Natural history of multiple myeloma patients refractory to venetoclax: A single center experience
Authors: Kathryn T. Maples, Ajay K. Nooka, Vikas Gupta, Nisha S. Joseph, Leonard T. Heffner, Craig Hofmeister, Madhav Dhodapkar, Shannon M. Matulis, Sagar Lonial, Lawrence H. Boise, Jonathan L. Kaufman
Journal: American Journal of Hematology (2020)

Over the last decade, a drastic survival improvement for multiple myeloma (MM) was observed and most patients live beyond 10 years. Nevertheless, in the constant quest for a functional cure, a demand for novel modern therapies exists.1 Venetoclax, a selective BCL-2 inhibitor, has emerged as a potential treatment option for relapsed refractory MM (RRMM) with its benefit more prominently seen in RRMM patients with the cytogenetic abnormality t(11;14). So, BCL2, an anti-apoptotic protein, is critical for myeloma cell survival.2 in vitro data confirmed MM samples positive for the t(11;14) were highly sensitive to ABT-737, a cell-permeant compound that binds to Bcl-2 and Bcl-x(L) but not to Mcl-1and had higher ratios of BCL2/MCL1.3 The phase three BELLINI trial investigated the relative benefit of venetoclax (Ven) over placebo, added to bortezomib and dexamethasone (Vd) among 291 patients with RRMM.4 While the trial enrolled RRMM patients that received one to three prior lines of therapy (LOT), 13% had t(11;14) positive and 79% were BCL2-high expressers by IHC. After a median follow-up of 28.6 months, the median progression free survival (PFS) was 23.2 months in patients treated with (VenVd) vs 11.4 months in patients treated with Vd alone (HR = 0.60 (95% CI 0.43-0.82, P = .01). Contrary to what was expected, the OS favored the Vd alone arm (HR 1.46, 95% CI = 0.91-2.34), likely from higher rates of death seen in the VenVd arm. There were 64 (33%) deaths in the VenVd group and 24 (25%) in the Vd group, with progressive disease being the most common cause of death. This finding raises the concern that patients who did not respond had shorter PFS and OS. As of the data cutoff of September 13, 2019, when specifically examined for patients with t(11;14), the median PFS had not been reached for those receiving VenVd vs 9.3 months for Vd alone (HR 0.09, 95% CI 0.02-0.41).4 The subgroup analysis of the BELLINI trial suggests that a careful patient selection may mitigate the safety concerns with venetoclax; however, the natural history of myeloma progressing on venetoclax remained a major concern. The purpose of this study was to investigate the clinical outcomes of myeloma patients who become refractory to venetoclax. This single-center, retrospective study, approved by the Institutional Review Board (IRB) at Emory University, examined patients 18 years or older with RRMM that were prescribed venetoclax alone or as combination therapy, both on and off clinical trials, from March 1, 2014 to February 28, 2020. The functional profiling of BCL2 family members to predict responses to therapy in myeloma have been previously described.5 We utilized this profiling and the presence of t(11;14) to inform the treatment of patients with venetoclax. The primary objective was to characterize the OS and PFS of myeloma patients from the time of venetoclax initiation and then subsequent refractoriness. Secondary objectives were to analyze outcomes with venetoclax when used as an early LOT vs late as well as responses in specific subgroups of patients. Baseline characteristics (n = 68) are presented in Table S1. Patients had received a median of three prior LOT (range, 1-13), 25% had high-risk cytogenetics (t(4;14), t(14;16), del17p), and 93% had t(11;14) by FISH/CTG. Forty-two of the 68 patients (62%) were treated with venetoclax-based therapy outside of ongoing or completed clinical trials. At a median follow-up of 16.7 months (range, 10.1-23.2), the median duration of venetoclax therapy was 10.4 months (range, 1.2-66.2), with an ORR of 71%. Twenty-five percent of patients achieved a complete response (CR) or better and 48.5% achieved a very good partial response (VGPR) or better. Response rates in the triple-refractory and penta-refractory patients are summarized in Table S2, with ORR being similar at 69.5% and 65%, respectively. The median PFS from initiation of venetoclax for the entire cohort was 14.1 months (95% CI, 8.6-19.6), with venetoclax use as an early LOT yielding better benefits. The PFS in patients with less than three prior LOT (BELLINI population) was 23.2 months vs 10.4 months for three or more LOT (P = .008). Notably, patients who received six or more LOT prior to venetoclax still had a prolonged PFS benefit of 8.1 months (95% CI, 5.6-10.6), which largely represents the penta-refractory patients (Figure S1A). The median OS for those with less than six LOT was not reached, after a median follow-up of 19 months, vs 16.2 months for six or more prior LOT (P = .01). Further, patients that were daratumumab sensitive had a longer PFS from initiation of venetoclax of 15.5 months vs 9.7 months in those daratumumab refractory (P = .023) (Figure S1B). The PFS on venetoclax for standard-risk vs high-risk patients and in patients based on copies of 1q are shown in Figure S1C,D, respectively. Of the 38 patients who progressed on venetoclax, 32 (84%) were treated with a next line of therapy (Table S3). The most common subsequent therapies were daratumumab-based (29%), carfilzomib-based (26%), or a clinical trial (21%). The median OS and PFS for this cohort from the time of venetoclax refractoriness was 31.4 months and 6.6 months, respectively, at a median follow-up of 19.2 months. Of all 32 patients who received a subsequent treatment, the ORR of the next line of therapy was 56.5%. Response rates in the triple- (n = 13) and penta-refractory (n = 8) patients are summarized in Table S4, with ORR of the subsequent line of therapy being 38.5% and 37.5%, respectively. The PFS on the next line of therapy differed by response, with median PFS being 8.8 months for those with stable disease or better vs 3.9 months for those with less than stable disease (P = .041). The median OS from venetoclax refractoriness was