Case study illustrates potential of venetoclax in MM subgroup

An interesting patient case demonstrating the safe and effective use of venetoclax for relapsed t(11;14) multiple myeloma in parallel with pembrolizumab for advanced non-small cell lung cancer (NSCLC) ‘strongly supports’ further development of venetoclax for this subset of multiple myeloma patients, UK clinicians say.

The FDA halted venetoclax trials in myeloma in March 2019 when a higher proportion of deaths was observed in the venetoclax arm compared to the control arm of the BELLINI trial.

Since then updated safety data has confirmed excess trial deaths were not seen in patients with relapsed or refractory multiple myeloma bearing the common t(11;14) translocation abnormality – the subgroup to which this patient belongs.

Treatment for both malignancies was guided not only by medical urgency but also by tumour biologies, specifically translocation t(11;14) in myeloma and high Programmed Death Ligand 1 (PDL1) and tumour mutational burden (TMB) in NSCLC, which may have contributed to their safe and effective use, say the team from The Royal Marsden Hospital, led by consultant haematologist Dr Martin Kaiser.

In the British Journal of Haematology they report on the 68-year-old male patient who was treated with pembrolizumab for advanced NSCLC, whilst on carfilzomib/ daratumumab/dexamethasone for myeloma, with excellent ongoing partial response.

In contrast to the NSCLC, the myeloma did not respond to pembrolizumab and paraprotein levels continued to rise over 10 months of concurrent pembrolizumab and anti-myeloma therapy until clinical progression.

Following detection of a t(11;14) translocation, off-label treatment with venetoclax/daratumumab/dexamethasone was initiated for relapsed multiple myeloma in parallel with pembrolizumab for advanced NSCLC.

The patient experienced no clinically significant infections throughout the venetoclax therapy, and at the time of the report enjoyed good performance status (ECOG 0). The myeloma and NSCLC remained in ongoing stable remission for over 12 months and 18 months respectively with ongoing venetoclax and parallel pembrolizumab therapy, without major breaks and without immune-related adverse events or other safety concerns.

CD38: a potential target in NSCLC?

 In trying to explain the lack of anti-myeloma activity with pembrolizumab in this case, the authors were doubtful it could be attributed to immune cell exhaustion caused by myeloma or anti-myeloma therapy, which has been discussed as a potential reason for the lack of efficacy for the pembrolizumab – immunomodulatory drug (IMiD) combination in the KEYNOTE-185 trial.

They note that interestingly, the NSCLC responded rapidly to pembrolizumab despite ongoing weekly 40 mg dexamethasone administered for myeloma.

“Whether CD38 blockade on the lung tumour cells through daratumumab may have enhanced cyctotoxic T-cell function and contributed to the excellent response of the NSCLC to pembrolizumab, as recently reported for an in-vivo model of lung cancer, is unknown,” they said.

Concurrent malignancies are a frequent challenge

Dr Kaiser says the management of simultaneously active cancers is a challenge that is becoming increasingly frequent, noting that this case demonstrates the safe and effective parallel management of concurrent malignancies with treatments that target the respective tumour biologies.

“Without pembrolizumab or venetoclax, care for this patient would have likely been limited to palliation both at the time of NSCLC diagnosis and myeloma progression, because of reduced performance status and relevant co-morbidities.”

The CANOVA Phase 3 trial of venetoclax in patients with multiple myeloma positive for the t(11;14) abnormality has resumed following revisions to the study protocol.

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