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Combinations Show Early Promise in Multiple Myeloma

Gina Columbus @ginacolumbusonc
Published: Tuesday, Mar 01, 2016

Craig Hofmeister, MD

Craig Hofmeister, MD

Findings from early clinical trials are demonstrating the strong potential of 2 combination regimens for patients with multiple myeloma.

In a phase I/II study presented at the 2015 ASH Annual Meeting,1 the combination of lenalidomide (Revlimid) and the anti–PD-1 monoclonal antibody pidilizumab (formerly MDV9300; CT-011) demonstrated tolerability and clinical activity in patients with relapsed/refractory multiple myeloma. Among 12 evaluable patients, there were 3 very good partial responses, 1 partial response, 2 minimal responses, and 2 occurrences of stable disease.

This is the first reported combination with an anti–PD-1 therapy for multiple myeloma, the study authors noted.

A second combination study examined Reolysin, an oncolytic virus, plus carfilzomib (Kyprolis) and dexamethasone in patients with relapsed multiple myeloma.2 In the phase I study, the triplet was found to be well tolerated and showed evidence of objective response in 86% of patients.

Both trials, though early, are generating excitement as potential options for relapsed patients who may be refractory to existing therapies, explains Craig Hofmeister, MD, an author on both studies.

In an interview with OncLive, Hofmeister, assistant professor of Internal Medicine, Division of Hematology, Department of Internal Medicine, at The Ohio State University Wexner Medical Center, discusses these 2 clinical trials and the potential for these regimens in relapsed/refractory patients with multiple myeloma.

OncLive: Can you discuss the phase I trial of Reolysin in patients with relapsed multiple myeloma?

Hofmeister: This is a phase I clinical trial looking at patients who have relapsed disease. Some of them are refractory to carfilzomib, and some are not. It is a combination of carfilzomib with the oncolytic virus Reolysin, which is the proprietor form for Reovirus.

We enrolled a small number of patients—just 12—for this combination at 2 different dose levels. These included the starting dose level and a dose-level decrease that occurred during the clinical trial. At the starting dose level, every patient had a response. At the dose-level decrease, only some of the patients responded. The majority did not at a lower dose level, which was an unexpected result.

We were very excited about the combination because, at the first dose level, patients continued to remain on therapy without progression. This was only about 6 patients, but it was remarkably well tolerated and incredibly effective in patients who were carfilzomib-refractory in a small population.

What are going to be the next steps with this trial?

We’re hoping to gather more efficacy data in the carfilzomib-refractory population, and we are also interested in finding the right dose. Dose seems to matter quite a lot when giving this oncolytic virus. Therefore, we’re interested in finding the right dose before we explore the true definitive efficacy setting.

The people who had a lower dose did not respond as well, or at least the response was short-lived. The majority of those who were treated at the original dose stayed on therapy.

There are differences between millions and billions of particles of virus that are infused, and we didn’t expect that there would be such a big difference in response with the decrease.

What are the biggest remaining questions with this drug?

This drug has been tested in a number of solid tumors; this is the first hematologic malignancy trial that is being tested, and only in myeloma. There are many questions for this drug. We need to know how it works, what the best patient population is, and what the right dose is.

What is Reolysin’s mechanism of action?

From what we know, Reolysin specifically enters myeloma cells. We know that it needs some type of cellular stress, something like carfilzomib to make the Reolysin produce an infection, which ultimately leads to cell death. We found this after patients were treated with the drug on day 1; we repeated the marrow 1 week later and saw productive infection just inside the myeloma cells.

Therefore, we were pretty sure about the mechanism of action, at least in terms of what leads to an infection, which kills the cells. Now, we need to figure out how to enhance this cell kill. Does it need to be combined with other agents? Can we get the right dose?

There was a phase I/II study looking at lenalidomide in combination with pidilizumab. Can you discuss these findings?

This is a really interesting combination. This was an efficacy test for pidilizumab and lenalidomide in patients with relapsed myeloma—to examine how well the patients respond and to understand the mechanism in these patients.

This enrolled a small number of patients—just 12—and all of them had to have prior lenalidomide-sensitivity, or at least not be refractory to the full dose of 25 mg lenalidomide.

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