Keytruda Plus Standard Therapy Fails to Improve Outcomes in Multiple Myeloma

The addition of Keytruda (pembrolizumab) to standard therapy — Revlimid (lenalidomide) or Pomalyst (pomalidomide) in combination with dexamethasone — failed to improve the clinical outcomes of patients with untreated or relapsed/refractory multiple myeloma, data from two Phase 3 trials show.

Findings from the trials were published in the studies “Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial” and “Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial.”

Along with an editorial comment discussing the findings titled, “The future of checkpoint inhibition in multiple myeloma?,” the studies were recently published in The Lancet Haematology.

Keytruda is a checkpoint blockade immunotherapy developed by Merck (known as MSD outside the United States and Canada). It has been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treating several types of cancer.

It is a monoclonal antibody designed to target and block the activity of the PD-1 receptor — a protein found on the surface of immune cells — preventing cancer cells from avoiding being targeted and killed by immune cells. Monoclonal antibody treatments enlist the body’s natural immune system functions to fight cancer.

Preliminary data from Phase 1/2 trials showed that patients with multiple myeloma responded positively to treatment with Keytruda in combination with standard therapy agents (Revlimid or Pomalyst in combination with dexamethasone).

These findings prompted the launch of two Phase 3, randomized, controlled trials — KEYNOTE-183 (NCT02576977) and KEYNOTE-185 (NCT02579863) — to assess the safety and efficacy of Keytruda in combination with standard therapy in patients with multiple myeloma.

KEYNOTE-183 compared the safety and efficacy of Keytruda in combination with Pomalyst and low-dose dexamethasone to that of Pomalyst plus low-dose dexamethasone in a group of 249 multiple myeloma patients who had already received at least two prior therapies.

The trial’s primary endpoint was to assess patients’ overall survival (OS) and progression-free survival (PFS; the time until disease progression or death, whichever occurred first). Secondary endpoints included safety and treatment response assessments.

According to data from an interim analysis, the addition of Keytruda to standard treatment with Pomalyst and low-dose dexamethasone is not beneficial to patients with relapsed or refractory multiple myeloma. Key findings showed that:

• Adding Keytruda to Pomalyst and low-dose dexamethasone lowered patients’ median PFS from 8.4 months to 5.6 months;
• At six-month follow-up, fewer Keytruda-treated patients remained alive and without signs of disease worsening (48%) compared to those on standard treatment (60%);
• Median OS was not reached among patients treated with Keytruda, meaning that more than half of patients were alive at the time of the analysis; conversely, those treated with Pomalyst and low-dose dexamethasone achieved an OS of 15.2 months;
• At six months follow-up, however, only 82% of those on Keytruda were alive, compared to 90% for those on standard therapy;
• A higher proportion of patients treated with Keytruda experienced serious adverse events, compared to those treated with standard therapy agents alone (63% versus 46%);
• Half of the treatment-related deaths reported during the trial were directly related to the use of Keytruda.

“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,” investigators from KEYNOTE-183 stated.

“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,” they added.

KEYNOTE-185 compared the safety and efficacy of Keytruda in combination with Revlimid and low- dose dexamethasone to that of Revlimid plus low-dose dexamethasone in a group of 301 newly diagnosed or previously untreated patients with multiple myeloma who were not eligible to receive an autologous stem cell transplant (ASCT).

The trial’s primary endpoint was to assess patients’ PFS, and the secondary endpoint was to assess patients’ OS.

In an interim analysis, researchers found that the addition of Keytruda to standard treatment with Revlimid and low dose-dexamethasone is not favorable from a benefit-risk standpoint for untreated or newly diagnosed patients with multiple myeloma. Key findings showed that:

• Median PFS was not reached in any of the treatment groups, but estimates at six months showed that fewer patients on Keytruda were alive and progression-free at that time — 82% vs. 85%;
• A higher proportion of patients treated with Keytruda experienced serious adverse events, compared to those treated with standard therapy alone (54% vs. 39%);
• From the eight treatment-related deaths reported during the trial, six occurred in patients treated with Keytruda.

“In July 2017, these data prompted the FDA to request the closure of both the KEYNOTE-183 and KEYNOTE-185 studies and several others (NCT02036502, NCT02726581, NCT01592370, and NCT02612779), raising questions about future targeting of the PD-1 and PD-L1 axis in multiple myeloma,” 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 the editorial comment.

“Future studies assessing the use of immunotherapy in multiple myeloma will require well-designed clinical trials, and careful selection of patients who might benefit the most from targeting PD-L1 expression. Immunotherapy remains an attractive option for the treatment of multiple myeloma; however, we have much to learn,” Costello said.