ORLANDO – Each of three bortezomib-based regimens was active as first-line therapy in elderly patients with multiple myeloma, and subsequent maintenance with bortezomib resulted in increases of very good partial responses or better in each trial arm, reported investigators from the phase IIIb UPFRONT study at the annual meeting of the American Society of Hematology.
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In the randomized community-based study, investigator-confirmed overall response rates after induction and maintenance were 71% with a bortezomib (Velcade)–dexamethasone combination (VD), 79% with bortezomib-thalidomide-dexamethasone (VTD), and 73% with bortezomib-melphalan-prednisone (VMP), reported Dr. Ruben Niesvizky of the New York Weill Cornell Medical Center in New York.
Progression-free survival did not differ significantly after a median 13.4 months’ follow-up. There appeared to be a trend favoring VTD, even though grade 3 or greater adverse events, peripheral neuropathies, and study discontinuations because of adverse events were highest with this regimen, the authors found.
"It is well understood that patients who are not candidates for stem cell transplant are indeed a challenge. ... At the time that this trial was designed, we had three major bortezomib-containing regimens, which were the best performing combinations," Dr. Niesvizky said.
The investigators enrolled patients with newly diagnosed multiple myeloma who were ineligible for high-dose therapy and stem cell transplant. Participants had to have a Karnofsky performance score of 50% or greater, as well as measurable disease requiring systemic therapy.
The trial randomly assigned them to eight cycles of induction therapy with VD, VTD, or VMP (100 patients in each group) followed by five additional cycles of bortezomib maintenance. Maintenance cycles were 35 days long, with bortezomib 1.6 mg/m2 given on days 1, 8, 15, and 22. The median age range was 72-73.5 years in the three arms.
The primary end point was progression-free survival. Secondary end points were efficacy of the various regimens, as well as their respective safety and tolerability.
During induction, patients in the VD group received 76% of planned doses of bortezomib, compared with 63% of patients in the VTD group and 69% of those in the VMP group. During maintenance, 73% in the VD group received the intended dose, compared with 77% of patients on VTD and 85% of those on VMP.
Investigator-assessed, best-confirmed rates in the response-evaluable population were very good partial response (VGPR) or better in 36% of those on VD induction and 39% after bortezomib maintenance; 44% of those on VTD induction and 47% after maintenance; and 40% on VMP induction, and 44% after maintenance.
At a median 13.4 months’ follow-up, median progression-free survival reached 13.8 months with VD, 18.4 months with VTD, and 17.3 months with VMP. There were no significant differences in any of the pairwise comparisons, although patients on VMP appeared to plateau beginning around 22 months and continuing out to 33 months, the longest follow-up thus far.
Grade 3 or greater adverse events occurred during induction in 69% of those on VD and in 78% each of patients on VTD and VMP. Grade 3 or greater peripheral neuropathy was reported in 15%, 24%, and 20% of patients, respectively, and neutropenia in 1%, 3%, and 21%.
Peripheral neuropathy was more common in the VTD arm, compared with either of the other arms, both before and after bortezomib maintenance.
Millennium Pharmaceuticals, maker of bortezomib, funded the study. Dr. Niesvizky disclosed serving as a consultant and receiving research funding from the company. Several coauthors also disclosed consulting, research support, or speakers bureau relationships with Millennium, and two were employees.