Adverse event (AE) data do not, furthermore, explain the OS discrepancy noted between the 2 arms. The researchers noted serious AEs in less than 1% more patients receiving venetoclax than those receiving placebo (28% vs 27.1%, respectively), and only about 5% more patients in the venetoclax arm had pneumonia (20.7% vs 15.6%, respectively).

Frequent causes of death not attributable to myeloma progression were, according to the press release, sepsis, pneumonia, and cardiac arrest — though the company did not provide specific statistics.

It’s open to question, then, what accounts for the unexpected survival discrepancy noted in BELLINI. At the time of the writing of this article, AbbVie had not released further information to explain the mortalities.


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S. Vincent Rajkumar, MD, Edward W. and Betty Knight Scripps Professor of Medicine at the Mayo Clinic in Rochester, Minnesota, expressed some concern on Twitter about the lack of information to account for the unexplained deaths in BELLINI.

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“The one and only RCT [randomized clinical trial] in myeloma shows double the number of deaths despite 2 times better response rate and PFS, 4-5 times better MRD- [minimal residual disease–negative] rates, AND despite no difference in serious adverse event rate,” Dr Rajkumar tweeted. “For patients already on therapy each physician will have to decide whether the benefits outweigh the risks. Do not be swayed by response. Its [sic] a surrogate. Not the goal.”

When contacted for an interview, Dr Rajkumar said only that he and others have submitted a paper with some potential hypotheses explaining what happened as it relates to the patient deaths, but gave permission to quote the tweets above.

AbbVie did not respond to requests from Cancer Therapy Advisor asking for an estimate for  the number of people currently taking venetoclax for myeloma worldwide — such as those who were currently participating in clinical trials investigating this indication, or otherwise, such as in an off-label setting.

The company’s spokesperson did note, however, that patients responding to the medication should not discontinue treatment just yet, particularly those who may be receiving venetoclax for CLL or AML. “We continue to investigate venetoclax in multiple myeloma, though it is important to note that the partial clinical hold applies to all trials evaluating venetoclax in multiple myeloma, and that we will continue working with the FDA and worldwide regulatory agencies to determine appropriate next steps for the multiple myeloma program,” Taveras told Cancer Therapy Advisor in an email. “Additionally, it’s important to note patients who are currently enrolled in studies and receiving benefit from venetoclax may continue with treatment, after consultation with their physician.”

Whether Dr Rajkumar and colleagues’ forthcoming paper accounts for the confounding survival data from BELLINI — and whether their hypotheses affect the likelihood of continued venetoclax research in myeloma — is still an open question.

According to results from ClinicalTrials.gov, 3 active trials — 2 recruiting and 1 not yet recruiting — are set to evaluate, at least by comparison with other drugs, the safety and efficacy in patients with myeloma (although 1 of these is intended only for patients who have completed a prior venetoclax trial).6-8

For the time being, the future of venetoclax in myeloma treatment is uncertain. In 2016, a Reuters report predicted that venetoclax sales would rise to nearly $1.5 billion by 2020; whether the drug’s success in CLL will fuel these sales remains to be seen.9

References

  1. US Food and Drug Administration. FDA Warns about the risks associated with the investigational use of Venclexta in multiple myeloma [news release]. US Food and Drug Administration website. Published March 21, 2019.
  2. National Cancer Institute. Approval expanded for venetoclax in chronic lymphocytic leukemia [news release]. Published June 22, 2018.
  3. US Food and Drug Administration. FDA approves venetoclax in combination for AML in adults. US Food and Drug Administration website. Updated December 14, 2018.
  4. Kumar S, Kaufman JL, Gasparetto C, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017;130(22):2401-2409.
  5. AbbVie. AbbVie provides update on Venclexta/Venclyxto (venetoclax) multiple myeloma program. Published March 19, 2019. Accessed May 16, 2019.
  6. An extension study of venetoclax for subjects who have completed a prior venetoclax clinical trial. NCT03844048. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT03844048. Updated March 21, 2019.
  7. Myeloma-developing regimens using genomics (MyDRUG) (MyDRUG). NCT03732703. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT03732703. Updated April 8, 2019.
  8. A study of cobimetinib administered as single agent and in combination with venetoclax, with or without atezolizumab, in participants with relapsed and refractory multiple myeloma. NCT03312530. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT03312530. Updated April 26, 2019.
  9. Drugs to watch 2016. Thomson Reuters website. http://images.info.science.thomsonreuters.biz/Web/ThomsonReutersScience/%7B7e677448-1313-40ae-9978-6be1a8532a08%7D_A4_MarketInsight_Report_0213_012__edits_2.pdf. Published 2016.