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Myeloma: New Agents Found Highly Active and Better Tolerated

Carlson, Robert H.

doi: 10.1097/01.COT.0000428317.52814.d0


ATLANTA—The survival of patients with multiple myeloma has significantly increased over the past decade with the introduction of highly effective drugs. Attention is now turning to developing agents that are not only highly effective, but also better tolerated.

Two such agents were described here at the American Society of Hematology Annual Meeting. Adding the investigational oral proteasome inhibitor MLN9708 to the standard lenalidomide-dexamethasone combination in an all-oral regimen as initial therapy in patients with previously untreated multiple myeloma appears to improve the overall response rate without increased peripheral neuropathy (Abstract 332).

And, the anti-angiogenic immunomodulator pomalidomide, a derivative of thalidomide, when combined with low-dose dexamethasone, demonstrated a longer progression-free and overall survival in patients with relapsed/refractory multiple myeloma than with the use of high-dose dexamethasone alone in a Phase III multicenter, randomized, open-label study (Abstract LBA-6 ).

In the Phase 1/2 study of weekly MLN9708 in combination with lenalidomide and dexamethasone, 92 percent of the 65 patients had a partial response or better, 55 percent a very good partial response or better, and a complete response rate of 23 percent, said the first author, Shaji K. Kumar, MD, Professor of Medicine in the Division of Hematology at the Mayo Clinic.

Not all patients had completed 12 cycles of therapy at the time of his report, he noted, saying that he believed responses were likely to further improve: “The data are all pointing to the likelihood of responses increasing in time with completion of therapy.”

There were no complications with stem cell collection among 20 patients in whom autologous stem cell was attempted, Kumar said. “Conspicuously absent was serious peripheral neuropathy, considering the results seen with the Velcade combination.” Twenty percent of patients had grade 1 peripheral neuropathy, six patients had grade 3, and two had grade 3.

The study was supported by Millennium: The Takeda Oncology Company.

Of the 65 patients, 15 enrolled in the Phase I portion of the trial and 50 in Phase II. The patients' median age was 66 (range of 34 to 86); 43 percent and 13 percent, respectively, had International Staging System Stage II and III.

The trial began with oral MLN9708 administered on days 1, 8, and 15, along with lenalidomide at a dose of 25 mg on days 1-21, plus dexamethasone at 40 mg on days 1, 8, 15, and 22, for up to 12 28-day cycles. Maintenance therapy with MLN9708 followed on the same schedule every 28 days until disease progression.

Patients could undergo stem cell collection after three cycles and discontinue for autologous stem cell transplant after six cycles. The Phase I dose escalated from 1.68 to 3.95 mg/m2. For Phase II, a dose of 2.23 mg/m2 was chosen, based on cycle 1 dose-limiting toxicities. Patients received a median of five cycles, and 42 patients (65%) remain on treatment, four from Phase I and 38 from Phase II.

A total of 22 patients discontinued participation in the trial: 16 to receive a stem cell transplant, four due to adverse events (three drug-related, one non-drug-related GI bleed), one due to the investigator's decision, and one due to disease progression.

Among all 65 patients, with a median follow-up of almost four months, the overall response rate was 88 percent (100% of the Phase I patients and 84% of the Phase II patients). That included very good or better partial response rates in 48 percent of patients (53% in Phase I and 36 percent in Phase II) and 18% complete response rates (33% in Phase I and 14 percent in Phase II).

Kumar said that the researchers are now proceeding with two Phase III trials, comparing this regimen with lenalidomide-dexamethasone. One trial is already enrolling patients with relapsed disease, and another trial was scheduled to open soon for newly diagnosed patients.

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Pomalidomide Adds Punch to Low-Dose Dex

In the other report, use of combined pomalidomide and low-dose dexamethasone was shown in a prospective, randomized Phase III trial to be superior to use of high-dose dexamethasone alone, which is currently the standard-of-care for patients with relapsed and refractory myeloma.

Lead author Meletios A. Dimopoulos, MD, Professor and Chair of the Department of Clinical Therapeutics at Alexandra Hospital in Athens, presented data on 455 patients: 302 received pomalidomide at a dose of 4 mg daily three weeks on, one week off, and low-dose dexamethasone at 40 mg (20 mg weekly for patients older than 75 years) on days 1, 8, 15, and 22 in a 28-day cycle (called LoDEX); and 153 received high-dose dexamethasone alone at 40 mg (20 mg for patients older than 75 years) on days 1-4, 9-12, and 17-20 in a 28-day cycle (HiDEX).

The control arm was high-dose dexamethasone because this is the treatment often used to palliate patients for whom there are no other treatment options, Dimopoulos explained.

At a median follow-up of 18 weeks, patients in the LoDEX arm had progression-free survival of 15.7 weeks, vs. 8.0 weeks for those in the HiDEX arm. Overall survival was also superior in the LoDEX arm, with a median not reached vs. 34 weeks in the HiDEX arm. Dimopoulos said the median for patients receiving LoDEX is expected to be 11 to 12 months. And, the objective response rates were 16.6 percent for LoDEX vs. 3.9 percent for HiDEX.

Toxicities reported in both groups included low neutrophil count (42% in LoDEX vs. 15% in HiDEX), low platelet count (21% vs. 24%), and fever (7% vs. 0%).

“Most of these patients were clearly refractory to both lenalidomide and bortezomib, and we believe that this may become a new standard-of-care for these hard-to-treat patients,” Dimopoulos said. “It may even offer greater benefit if studied among less heavily treated patients as a first-line therapy for the disease.”

© 2013 Lippincott Williams & Wilkins, Inc.
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