Pembrolizumab Addition Fails To Improve Multiple Myeloma Outcomes

The use of pembrolizumab alongside standard multiple myeloma therapy has failed to improve the risk–benefit profile for patients with treatment-naïve or relapsed and refractory disease

medwireNews: Phase III trial results challenge the addition of pembrolizumab to standard care for multiple myeloma, demonstrating an unfavourable risk–benefit profile with its use in both patients with a new diagnosis and those with relapsed or refractory disease. 

Unplanned interim analyses for the KEYNOTE-183 and KEYNOTE-185 studies were requested by the US Food and Drug Administration (FDA) and the findings have been published in The Lancet Haematology

“[T]hese data prompted the FDA to request the close of both the KEYNOTE-183 and KEYNOTE-185 studies and several others […], raising questions about future targeting of the PD-1 and PD-L1 axis in multiple myeloma”, says Caitlin Costello, from the University of California,San Diego, in La Jolla, California, USA, in a comment accompanying the reports. 

KEYNOTE-183 assessed the impact of adding pembrolizumab 200 mg every 21 days to a standard regimen of pomalidomide and dexamethasone for patients who had received at least two prior lines of treatment and had refractory disease on their last regimen. 

After a median of 8.1 months, progression-free survival (PFS) was 5.6 months for the 125 patients who received pembrolizumab and 8.4 months for the 124 patients who received only standard care, with estimated 6-month rates of 48% versus 60%, a nonsignificant difference. 

Median overall survival (OS) was unreached in the pembrolizumab arm versus 15.2 months with standard therapy alone, with 6-month estimates of 82% and 90%, but the differences between the groups did not reach statistical significance. 

However, serious adverse events (SAEs) occurred in 63% of the pembrolizumab arm and 46% of patients using only pomalidomide plus dexamethasone. There were four treatment-related deaths among pembrolizumab-treated patients – from an unknown cause, neutropenic sepsis, myocarditis and Stevens–Johnson syndrome, respectively – with the last two attributed to pembrolizumab. By contrast, there were no treatment-related deaths with the standard regimen alone. 

Discussing the imbalance in deaths between the treatment groups, Maria-Victoria Mateos, from University Hospital of Salamanca in Spain, and co-investigators caution that the “interim analyses were underpowered and inconclusive because of the shortened follow-up”. Nevertheless, they hope that the findings “provide valuable information to guide the design of future clinical studies involving checkpoint inhibitors in relapsed or refractory multiple myeloma.” 

In the KEYNOTE-185 trial of patients with newly diagnosed multiple myeloma, after a median of 6.6 months, PFS was not reached in the 151 patients who received the same regimen of pembrolizumab plus a standard regimen of lenalidomide and dexamethasone or the 150 patients who received usual care only, with comparable 6-month rates of 82% and 85%. 

Median OS was not reached in either treatment arm, with 6-month OS achieved by a comparable 87.2% of pembrolizumab-treated patients and 93.9% of those given only the standard regimen, report Saad Zafar Usmani, from Levine Cancer Institute in Charlotte, North Carolina, USA, and co-authors. 

SAEs occurred in 54% of the pembrolizumab arm and 39% of usual care patients. Treatment-related deaths were reported in 4% and 1% of these arms, respectively, with deaths from cardiac arrest, cardiac failure, myocarditis and pneumonia attributed to pembrolizumab. 

The shortened follow-up time precludes a conclusion on the imbalance of deaths between the treatment arms, the researchers say, but they nevertheless suggest that “[f]uture study designs testing PD-1 inhibitors with lenalidomide and dexamethasone in multiple myeloma should consider excluding unfit patients, patients older than 75 years, and patients with high tumour burden or tumour staging.”

“Other treatment combinations should also be assessed and excluding dexamethasone might reduce toxicity and improve T-cell activation”, the team says. “Stratification of patients by renal function and ECOG performance status could also be considered in future study designs.” 

 

References 

Costello C. The future of checkpoint inhibition in multiple myeloma? Lancet Haematol; Advance online publication18 July 2019. http://dx.doi.org/10.1016/S2352-3026(19)30149-8  

Mateos M-V, Blacklock H, Schjesvold F, et al. Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised , open-label, phase 3 trial . Lancet Haematol; Advance online publication 18 July 2019. https://doi.org/10.1016/S2352-3026(19)30110-3  

Usmani SZ, Schjesvold F, Oriol A, et al. Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised , open-label, phase 3 trial . Lancet Haematol; Advance online publication 18 July 2019. https://doi.org/10.1016/S2352-3026(19)30109-7

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