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Pembrolizumab fails to improve outcomes in multiple myeloma
The addition of pembrolizumab to standard therapy failed to improve clinical outcomes for patients with untreated or relapsed/refractory multiple myeloma, according to results of two randomized phase 3 trials published in The Lancet Hematology.
“Multiple myeloma — a malignant disorder of clonal plasma cells characterized by osteolytic bone lesions, renal disease and immunodeficiency — accounts for about 1% of all cancers and 10% of hematological cancers,” Maria-Victoria Mateos, MD, PhD, consultant physician in the hematology department at University Hospital of Salamanca in Spain, and colleagues wrote. “Prognosis is poor [for] patients who are refractory to immunomodulatory imides or proteasome inhibitors. Effective combination of novel therapies with different mechanisms of action remains an unmet need.”
Relapsed or refractory disease
Pomalidomide (Pomalyst, Celgene) with dexamethasone is a standard of care for patients with relapsed or refractory multiple myeloma. The addition of pembrolizumab (Keytruda, Merck) to the combination showed promising antitumor activity with a manageable safety profile among this patient population in previous phase 1 and phase 2 trials.
The phase 3 KEYNOTE-183 trial included 249 adults with multiple myeloma refractory to the last of at least two previous lines of therapy.
All patients received 4 mg oral pomalidomide daily on days 1 to 21 and 40 mg oral dexamethasone (20 mg for patients aged 75 years and older) on days 1, 8, 15 and 22 of 28-day cycles.
Mateos and colleagues randomly assigned 125 patients (median age, 65 years; 62% men) to also receive 200 mg IV pembrolizumab every 3 weeks. The other 124 patients (median age, 67 years; 63% men) received no pembrolizumab.
PFS and OS served as the study’s primary endpoints.
Median follow-up was 8.1 months (interquartile range [IQR], 4.5-10.9).
Results showed median PFS of 5.6 months (95% CI, 3.7-7.5) for patients who received pembrolizumab vs. 8.4 months (95% CI, 5.9-not reached) with pomalidomide-dexamethasone alone.
Six-month PFS estimates were 48% (95% CI, 37-58) with pembrolizumab vs. 60% (95% CI, 49-69) with pomalidomide and dexamethasone alone (HR = 1.53; 95% CI, 1.05-2.22).
Median OS in the pembrolizumab group was not reached (95% CI, 12.9 months-not reached) vs. 15.2 months (95% CI, 12.7-not reached) with pomalidomide and dexamethasone alone (HR = 1.61; 95% CI, 0.91-2.85).
Researchers estimated OS rates at 6 months of 82% (95% CI, 74-88) with pembrolizumab vs. 90% (95% CI, 82-95) without.
Serious adverse events occurred among 75 patients (63%) in the pembrolizumab group and 56 patients (46%) in the pomalidomide-dexamethasone group. Four treatment-related deaths occurred in the pembrolizumab group, two of which researchers considered related to pembrolizumab. No treatment-related deaths occurred among patients who received pomalidomide and dexamethasone alone.
Early termination of the unplanned analysis limited generalizability of the results, according to the researchers.
“Our findings are disappointing given the positive outcomes reported in the previous phase 2 study of pembrolizumab plus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma,” Mateos and colleagues wrote. “Although these data showed an imbalance in the number of deaths between treatment groups, the interim analyses were underpowered and inconclusive because of the shortened follow-up at termination. Additional studies are necessary to optimize identification of patients who would benefit from PD-1 inhibition in combination with pomalidomide.”
Treatment-naive disease
In this phase 3 KEYNOTE-185 study, Saad Zafar Usmani, MD, FACP, chief of plasma cell disorders and director of clinical research in hematologic malignancies at Levine Cancer Institute at Atrium Health, as well as a HemOnc Today Editorial Board Member, and colleagues evaluated pembrolizumab with lenalidomide (Revlimid, Celgene) and dexamethasone among transplant-ineligible adults with newly diagnosed multiple myeloma.
All 301 patients received 25 mg oral lenalidomide on days 1 to 21 and 40 mg dexamethasone on days 1, 8, 15 and 22 of 28-day cycles. Researchers randomly assigned 151 patients (median age, 74 years; 54% women) to receive 200 mg IV pembrolizumab every 3 weeks. The other 150 patients (median age, 74 years, 53% women) received no additional therapy.
PFS and OS served as the study’s primary endpoints.
Median follow-up was 6.6 months (IQR, 3.4-9.6). The FDA terminated the study early because of an imbalance of deaths between the groups.
Median PFS was not reached in either group.
Six-month PFS estimates were 82% (95% CI, 73.2-88.1) in the pembrolizumab group vs. 85% (95% CI, 76.8-90.5) for the lenalidomide-dexamethasone group (HR = 1.22; 95% CI, 0.67-2.22).
Eighty-one patients (54%) who received pembrolizumab and 57 patients (39%) who received lenalidomide-dexamethasone alone experienced serious adverse events, the most common of which was pneumonia (6% in each group). Six treatment-related deaths occurred in the pembrolizumab group, whereas two occurred in the group treated with lenalidomide and dexamethasone alone.
“An imbalance was observed between groups in the number of deaths. However, the shortened follow-up time resulting from premature study termination rendered this interim analysis underpowered and inconclusive,” Usmani and colleagues wrote. “Future 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 tumor burden or tumor staging.”
Future research
Future use of checkpoint inhibitors to treat multiple myeloma will depend on the understanding of several fundamental aspects of the disease, Caitlin Costello, MD, assistant professor of medicine in the division of blood and marrow transplant at Moores Cancer Center at UC San Diego Health, wrote in an accompanying editorial.
The immune dysfunction seen in multiple myeloma is unique because it includes a senescent phenotype of T cells instead of the exhausted phenotype seen in solid tumors, Costello wrote.
Researchers must identify alternative combinations with checkpoint inhibitors that include anti-CD38 monoclonal antibodies, tumor vaccines or radiotherapy, Costello added, noting that use of checkpoint inhibitors after autologous stem cell transplants or chimeric antigen receptor T cell therapy could induce antimyeloma effects and increase the duration of response.
“Ultimately, once the appropriate partner drugs are identified for combination therapy with checkpoint inhibitors, physicians will need to become more aware of the identification and management of the distinct toxicity profiles and associated immune-related adverse events that have not been previously encountered with historic myeloma therapies,” Costello wrote. “Immunotherapy remains an attractive option for the treatment of multiple myeloma, however, we have much to learn.” – by John DeRosier
Disclosures: Mateos reports consultant roles with Amgen, Celgene, Janssen and Takeda. Usmani reports consultant roles with AbbVie, Amgen, Bristol-Myers Squibb, Merck and Sanofi. Please see the studies for all other authors’ relevant financial disclosures. Costello reports research funding from Celgene and Takeda.