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CHICAGO -- A trial comparing two immunomodulatory regimens for myeloma failed to demonstrate noninferiority for the newer drug.

Patients treated with a thalidomide-based regimen had a median progression-free survival (PFS) of 21 months compared with 18.7 months with a newer lenalidomide (Revlimid) regimen. The 2-year PFS, overall response rate, and overall survival did not differ significantly between groups, but all of the endpoints favored the thalidomide arm.

Lenalidomide was associated with less toxicity and better quality of life, A. Keith Stewart, MBChB, of the Mayo Clinic in Scottsdale, Ariz., reported here at the American Society of Clinical Oncology meeting.

"The study was statistically inconclusive," said Stewart. "It did not prove inferiority or noninferiority of melphalan-prednisone-lenalidomide compared to melphalan-prednisone-thalidomide."

Whether the results will have an impact on clinical practice remains to be seen, since "in the U.S., melphalan-based regimens are now seldom utilized due to availability of lenalidomide and bortezomib in newly diagnosed patients with myeloma," he added.

When the NCI-sponsored randomized trial began, the combination of melphalan, prednisone, and thalidomide (MPT) was a widely used standard treatment option for transplant-ineligible patients with newly diagnosed multiple myeloma. Phase I/II clinical trials suggested that substitution of lenalidomide (MPR) for thalidomide would achieve similar results with less toxicity.

Additionally, multiple trials demonstrated that continuous treatment with either immunomodulatory agent improves PFS, said Stewart.

Following the accumulation of evidence, investigators performed a multicenter trial to compare MPT followed by daily thalidomide maintenance (MPT-T) and MPR followed by lenalidomide maintenance (MPR-R). Patients in both groups received enteric-coated aspirin. The trial protocol included 12 cycles of induction therapy followed by maintenance therapy until disease progression.

The primary endpoint was PFS, and the trial was designed to test the noninferiority of MPR-R to MPT-T.

The trial opened in February 2008 and closed prematurely in November 2011 when the data and safety monitoring committee concluded that continued accrual was unlikely to demonstrate noninferiority of MPR-R to MPT-T.

The trial ended with an enrollment of 306 patients who had a median age of 75.7. The arms did not differ significantly with respect to major prognostic features, and the trial had a median follow-up of 40.7 months.

Stewart reported that 275 patients dropped out of the study: 42% because of adverse events or complications, 34% because of progressive disease, and 10% because of patient choice. Half of the study population dropped out before completing induction therapy, and 46% of patients initiated maintenance therapy.

The median time on maintenance therapy was 10.5 months, and did not differ between treatment arms. Median total duration of treatment was 23 months.

Stewart reported that 64% of patients in the MPT-T arm achieved better than partial response compared with 60% in the MPR-R arm. Response rates of very good partial response or better were 19% and 23% for the MPT-T and MPR-R groups, respectively, and complete responses occurred in 5% of the MPT-T arm and 9% of the MPR-R arm.

Comparison of median PFS yielded a 16% hazard reduction in favor of the thalidomide group, but the difference did not achieve statistical significance (95% CI 0.64-1.09). Subgroup analysis showed a consistent pattern in favor of MPT-T.

Median overall survival was 52.6 months in the thalidomide group and 47.7 months in the lenalidomide group, and 2-year survival was 78% versus 72%, also in favor of MPT-T.

Grade ≥3 toxicity occurred significantly more often with the thalidomide regimen (73% versus 58%, P=0.007), and an even larger difference existed with respect to nonhematologic toxicity (59% versus 40%, P=0.001). Second primary malignancies occurred in 9.5% of the MPT-T group and 5.3% of the MPR-R group. Quality-of-life assessment at the end of induction therapy showed a significant advantage in favor of MPR-R (P=0.007).

Invited discussant Robert Z. Orlowski, MD, PhD, of MD Anderson Cancer Center in Houston, began with a review of progress in treating myeloma over the past decade. In 2004 melphalan-prednisone was a standard regimen. In the subsequent 10 years, multiple agents and regimens have become available and improved disease management to the point that patients like those in Stewart's presentation now can expect a PFS comparable to what overall survival was in 2004.

Orlowski also cited some differences between the trial and earlier European studies that showed better results with MPR-R in newly diagnosed patients. The patients in the U.S. trial were older, and the trial had a higher discontinuation rate consistent with an older, "more brittle" patient population.

"This is where you can run into a little bit of a problem comparing U.S. versus European studies because the nontransplant patients are defined differently," said Orlowski. "Some European patients in the 65-to-75 age range are considered not eligible, whereas at least some of them are eligible for transplant here in the U.S."

Previous studies of thalidomide often did not include thalidomide maintenance, which could have led to improved performance in the current study, he continued. Additionally, better salvage regimens are available today, offering better treatment options for patients who progress on MPT or MPR.

As a final comment on the lack of difference between MPR-R and MPT-T, Orlowski cited a study presented at the 2013 American Society of Hematology meeting, showing that the combination of lenalidomide and dexamethasone led to better PFS and overall survival compared with MPT.

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