The Hematologist

November-December 2017, Volume 14, Issue 6

Programming Myeloma Cell Death With Venetoclax

Andrew J. Yee, MD Instructor in Medicine, Harvard Medical School, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center
Boston, Massachusetts
Noopur Raje, MD Associate Professor of Medicine at Harvard Medical School; Director of the Multiple Myeloma Center at Massachusetts General Hospital
Massachusetts General Hospital, Boston, Massachusetts

Published on: October 11, 2017

Moreau P, Chanan-Khan A, Roberts AW, et al. Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood. 2017;doi: 10.1182/blood-2017-06-788323. [Epub ahead of print].

While there has been significant progress in multiple myeloma (MM) with immunomodulatory drugs, proteasome inhibitors, and now anti-CD38 monoclonal antibodies like daratumumab, MM remains an incurable malignancy where relapse becomes more difficult to treat over time. To meet this challenge, there is an ongoing effort to identify new pathways as therapeutic targets. Dysregulation of the apoptotic pathway mediated by anti-apoptotic proteins such as BCL-2, BCL-XL, and MCL-1 plays an important role across a range of malignancies.1 Venetoclax (ABT-199) is an oral selective inhibitor of BCL-2, and is the first drug approved by the U.S. Food and Drug Administration, with an indication in patients with chronic lymphocytic leukemia (CLL) with 17p deletion and one or more prior lines of treatment.2 In MM, targeting BCL-2 began with preclinical work showing activity of venetoclax in MM cell lines, especially in cell lines with the t(11;14) translocation or a high BCL-2/MCL-1 ratio.3 The increased activity in t(11;14) MM may reflect a higher BCL-2/MCL-1 ratio compared to other subgroups, based on gene expression profiling.4 Additionally, in a xenograft model, the proteasome inhibitor bortezomib can enhance the activity of venetoclax by upregulating NOXA, a pro-apoptotic factor that neutralizes MCL-1.5 Furthermore, in vitro, dexamethasone promotes the binding of the pro-apoptotic protein BIM to BCL-2, increasing the sensitivity of MM cell lines to venetoclax.6

With this background, Dr. Philippe Moreau and colleagues evaluated the combination of venetoclax, bortezomib, and dexamethasone in a phase Ib trial in relapsed/refractory MM.7 Venetoclax was given orally daily at doses ranging from 100 to 1,200 mg combined with bortezomib given subcutaneously and dexamethasone. For the first eight cycles, bortezomib and dexamethasone were given according to the conventional 21-day, twice-per-week schedule. For cycles nine to 11, bortezomib and dexamethasone were given weekly according to a 35-day cycle. From cycles 12 onward, venetoclax was given as monotherapy. In the initial cohort, to assess for the risk of tumor lysis syndrome (which was seen in clinical trials in CLL), there was a one-week lead-in period of 50 mg alone prior to starting the combination. The study enrolled 66 patients, with a median of three prior lines of treatment (range 1-13); 39 percent were refractory to bortezomib and 53 percent were refractory to lenalidomide. The combination was tolerated well, with grade 3 to 4 adverse events reflecting mainly myelosuppression: thrombocytopenia (29%), anemia (15%), and neutropenia (14%). Gastrointestinal adverse events were common but low grade, with 6 percent grade 3 to 4 diarrhea. Tumor lysis syndrome was not seen. The maximum tolerated dose of venetoclax was not reached.

The combination was effective, with an overall response rate (ORR) of 67 percent, and 42 percent with a very good partial response or better. The median time to progression was 9.5 months (95% CI, 5.7-10.4). In patients who were not refractory to bortezomib, the ORR was 90 percent; responses were also seen in patients who were refractory to bortezomib (ORR, 31%) or lenalidomide (ORR, 60%). Importantly, patients with higher expression of BCL2 had the best responses to the combination, with an ORR of 94 percent compared to an ORR of 59 percent in patients with low BCL2 expression. Based on efficacy and safety, a venetoclax dose of 800 mg was chosen as a recommended dose going forward.

The results of this trial indicate that the combination of bortezomib and venetoclax improved responses without adding significant side effects. The high correlation between response and BCL2 expression raises the possibility of using it as a biomarker to individualize treatment in a subset of BCL2-expressing MM. Venetoclax has also been evaluated as a single agent in MM, with higher responses observed in patients with t(11;14).8 The current combination with bortezomib and dexamethasone appears to show responses independent of t(11;14), and this may reflect the synergy provided by bortezomib and dexamethasone. Ongoing studies include venetoclax in combination with carfilzomib and dexamethasone, as well as a phase III trial comparing venetoclax with bortezomib and dexamethasone versus bortezomib and dexamethasone in patients with one to three prior lines of treatment (NCT02755597). With its encouraging activity and potential for biomarker-based response prediction, venetoclax holds substantial promise as a new tool in the therapeutic armamentarium against MM.

References

  1. Ashkenazi A, Fairbrother WJ, Leverson JD, et al. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov. 2017;16:273-284.
  2. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311-322.
  3. Touzeau C, Dousset C, Le Gouill S, et al. The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia. 2014;28:210-212.
  4. Wu J, Ross J, Peale Jr. FV, et al. A favorable BCL-2 family expression profile may explain the increased susceptibility of the t)11;14) multiple myeloma subgroup to single agent venetoclax. Blood. 2016;128:5613.
  5. Punnoose EA, Leverson JD, Peale F, et al. Expression profile of BCL-2, BCL-XL, and MCL-1 predicts pharmacological response to the BCL-2 selective antagonist venetoclax in multiple myeloma models. Mol Cancer Ther. 2016;15:1132-1144.
  6. Matulis SM, Gupta VA, Nooka AK, et al. Dexamethasone treatment promotes Bcl-2 dependence in multiple myeloma resulting in sensitivity to venetoclax. Leukemia. 2016;30:1086-1093.
  7. Moreau P, Chanan-Khan A, Roberts AW, et al. Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood. 2017;doi: 10.1182/blood-2017-06-788323. [Epub ahead of print].
  8. Kumar S, Vij R, Kaufman JL, et al. Venetoclax monotherapy for relapsed/refractory multiple myeloma: safety and efficacy results from a phase I study. Blood. 2016;128:488.

Conflict of Interests

Dr. Raje and Dr. Yee indicated no relevant conflicts of interest. back to top