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Lenalidomide–dexamethasone extended PFS, OS in transplant-ineligible multiple myeloma
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Continuous lenalidomide plus low-dose dexamethasone significantly extended PFS compared with melphalan, prednisone and thalidomide in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, according to phase 3 study results.
Results of an interim analysis showed the combination of lenalidomide (Revlimid, Celgene) and dexamethasone also demonstrated a trend toward improved OS.
Lotfi Benboubker, MD, of Centre Hospitalier Régional Universitaire in Tours, France, and colleagues evaluated data from 1,623 patients. The analysis included patients aged 65 years or older, as well as patients aged younger than 65 years who were ineligible for stem-cell transplantation.
Researchers assigned 535 patients continuous lenalidomide–dexamethasone until disease progression; 541 patients to 18 cycles of the same combination; and 547 patients to melphalan (Alkeran, GlaxoSmithKline), prednisone and thalidomide (Thalomid, Celgene) for 18 cycles.
Patients received treatment for a median duration of 18.4 months in the continuous lenalidomide–dexamethasone arm; 16.6 months in the combination 18-cycle arm; and 15.4 months in the melphalan, prednisone and thalidomide (MPT) arm.
Median follow up for surviving patients was 37 months (range, 0-56.7).
Patients assigned continuous lenalidomide–dexamethasone experienced significantly longer PFS than those who received the combination for 18 cycles (25.5 months vs. 20.7 months; HR=0.7; 95% CI, 0.6-0.82). Researchers also observed significantly longer median PFS in the continuous lenalidomide–dexamethasone arm than the MPT arm (25.5 months vs. 21.2 months; HR=0.72; 95% CI, 0.61-0.85).
The risk for progression or death was comparable between patients who received 18 cycles of lenalidomide–dexamethasone and those who received MPT (HR=1.03; 95% CI, 0.89-1.2).
Results of an interim analysis indicated a greater proportion of patients who received continuous lenalidomide–dexamethasone achieved 4-year OS (59%) than patients assigned 18 cycles of the combination (56%) or those assigned MPT (51%). These differences did not meet the prespecified threshold for statistical significance; however, continuous lenalidomide–dexamethasone reduced the risk for death compared with MPT (HR=0.78; 95% CI, 0.64-0.96).
Fewer patients assigned continuous lenalidomide–dexamethasone compared with those assigned MPT experienced a grade 3 to grade 4 adverse event (89% vs. 85%).
More patients assigned MPT than continuous lenalidomide–dexamethasone experienced grade 3 to grade 4 neutropenia (45% vs. 28%) and second hematologic cancers (2% vs. ˂1%). However, more patients in the continuous lenalidomide–dexamethasone arm experienced a grade 3 to grade 4 infection (29% vs. 17%).
David Avigan
“Although additional follow-up is needed to fully assess the survival benefit with continuous lenalidomide-dexamethasone vs. 18 cycles of lenalidomide–dexamethasone, this trial provides substantial evidence that among patients with newly diagnosed multiple myeloma, those who are elderly or are ineligible for stem-cell transplantation may benefit from continuous therapy,” Benboubker and colleagues wrote.
Continuous treatment may be key to the advantage seen with lenalidomide–dexamethasone compared with MPT, David Avigan, MD, and Jacalyn Rosenblatt, MD, both of the hematologic malignancies and bone marrow transplantation program at Beth Israel Deaconess Medical Center, wrote in an accompanying editorial.
“Although the response was higher with both lenalidomide–dexamethasone regimens than with MPT, improved outcomes were noted only with continuous therapy,” Avigan and Rosenblatt wrote. “The study suggests that treatment until disease progression is preferable to suspending treatment after achieving a maximal response.”
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Disclosure: Rosenblatt reports grant support from Millennium outside the submitted work. See the study for a full list of the researchers’ relevant financial disclosures.
Perspective
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Saad Z. Usmani, MD
Management of transplant-ineligible, elderly patients with multiple myeloma remains a challenge despite the availability of novel drug classes beyond the traditional alkylator-steroid backbone. In the mid-2000s, several phase 3 trials compared melphalan–prednisone (MP) with or without a novel agent, such as thalidomide or bortezomib (Velcade, Millennium). As results from these trials emerged, the MP-plus-novel-agent combinations became a new standard of care for this group of patients in Europe. Interestingly, the ECOG E4A03 phase 3 trial was being conducted in the United States during the same time period, comparing lenalidomide plus low-dose dexamethasone (Rd) and lenalidomide plus high-dose dexamethasone (RD). Given its ease of administration (oral), overall good tolerability and access through the ECOG E4A03 trial, Rd became a popular regimen for newly diagnosed multiple myeloma. This was especially true for transplant-ineligible elderly patients, despite the paucity of comparative data to an MP or MP-based regimen. The FIRST trial by Benboubker and colleagues provides validity to the US practice pattern. It augments the Rd regimen’s claim as a safe and efficacious regimen. Although a longer follow-up is still needed for true impact on outcomes (median follow-up was 37 months), the trial provides strong support for the “treat-to-progression-or-intolerance” paradigm (continuous therapy) rather than the “treat-to-best-response” paradigm (fixed-duration therapy).Click Here to Manage Email Alerts