Activity and Safety of Venetoclax (VEN)-Based Treatment in t(11;14)-Positive Relapsed/Refractory Multiple Myeloma (R/R MM)
Authors: Ionescu Filip , Thapa Shrinjaya B , Patel Parth C , Drekolias Dimitrios , Siqueira Silva Ariosto , Sudalagunta Praneeth R , Agius Phaedra , Blue Brandon , Hansen Doris K. , Castaneda Omar , Liu Hien , Ochoa-Bayona Jose L. , Freeman Ciara Louise , Locke Frederick , Nishihori Taiga , Alsina Melissa , Shain Kenneth H. , Baz Rachid , Grajales-Cruz Ariel 
Published: December 2024

Background: VEN is an oral BCL-2 inhibitor with demonstrated activity in t(11;14) MM. Here, we report the impact of VEN-based therapy in a large cohort of t(11;14)-positive MM in terms of efficacy and safety. We also investigate molecular- and treatment-related factors impacting response to VEN.
Methods: We retrospectively analyzed all t(11;14)-positive MM patients diagnosed at Moffitt Cancer Center between 9/2000-7/2023. The primary endpoint was OS measured from the time of MM diagnosis compared between VEN-treated patients and those who did not receive VEN. Secondary endpoints were ≥VGPR rate, treatment- and disease-specific determinants of ≥VGPR, time to next treatment on VEN, and key toxicities. Infections were defined radiographically, microbiologically, or by strong clinical suspicion. Kaplan-Meier estimates and Cox regression were employed to analyze time-to-event data. We also analyzed the expression of genes postulated to impact VEN sensitivity and how these impacted response rates. Z-normalized (925 patient cohort) log2(FPKM) from RNAseq of CD138+ cells of 24 t(11;14)-positive MM patients were used to estimate BCL2/MCL1 ratio to determine the association with ≥VGPR using logistic regression.
Results: We identified 381 t(11;14)-positive MM patients (median age 65 [range, 33-86], 62% men, 83% white, 10% black). VEN regimens (+anti-CD38 [51%], +proteasome inhibitor [35%], +other [14%]) were utilized in 97 (25%) patients, on median in the 5th line (IQR, 4-6). VEN and non-VEN groups were balanced in terms of median age (63 vs 65 years, p=.22), male sex (63% vs 62%, p=.9), white race (82% vs 83%, p=.81) and the presence of high-risk cytogenetic abnormalities (21% vs 13%, p=.1). VEN treated patients were more likely to be diagnosed before 2015 (41% vs 30%, p=.04), to be penta-exposed (26% vs 9%, p&lt;.01) and to have received autologous stem cell transplant (65% vs 49%, p&lt;.01) or CAR T/bispecific antibodies (48% vs 4%, p&lt;.01). Median OS was superior for VEN-treated patients both in the overall population (142 [95% CI 112-202] vs 97 [95% CI 80-116] months, Log-Rank p&lt;.01) and in Daratumumab-exposed patients (202 [95% CI 128-NE] vs NE [95% CI 72-NE], p=.08). In multivariable Cox regression accounting for age, sex, race, 1q abnormalities, anti-CD38 antibody exposure, penta-exposed status and receipt of CAR T/bispecifics, VEN-based therapy was associated with a lower risk of death of any cause (aHR = 0.54; 95% CI 0.3-0.97). VEN-based treatments resulted in ≥VGPR in 38/95 (40%) and in CR in 20/95 (21%). Median time to next treatment on VEN regimens was 8.5 months (IQR, 4-19; range, 0-83 months). For patients with FISH within 3 months of VEN initiation (N=38), the t(11;14) burden did not predict ≥VGPR (OR 0.98 per 1%-change, p=.99). As a VEN partner, anti-CD38 antibodies appeared to increase the odds of ≥VGPR (OR 3.98, p=.05) compared to proteasome inhibitor partners (OR 1.59, p=.5) or other VEN combinations (reference). VEN regimens resulted in adverse events in 34% with 26% representing cytopenias. Non-hematologic toxicities required interruption of VEN in 14%. VEN was permanently discontinued in 8% due to toxicity. Infections occurred in 18/97 (19%) of VEN patients; 7/18 required admission for IV antibiotics and 1/18 died of pneumonia while on VEN. IgG levels were &lt;500 in 25% of VEN patients and infections were more common below this threshold (46% vs 10%, p&lt;.01); however, IVIG use was low (4/97). RNAseq analysis revealed that increases in the BCL2/MCL1 gene expression ratio was associated with greater odds of ≥VGPR (OR 3 per 1-unit change, p&lt;.01).
Conclusions: VEN-based regimens (especially in combination with anti-CD38 antibodies) are effective in t(11;14)-positive MM. We report reasonable and potentially durable response rates, as well as an association with a survival benefit for VEN. The toxicity profile was similar to that observed in reported trials with infection the main concern especially in the setting of hypogammaglobulinemia. Gene expression analysis may be helpful in predicting response to VEN beyond t(11;14) status alone and we will present expanded transcriptomic data analysis in this cohort at the meeting. Future efforts to prospectively investigate the best VEN combination and IVIG to mitigate the risk of infection are warranted.