First targeted therapy in multiple myeloma

In this issue of Blood, Kumar et al and Moreau et al both report venetoclax to be safe and effective in the treatment of multiple myeloma (MM), the second most common hematological malignancy.^1,2 

Venetoclax is an oral compound designed to specifically inhibit the B-cell lymphoma 2 (BCL-2) protein in cancer cells.³  BCL-2 is an inhibitor of intrinsic apoptosis signals (thus, a mediator of tumor growth), and overexpression of antiapoptotic BCL-2 has been correlated with chemoresistance. Venetoclax has shown antitumor effects in various malignancies, including chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), through binding to BCL-2 and induction of tumor cell apoptosis. As a consequence, the US Food and Drug Administration approved venetoclax, formerly known as ABT199, in 2016 for the treatment of del17p-defined high-risk CLL in patients who had received at least 1 prior treatment. In addition, breakthrough therapy designation for venetoclax in combination with low-dose cytarabine was granted for treatment-naive elderly patients with AML who are ineligible for intensive chemotherapy.

Kumar et al now provide data on the single-agent activity of venetoclax in the treatment of MM. In 66 relapsed refractory patients treated in a phase 1 study, venetoclax demonstrated an excellent safety profile with manageable, mainly mild-to-moderate gastrointestinal and hematological toxicities. Responses were observed in 21% across all cohorts of patients. In particular, the cohort of patients with t(11;14) had an impressive overall response rate (ORR) of 40%. Of note, responses achieved were of high quality, with more than a quarter of them very good partial response (VGPR) or better and durable with time to disease progression up to 11.5 months.

Back in 2002, in Blood, Rafael Fonseca described t(11;14)-translocated MM as a unique biologic entity but his hope that “the molecular classification of the subtypes of multiple myeloma may allow for a more rational approach to their treatment” has remained unfulfilled for >15 years.⁴  This translocation results in an overexpression of cyclin D1 and is identified in 15% to 20% of myeloma patients by fluorescence in situ hybridization. Myeloma cells harboring this genomic alteration present with a mature, lymphoplasmocytic phenotype, with predominantly CD56⁻, CD20/CD79a⁺ B-lineage–like antigen expression. The translocation t(11;14) is linked to rarer myeloma subtypes, as immunoglobulin D (IgD) and IgM, as well as to oligosecretory or nonsecretory variants, and also with plasma-cell leukemia, which is associated with a very poor prognosis. This, in part, may explain the inferior outcome of t(11;14) patients, compared with genomically defined standard-risk disease.⁵ 

Moreau et al demonstrate synergistic effects between venetoclax and the first-generation proteasome inhibitor bortezomib and dexamethasone in 66 relapsed/refractory MM patients, regardless of the t(11;14) status. Administration of the combination therapy was safe and a remarkable 67% ORR was observed across the cohort. Of note, in almost half (42%) of the highly resistant patients, VGPR or better was induced. The response rate and the depth of response to the venetoclax, bortezomib, and dexamethasone combination correlated with the BCL-2 expression as well as with the sensitivity to bortezomib. In bortezomib-sensitive or -naive patients, ORR was 90% and high-quality remissions, including VGPR or better, were achieved in two-thirds of patients (64%). Conversely, in bortezomib-resistant patients, only 31% of patients responded to the treatment and not more than 8% achieved VGPR. This implies that venetoclax cannot fully overcome bortezomib resistance and that, in non-t(11;14) disease, additional inhibitory effects on myeloid cell leukemia sequence 1 may be needed to fully exploit the antitumor effects of venetoclax.

Venetoclax is one of the most promising agents currently undergoing clinical testing in MM. Single-agent activities are impressive and include deep and long-lasting remissions in heavily pretreated patients, having progressed through all standard therapies. MM harboring t(11;14) is particularly sensitive to the treatment. For non-t(11;14) MM, venetoclax combination with bortezomib was shown to be highly effective and to be well tolerated. Trials investigating other combinations, as for example, the monoclonal CD38 antibody daratumumab, are ongoing and results are eagerly awaited. To match drugs and genomics is an ultimate aim of personalized medicine. We foresee venetoclax as the first targeted drug to be approved for a distinct subcohort of genetically defined MM, thus being the first candidate to open a new chapter of precision medicine in the treatment of MM.