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‘Much to learn’ about toxicity, outcomes with pembrolizumab for multiple myeloma
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CHICAGO — The addition of pembrolizumab to standard-of-care therapy was associated with decreased OS among patients with newly diagnosed or relapsed or refractory multiple myeloma, according to data from an exploratory analysis conducted by the FDA presented at the ASCO Annual Meeting.
The development of immune-related adverse events appeared associated with a higher response rate among patients with newly diagnosed disease, but not among patients with relapsed or refractory disease.
The development of immune-related adverse events with checkpoint inhibition is associated with response in certain disease settings, according to study background.
“The utility of immunotherapy in patients unable to mount adequate immune responses merits further study, as does the worse OS observed in [KEYNOTE-183 and KEYNOTE-185 trials],” Aviva C. Krauss, MD, medical officer in the division of hematology products at the FDA, said during her presentation.
Krauss and colleagues sought to assess OS, safety and objective response rate among patients who developed immune-related adverse events compared with those who did not in KEYNOTE-183 and KEYNOTE-185 trials. Last July, FDA placed these trials on clinical hold due to increased deaths observed among patients treated with pembrolizumab (Keytruda, Merck).
In KEYNOTE-183, researchers randomly assigned 249 patients with relapsed or refractory multiple myeloma to receive pomalidomide (Pomalyst, Celgene) and dexamethasone with or without pembrolizumab.
Median follow-up was 8.1 months.
Twenty-nine deaths occurred in the pembrolizumab arm compared with 21 deaths in the control arm (HR = 1.61; 95% CI, 0.91-2.85). Researchers reported an ORR of 34% in the pembrolizumab arm and 40% in the control arm.
Nearly 60% of patients in the pembrolizumab arm experienced an immune-related adverse event compared with 45% of the control arm.
Researchers did not observe a correlation between the development of immune-related adverse events and ORR with pembrolizumab in this trial. Among patients who received pembrolizumab, ORR was 37% among those who experienced an immune-related adverse event, 29% among those who experienced a grade 3 or worse event, and 31% among those without an immune-related adverse event. In the control arm, ORR increased from 33% among patients without an adverse event to 49% among those with an event and 50% among those with a grade 3 or worse event.
In KEYNOTE-185, researchers randomly assigned 301 patients with newly diagnosed multiple myeloma ineligible for autologous stem cell transplant to lenalidomide (Revlimid, Celgene) and dexamethasone with or without pembrolizumab.
Median follow-up was 6.6 months.
Nineteen deaths occurred in the pembrolizumab arm compared with nine deaths in the control arm (HR = 2.06; 95% CI, 0.93-4.55).
Researchers reported an ORR of 64% in the pembrolizumab arm vs. 62% among controls.
More patients in the pembrolizumab arm experienced any immune-related adverse event (68% vs. 44%) or a grade 3 or worse event (36% vs. 8%).
Among patients without an immune-related adverse event, ORR was 45% in the pembrolizumab arm and 53% in the control arm. ORR increased to 73% in both arms among patients with any immune-related adverse event, and was 70% for the pembrolizumab arm and 67% for the control arm among patients with a grade 3 or worse event.
Of note, neither trial demonstrated a significant difference in time-to-progression between the two arms.
“There remains much to learn about these therapies,” Krauss said. “We need more data to help us assess the association in efficacy on one hand and toxicity on the other.” – by Jennifer Southall
Reference:
Krauss AC, et al. Abstract 8008. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.
Disclosures: Krauss and the other authors report no relevant financial disclosures.
Perspective
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Noa Biran, MD
This analysis showed that pembrolizumab in combination with a pomalidomide or lenalidomide led to inferior outcomes. These outcomes — ORR, death on trial and PFS — were inferior to the combination of pembrolizumab plus standard-of-care therapy vs. pembrolizumab alone.
We can learn many things from this. The first is that it is a lesson in clinical development. It is very important to perform randomized phase 3 trials so we can compare our treatments to standard of care.
The second thing that we can learn is about the role of checkpoint inhibitors in multiple myeloma. There still is a role, but the question now is, what is the best combination to use? We need to look at checkpoint inhibitors in different combinations in a more refractory population and really examine the safety of checkpoint inhibitors in combination with other drugs among refractory patients who have very few alternatives.
I do think there is a role for checkpoint inhibition in multiple myeloma, we just have to figure out what that is and when to administer it.
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