Precision medicine for multiple myeloma: The case for translocation (11;14).

The t(11;14) translocation is among the most prevalent cytogenetic abnormalities in multiple myeloma (MM), distinguished by its unique features and biology that have been thoroughly explored for decades. What further sets this MM subtype apart is its oscillating prognostic significance, from initially being considered a favorable alteration to intermediate risk and potential future reclassification as favorable risk. Despite not being inherently a high-risk alteration indicative of an aggressive phenotype, it appears that t(11;14)-MM is less responsive to novel agents like proteasome inhibitors and immunomodulatory drugs which have otherwise transformed the disease's treatment landscape, perhaps partially explained by its reduced propensity for immunoglobulin production and oligosecretory nature. However, its distinct reliance on Bcl-2 has heightened its sensitivity to venetoclax. Further subclassification based on morphological and genomic characteristics could enhance our prediction models of treatment responses and enable more tailored therapeutic strategies for patients. This review aims to encapsulate the existing research evidence in this area.

Bazarbachi AH ，Avet-Loiseau H ，Harousseau JL ，Bazarbachi A ，Mohty M ... -  《-》

Venetoclax plus bortezomib and dexamethasone in heavily pretreated end-stage myeloma patients without t(11;14): A real-world cohort.

Jelinek T ，Popkova T ，Duras J ，Mihalyova J ，Kascak M ，Benkova K ，Plonkova H ，Cerna L ，Koristek Z ，Simicek M ，Hajek R ... -  《-》

Multiple myeloma with t(11;14)-associated immature phenotype has lower CD38 expression and higher BCL2 dependence.

CD38 expression on myeloma cells is a critical factor affecting the early response to the anti-CD38 antibody daratumumab. However, factors affecting CD38 expression in untreated multiple myeloma are not fully elucidated. In this study, we found that CD38 expression was significantly lower in myeloma patients with the translocation t(11;14)-associated immature plasma cell phenotype, and particularly in those expressing B-cell-associated genes such as PAX5 and CD79A. CD138, a representative marker of plasmacytic differentiation, was also significantly lower in these patients, suggesting that CD38 expression may be associated with the differentiation and maturation stages of myeloma cells. Furthermore, the BCL2/BCL2L1 ratio, a response marker of the BCL2 inhibitor venetoclax, was significantly higher in patients with the immature phenotype expressing B-cell-associated genes. The BCL2/BCL2L1 ratio and CD38 expression were significantly negatively correlated. We also confirmed that patients with translocation t(11;14) expressing B-cell-associated genes were indeed less sensitive to daratumumab-mediated direct cytotoxicity but highly sensitive to venetoclax treatment in ex vivo assays. Moreover, all-trans-retinoic acid, which enhances CD38 expression and induces cell differentiation in myeloma cells, reduced B-cell marker expression and the BCL2/BCL2L1 ratio in myeloma cell lines, leading to reduced efficacy of venetoclax. Venetoclax specifically induces cell death in myeloma with t(11;14), although why patients with translocation t(11;14) show BCL2 dependence is unclear. These results suggest that BCL2 dependence, as well as CD38 expression, are deeply associated with the differentiation and maturation stages of myeloma cells. This study highlights the importance of examining t(11;14) and considering cell maturity in myeloma treatment strategies.

Kitadate A ，Terao T ，Narita K ，Ikeda S ，Takahashi Y ，Tsushima T ，Miura D ，Takeuchi M ，Takahashi N ，Matsue K ... -  《-》

Use of venetoclax in t(11;14) positive relapsed/refractory multiple myeloma: A systematic review.

Khan WJ ，Ali M ，Hashim S ，Nawaz H ，Hashim SN ，Safi D ，Inayat A ... -  《-》

Real-world data on safety and efficacy of venetoclax-based regimens in relapsed/refractory t(11;14) multiple myeloma.

The treatment for relapsed/refractory multiple myeloma (RRMM) continues to be challenging despite recent therapeutic advancements. Venetoclax, an inhibitor of the anti-apoptotic protein BCL-2, is a promising agent, especially in patients harbouring t(11;14). Our objective was to review our experience with venetoclax-based regimens at our institution. All ten RRMM patients treated with venetoclax were included and had a median of six prior lines of therapy. The overall response rate was 78% and one patient with cardiac amyloidosis and MM achieved a cardiac organ response. Haematologic toxicities requiring red blood cell and platelet transfusion and non-haematologic toxicities, most commonly gastrointestinal upset, were observed.

Basali D ，Chakraborty R ，Rybicki L ，Rosko N ，Reed J ，Karam M ，Schlueter K ，Dysert H ，Kalaycio M ，Valent J ... -  《-》