significantly longer at 31.4 months in patients who were not penta-refractory vs 13.7 months for those who were penta-refractory (P = .036) (Figure 1A). Similarly, the median OS for patients with seven or more prior LOT was 13.7 months (95% CI, 0.8-26.6) (Figure 1B). Daratumumab refractory patients were found to have a median OS of 18.6 months (95% CI, 8.6-28.7) (Figure 1C), and the subgroup of standard risk patients (n = 24) had a prolonged OS from venetoclax refractoriness of 31.4 months vs 13.0 months for high risk patients (n = 14) (P = .06) (Figure 1D). Prior studies raised concern that venetoclax may alter the natural history of myeloma progression, leading to increased mortality among patients progressing on venetoclax.4 In this retrospective review, the median PFS from the initiation of venetoclax was significantly longer when venetoclax was used as earlier line of treatment (fewer than three prior lines) at 23.2 months vs 10.4 months in those with three or more prior lines, respectively, P = .008. Additionally, a longer PFS was found in those who were daratumumab sensitive (P = .023) (Figure S1B). Kambhampati et al. have previously reported their single-center experience with venetoclax for RRMM, which included 47 patients with a median of seven prior lines of therapy and 38% had known cytogenetic abnormality t(11;14).6 The ORR was reported to be 39% for the entire cohort, and the median PFS was 2.1 months. Our results among a similar patient population treated with veneotoclax had a median PFS of 8.1 months, with the differential outcome possibly related to patient selection with 93% of our patients having t(11;14). These findings support the use of venetoclax as earlier lines of therapy in myeloma patients that are positive for t(11;14). Currently, there is a lack of data describing outcomes in RRMM who progress on venetoclax. The MAMMOTH study evaluated outcomes in 275 patients with MM refractory to CD38 monoclonal antibodies (CD38 MoAbs), and reported a median OS of 8.6 months (95% CI 7.6-9.9) from the time of CD38 MoAB refractoriness.7 The ORR to the first regimen after CD38 MoAB refractoriness was 31%, with a median PFS and OS of 3.4 and 9.3 months, respectively. This cohort of patients served as a comparison group for the patients treated with selinexor and dexamethasone on the STORM trial, which led to the approval of selinexor for penta-refractory patients. In our patients who become venetoclax refractory, the median OS was 31.4 months from the time of venetoclax refractoriness suggesting that patients can experience good long-term outcomes post-venetoclax. Patients that were daratumumab refractory still achieved a prolonged median OS benefit of 18.6 months (Figure 1C) from the time of venetoclax refractoriness, which is longer than the median OS found in MAMMOTH.7 Additionally, the MAMMOTH study noted the median OS to be 5.6 months for the penta-refractory patients from the time of CD38 MoAB refractoriness, and our study revealed a median OS of 13.7 months in the penta-refractory patients from the time of venetoclax refractoriness (Figure 1A). Our study also showed the ORR to the first regimen after venetoclax was 38.5% and 37.5% for the triple-refractory and penta-refractory patients, respectively, which is higher than the ORR of 31% found in the MAMMOTH study with the next line of therapy after CD38 MoAB refractoriness.7 Lastly, these results are supportive of venetoclax for high-risk patients, which were well represented in study with 25% of the overall population, and 41% of the penta-refractory subset, expressing high-risk cytogenetics. With a median PFS on venetoclax of 7.3 months and OS of 13.0 months from the time of venetoclax refractoriness, it appears that high-risk patients will respond to venetoclax and this treatment does not negatively alter their disease progression. The limitations of this study include its retrospective design and limited sample size. Nevertheless, to our knowledge, this study is the first to assess OS from time of venetoclax refractoriness in MM patients. We believe patients with venetoclax-refractory myeloma can still experience good long-term outcomes, and our experience does not support the hypothesis that venetoclax resistance leads to a more refractory myeloma phenotype. These data support the early use of venetoclax or venetoclax combinations in the t(11;14) cohort of patients. This research was not financially supported in any manner. Dr. Boise receives research funding and honoraria from AstraZeneca. He is a consultant for Abbvie/Genentech and AstraZeneca. Dr. Dhodapkar serves as consultant for Amgen, Celgene, Janssen, Kite Pharma, LAVA Therapeutics, and Roche/Genentech. Dr. Heffner receives research funding from ADC Therapeutics, Astex Pharmaceuticals, Genentech, Kite Pharma, and Pharmacyclics. Dr. Hofmeister receives research funding from Bristol-Myers Squibb, Celgene, and Cellularity. He is a consultant for Celgene, Imbrium, Janssen, Karyopharm, Nektar, Oncopeptides, and Sanofi Pasteur. Dr. Kaufman receives research funding from Abbvie/Genentech, Amgen, Bristol-Myers Squibb, Gelgene, Fortis Therapeutics, Janssen, Merck, and Sutro Biopharm, Inc. He is a consultant for Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm Therapetuics, Sanofi, Takeda, Ecnofarma, and TG Therapeutics. He receives honoraria from Tecnofarma. Dr. Lonial receives research funding from Bristol-Myers Squibb, Celgene, and Takeda. He is a consultant for Abbvie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Juno Therapeutics, Merck, Novartis, and Takeda. Dr. Maples serves as consultant for The Lynx Group, GlaxoSmithKline, and Sanofi. Dr. Nooka receives research funding from Amgen, Janssen, and Takeda. He is a consultant for Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm Therapeutics, Oncopeptides, Sanofi Pharmaceuticals, and Takeda. All other authors declare no conflict of interest. Data available on request from the authors Figure S1 Profession free survival (PFS) from initiation of venetoclax by subgroups. Appendix S1 Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.