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Paradigm Shift in Myeloma Care

Fuerst, Mark L.

doi: 10.1097/01.COT.0000481191.81681.f5
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ORLANDO—Two newly approved multiple myeloma drugs—one an oral proteasome inhibitor, the other a targeted therapy—can be safely combined with standard therapy and induce clinically meaningful responses in relapsed/refractory disease, according to two new studies presented here at the American Society of Hematology annual meeting.

Innovations in multiple myeloma therapy, such as the recent approvals of the oral proteasome inhibitor ixazomib and the monoclonal antibody daratumumab, have been touted as the next wave of therapies that may lead to a paradigm shift in myeloma care.

In an interview, Robert Hromas, MD, Chair and Professor of the Department of Medicine at the University of Florida in Gainesville, Florida, commented: “The new exciting data from these two drugs will change the landscape in multiple myeloma. The goal is to get patients to minimal residual disease. This is something we could not talk about 10 years ago. Now we see survival curves that plateau and last for years. In the next five to 10 years, we will be talking about cure rates.”

First All-Oral Treatment

Ixazomib was recently approved by the FDA in combination with standard immunomodulatory drugs (IMiDs) lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy (OT 1/10/16 issue). The approval was based on the Phase III TOURMALINE-MM1 data, with the study's findings presented at ASH by lead author Philippe Moreau, MD, University of Nantes in Nantes, France (Abstract 727).

The triple combination of ixazomib, lenalidomide, and dexamethasone prolonged progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma.

“This all-oral regimen may become one of the new standards of care in the relapse setting of multiple myeloma. It has a very safe profile, is a very effective combination, and is simple and convenient,” said Moreau.

Study Participants

In this randomized, double-blind, placebo-controlled, international, multicenter Phase III trial, 722 patients (median age 66 years) with relapsed/refractory multiple myeloma were randomized to receive either the standard treatment regimen of lenalidomide and dexamethasone or a combination of the standard treatment with weekly doses of ixazomib. Patients were eligible if they had received one to three prior lines of therapy and were not refractory to prior lenalidomide or proteasome inhibitor-based therapy. More than two-thirds of the patients had been exposed to a proteasome inhibitor. They were treated until disease progression or unacceptable toxicity.

At the first interim analysis after more than 14 months follow-up, Moreau reported that patients who received ixazomib had a median progression-free survival (PFS) of 20.6 months as compared to 14.7 months for those who received placebo instead of ixazomib. “This is a significant, clinically relevant 35 percent improvement in PFS with ixazomib-lenalidomide-dexamethasone versus placebo-lenalidomide-dexamethasone,” he said.

The overall response rate (ORR), complete response (CR), and duration of response were also improved among the ixazomib-treated patients. Overall survival (OS) data are not yet mature.

In addition, in the 19 percent of patients who had high-risk cytogenetics, those patients receiving ixazomib achieved a similar PFS response as the entire study population, “indicating ixazomib may overcome the negative impact of cytogenetic alterations,” said Moreau.

The ixazomib combination had a “very safe profile” that was similar to lenalidomide-dexamethasone, he said, adding that adverse events after median follow-up of 23 months found increased rates with ixazomib-lenalidomide-dexamethasone driven by low-grade events.

Grade 3 or higher adverse events occurred in 68 percent of those taking ixazomib as compared to 61 percent of those in the placebo group. This was largely driven by thrombocytopenia and was consistent with reported safety profiles for the individual agents, Moreau said, noting that the higher rate of thrombocytopenia in the ixazomib arm did not affect the number of transfusions needed or severe bleeding events.

In conclusion, Moreau said: “Ixazomib, when combined with lenalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma, was associated with a significant and clinically meaningful improvement in PFS, significantly improved time to progression and confirmed response rates, and improved PFS in high-risk patients similar to that in the overall patient population and in standard-risk patients.”

He stated that ixazomib added limited additional toxicity with low rates of peripheral neuropathy and no cardiovascular or renal signals, and patient-reported quality of life was maintained.

First Targeted Therapy for Multiple Myeloma

Daratumumab was recently approved by the FDA in multiple myeloma patients with three or more prior lines of therapy, including a proteasome inhibitor or an IMiD, or double refractory to both a proteasome inhibitor and an IMiD.

In two previous monotherapy studies of daratumumab in patients with heavily pretreated/highly refractory multiple myeloma, researchers observed a combined ORR of 31 percent and a median OS of 19.9 months. At ASH, Torben Plesner, MD, of Vejle Hospital, University of Southern Denmark in Vejle, Denmark, presented data from an ongoing, open-label Phase 1/2 study of daratumumab plus lenalidomide and dexamethasone in 32 relapsed/refractory multiple myeloma patients (Abstract 507).


He explained that CD38 is highly expressed on myeloma cells. Daratumumab is a human IgG1 monoclonal antibody that binds CD38-expressing cells and induces tumor cell death through direct and indirect mechanisms.

The patients received weekly doses of daratumumab in combination with lenalidomide-dexamethasone during the first two 28-day therapy cycles, then biweekly infusions during the next four cycles, followed by once monthly infusions. Patients received the treatment until disease progression or unacceptable toxicity.

Study Data

The 12-month duration of response data show ORR was 81 percent, with a 28 percent very good partial response rate, and CR or better in 34 percent of patients, including a stringent CR in 25 percent of patients. The clinical benefit rate was 88 percent.

The median time to first response was one month and median time to best response was 5.1 months. Median duration of response was not reached. Virtually all (91%) of the patients were disease progression-free at 12 months, he said.

“Over time, responses improved. Many patients are still on treatment,” Plesner said.

The 18-month PFS rate was “an impressive” 72 percent, he said, and the 18-month OS rate was 90 percent.

No new safety signals were identified with the addition of daratumumab to standard therapy. “Few patients (3 of 32) discontinued treatment due to adverse events,” he said. The most common adverse events were neutropenia (84%), cough (50%), diarrhea (44%), and muscle spasms (44%).

Half of the patients experienced serious adverse events, but only neutropenia, gastroenteritis, and pyrexia occurred in more than one patient. Infusion-related reactions occurred in 56 percent of patients. This was usually in the first infusion and grade 2 or less, he said, and was easily managed with pre-medication or by slowing the infusion rate.

In conclusion, Plesner said: “Daratumumab plus lenalidomide and dexamethasone induced rapid, deep, and durable responses. Daratumumab can be safely combined with lenalidomide and dexamethasone with a favorable safety profile, manageable toxicities, and with no additional safety signals observed.”

Randomized phase 3 studies of daratumumab plus lenalidomide and dexamethasone are ongoing in relapsed/refractory patients and newly diagnosed multiple myeloma patients, he said.

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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