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

Abstract

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.

A Clinical Perspective on Plasma Cell Leukemia: A Single-Center Experience

“…Deletion 17p was also noted with a higher incidence in the sPCL (66%) and iCPC (50%) groups. In contrast to previously reported higher incidence of t(11;14) in up to 52% of pPCL patients, t(11;14) was only seen in 19% of our pPCL cohort [ 26 ]. Moreover, t(11;14) was also interestingly uncommon in Black patients in our cohort, presenting in 18% of the total Black cohort (n = 9), 15% pPCL, 24% sPCL, and 11% iCPC.…”

The Role of t(11;14) in Tailoring Treatment Decisions in Multiple Myeloma

“…Importantly, it has been shown that the presence of numerous high-risk cytogenetic abnormalities in the same patient, such as multiple gains(1q)m del(1p)m del(IGH) and del(13q), has a greater impact on outcomes compared to a single high-risk aberration such as an isolated t(11;14) [43,44]. Therefore, we advocate for patients with t(11;14) and co-existing chromosomal abnormalities to be categorized as at least intermediate-risk than standard-risk [16,45].…”

Selinexor: Targeting a novel pathway in multiple myeloma

“…In addition to these agents, other small molecule targeted therapies have been developed to exploit specific characteristics of MM cells and pathways that are upregulated in cancer cells more broadly. These have included the histone deacetylase inhibitor panobinostat [21], the novel targeted cytotoxic drug–peptide conjugate melphalan flufenamide (‘melflufen’) targeting extramedullary disease in particular [22], and the selective inhibitor of BCL‐2 venetoclax, which is emerging as a biomarker‐directed therapy for patients with t(11;14) MM [23]. Having such options is valuable and important in the RRMM setting following prior mAb‐based and immunomodulatory drug‐based treatment and, increasingly, post CAR T‐cell or bispecific antibody therapy.…”

“…These have included the histone deacetylase inhibitor panobinostat [21], the novel targeted cytotoxic drug-peptide conjugate melphalan flufenamide ('melflufen') targeting extramedullary disease in particular [22], and the selective inhibitor of BCL-2 venetoclax, which is emerging as a biomarker-directed therapy for patients with t(11;14) MM [23].…”