Pembrolizumab Looks Promising in Multiple Myeloma


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Initial efficacy results show promising activity in heavily pretreated patients with relapsed or refractory multiple myeloma and support the continued development of pembrolizumab in these patients.

—Jesus San Miguel, MD

Monoclonal antibodies targeting the programmed cell death protein (PD-1) receptor look promising in multiple myeloma, according to early reports presented at the 2015 ASH Annual Meeting and Exposition. Early signs of activity in heavily pretreated patients may indicate that, as in solid tumors, these immunotherapy agents may be beneficial in at least some hematologic malignancies.

Preliminary findings from the phase I KEYNOTE-023 study of pembrolizumab (Keytruda) were presented by Jesus San Miguel, MD, of the University of Navarra, Pamplona, Spain,1 and Ashraf Z. Badros, MD, of the University of Maryland, Baltimore, presented results of a phase II study combining pembrolizumab with pomalidomide (Pomalyst) and dexamethasone.2 Both trials are continuing to accrual, and final results are expected.

“Initial efficacy results show promising activity in heavily pretreated patients with relapsed or refractory multiple myeloma and support the continued development of pembrolizumab in these patients,” Dr. San Miguel said.

Possible Antitumor Synergy

PD-1 is upregulated on the surface of activated T cells and its ligands (PD-L1 and PD-L2) are expressed on the surface of antigen-presenting cells and tumor cells. Binding of the PD-1 receptor to its ligands inhibits T-cell activation. The PD-1 pathway is often exploited by tumors to evade immune surveillance, Dr. San Miguel explained.

Ashraf Z. Badros, MD

Ashraf Z. Badros, MD

Pembrolizumab is a potent and highly selective humanized anti–PD-1 monoclonal antibody that directly blocks the interaction between PD-1 and its ligands. Pembrolizumab is approved for advanced melanoma and non–small cell lung cancer and has demonstrated robust antitumor activity in multiple cancers.

According to Dr. San Miguel, antitumor synergy is observed when anti–PD-1 antibodies and immunomodulatory drugs are used in combination. “We tested the possibility of combining these two types of treatments that have immune effects, trying to enhance the capacity of the immune system to control tumor cells,” he explained.

KEYNOTE-023 Details

The phase I KEYNOTE-023 trial enrolled 50 patients with relapsed/refractory myeloma who progressed on two or more prior therapies (median of four). The study had a dose determination phase, a dose confirmation phase, and a dose expansion phase.

Dr. San Miguel emphasized the refractory nature of this population, noting that 70% had at least three prior lines; more than 95% were exposed to both lenalidomide and bortezomib (Velcade) and 25% were exposed to carfilzomib (Kyprolis) and pomalidomide; 80% had undergone autologous transplantation; and 80% were refractory to their last regimen. All 50 patients were evaluable for safety, and 17 from the dose determination and confirmation phases were evaluable for efficacy, a secondary endpoint.

The dose-finding study determined the maximum tolerated dose to be pembrolizumab at 200 mg intravenously every 2 weeks in combination with lenalidomide at 25 mg and low-dose dexamethasone at 40 mg. 

High Response Rates

The addition of pembrolizumab to this established myeloma regimen (lenalidomide plus dexamethasone) produced responses in 76% of the 17 evaluable heavily pretreated patients, without excessive toxicity, Dr. San Miguel reported. “If you focus on the nine lenalidomide-refractory patients, five achieved a partial response or better (56%), and three additional patients achieved stable disease,” he added. 

The overall disease control rate, indicating response or stable disease for at least 12 weeks, was 88%; only 6% of patients overall and 11% of lenalidomide-refractory patients had progressive disease.

The median duration of response was 9.7 months, and the median time to first response was 1.2 months; in 11% of patients, response deepened over time. Almost all patients (94%) had a reduction in M protein or free light chains, with 13 of 17 patients experiencing at least a 50% decrease.

Toxicity

The combination was well tolerated, with an adverse-event profile that was consistent with reports of pembrolizumab in solid tumors. Adverse events of any grade were reported by 72% of patients. The most common ≥ grade 3 drug-related events were neutropenia (22%), thrombocytopenia (8%), and anemia (8%). Side effects were consistent with the individual drug safety profiles for the approved indications.

“We did not see any toxicities that were not expected,” said Dr. San Miguel. “We saw both hypothyroid and hyperthyroid adverse events, but we have not seen pneumonitis or colitis so far…. We observed that the safety profile is relatively good, but we are probably underestimating the side effects because the exposure to the drug has been limited. The study is ongoing.” He further cautioned that although the data are “encouraging” they are still preliminary and suggested this combination not be used outside of clinical trials.

Pembrolizumab Plus Pomalidomide and Dexamethasone

Researchers from the University of Maryland combined pembrolizumab with pomalidomide and dexamethasone in a phase II study of 33 relapsed/refractory patients with at least two prior lines of therapy. All patients had abnormal cytogenetics, including 42% with high-risk features; 82% were refractory to proteasome inhibitors, 89% were refractory to lenalidomide, and 70% were refractory to both classes of agents.

Patients received pembrolizumab at 200 mg, pomalidomide at 4 mg and dexamethasone at 40 mg. After 24 months, responding patients are being allowed to continue pomalidomide/dexamethasone alone until disease progression.

All 33 patients were assessed for safety, and 27 were evaluable for response; the median number of cycles was six, and the median follow-up was 7.4 months.

“The regimen shows promising antimyeloma activity and has a predictable and manageable side-effect profile,” Dr. Badros reported.

Pembrolizumab in Myeloma

Pembrolizumab was combined with lenalidomide/dexamethasone in a phase I study of 50 patients and with pomalidomide/dexamethasone in a phase II study of 33 patients; all patients were heavily pretreated. The response rate was 76% to pembrolizumab/lenalidomide/dexamethasone and 60% to pembrolizumab/pomalidomide/dexamethasone. Adverse events were consistent with previous studies of the drug in other cancers.

The objective response rate for this regimen was 60% overall, 55% among double-refractory patients, and 50% among patients with high-risk cytogenetics. Only 10% of patients had progressive disease, and 23 of the 27 patients had some reduction in M protein or free light chains. “It’s too early to look at progression-free and overall survival, but the signal we are seeing is quite impressive,” he said. At 6 months, more than 75% of patients appeared progression-free, and approximately 90% were alive.

The researchers are currently working on a means of standardizing the assessment of PD-L1 expression on bone marrow biopsy and exploring methods for determining the impact of fixation and decalcification on the level of expression. ■

Disclosure: Dr. San Miguel is on the advisory board of Millennium, Celgene, Novartis, Onyx, Janssen, BMS, MSD, and Amgen. Dr. Badros reported no potential conflicts of interest. 

References

1. San Miguel J, Mateos M-V, Shah JJ, et al: Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma: KEYNOTE-023. 2015 ASH Annual Meeting. Abstract 505. Presented December 7, 2015.

2. Badros AZ, Kocoglu MH, Ma N, et al: A phase II study of anti PD-1 antibody pembrolizumab, pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma. 2015 ASH Annual Meeting. Abstract 506. Presented December 7, 2015.


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