clinical RR. Additionally, patient material from venetoclax non-treated group including non-t(11;14) diagnosis (n = 27), t(11;14) diagnosis (n = 17), t(11;14) relapse (n = 7), hyperdiploidy (n = 6) and hyperdiploidy + t(11;14) (n = 6) was used for RNA sequencing (RNASeq) and validation by qPCR. Venetoclax treatment in t(11;14) patients demonstrated manageable safety and promising efficacy. Partial responses or better were observed in eleven patients (44%). Responding patients had significantly higher BCL2/MCL1 (p = 0.031) as well as BCL2/BCL-XL (p = 0.021) ratio, regardless of time of measurement before venetoclax treatment. Furthermore, an IRF5 motif was enriched (p < .001) in the downregulated genes in t(11;14) relapses vs diagnoses. The RR with single agent venetoclax was 71% in AL-amyloidosis and 33% in MM, and IHC proved useful in prediction of treatment outcome. We could also demonstrate possible resistance mechanisms of t(11;14), downregulation of IRF5 targeted genes, which can be exploited for therapeutic advantages.

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Natural history of multiple myeloma patients refractory to venetoclax: A single center experience

Cited by 9 publications

References 8 publications

Exploring the current molecular landscape and management of multiple myeloma patients with the t(11;14) translocation

Exploring the current molecular landscape and management of multiple myeloma patients with the t(11;14) translocation

BCL2 Family Inhibitors in the Biology and Treatment of Multiple Myeloma

Low dose venetoclax as a single agent treatment of plasma cell malignancies harboring t(11;14)

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