Real-World Data on Safety and Efficacy of Venetoclax-Based Regimens in Relapsed/Refractory t[11;14] Multiple Myeloma
Authors: Basali Diana , Chakraborty Rajshekhar , Rybicki Lisa , Rosko Nathaniel , Reed Janice , Karam Mary Ann , Schlueter Kristen , Dysert Hayley , Faiman Beth M. , Hamilton Kimberly , Kalaycio Matt , Valent Jason 
Published: November 2019

Background: Venetoclax is an orally bioavailable inhibitor of the anti-apoptotic protein Bcl-2. In Multiple Myeloma [MM] characterized by t[11;14], it is particularly effective with a single-agent response rate of 40%. However, there have been recent safety concerns due to a higher mortality in the venetoclax-arm of BELLINI trial [Kumar et al. EHA 2019]. At our institution, venetoclax has been used off-label for patients with relapsed/refractory t[11;14] MM and AL amyloidosis. Our objective was to present the efficacy and safety data on venetoclax-based regimens at our institution.
Methods: The Cleveland Clinic MM database was queried to identify patients meeting the following inclusion criteria: [a] Relapsed or refractory MM [b] Treated with ≥1 cycle of venetoclax-based regimen outside of a clinical trial. All patients meeting the above criteria through April 2019 were included and followed until June 30, 2019. Clinical data were independently reviewed by two investigators, D.B. and R.C., and conflicts were resolved by consensus. The primary endpoint was overall response rate [ORR], per International Myeloma Working Group criteria.
Results: A total of ten patients were included in our analysis. Among them, five were males, all were Caucasian, and five had an ECOG performance status of 2 or 3 at treatment initiation. Four patients had ISS stage III at diagnosis. All had t[11;14] translocation, five had deletion [13q], three had deletion [17p], and three had abnormal metaphase cytogenetics with complex karyotype. Patients received a median of 6 lines of treatment prior to venetoclax [range, 2-19]. Notably, 10/10 were refractory to bortezomib, 4 to carfilzomib, 4 to ixazomib, 9 to lenalidomide, 7 to pomalidomide, 3 to elotuzumab, and 8 to daratumumab. Five patients had received prior autologous stem cell transplantation, among whom, two had relapsed within one year post-transplant. A total of five patients had clinical relapse without extramedullary disease, three had clinical relapse with extramedullary disease, and two had biochemical-only relapse at initiation of venetoclax. The most common regimen used was venetoclax in combination with bortezomib and dexamethasone. Venetoclax was initiated at 400 mg for one week and then titrated to 800 mg depending on tolerability and insurance approval. Among nine patients who were evaluable for response, the ORR was 78% [7 out of 9 patients]. Among these seven responding patients, one achieved a complete response, one achieved a very good partial response, four achieved a partial response, and one achieved a minimal response to therapy. One patient [Patient #10 in Table I] who had cardiac amyloidosis achieved an organ response, with around 45% reduction in NT-pro-BNP. The median follow-up in surviving patients was 5.2 months [range, 3.1-13.5 months]. Six patients were alive at most recent follow-up. The cause of death was relapsed MM in three and septic shock/acute hypoxemic respiratory failure due to invasive aspergillosis [in the setting of disease progression] in one patient. The toxicity profile in individual patients has been summarized in Table I. Non-hematologic toxicities seen in more than one patient included fatigue, weight loss, appetite loss, and gastrointestinal toxicity [nausea, diarrhea, and abdominal cramps]. Four out of ten patients required red blood cell or platelet transfusions for hematologic toxicity.
Conclusion: Venetoclax is effective in patients with heavily pre-treated relapsed/refractory t[11;14] MM, with six out of nine response-evaluable patients achieving at least a partial response. Common hematologic toxicities included anemia and thrombocytopenia, with four patients requiring transfusions. Fatigue, nausea, abdominal pain, and weight loss were the major symptomatic toxicities observed in our cohort. One bortezomib and daratumumab-refractory patient with concomitant systemic amyloidosis and MM achieved a cardiac organ response after addition of venetoclax. Further studies in larger cohorts of patients are warranted.

Disclosures
Valent: Amgen corporation: Speakers Bureau; Takeda pharmaceuticals: Speakers Bureau; Celgene corporation: Speakers Bureau.

OffLabel Disclosure:
Drug: Venetoclax Purpose: Relapsed/Refractory Multiple Myeloma