San Diego, CA—The value of maintenance therapy in patients with newly diagnosed multiple myeloma who are not eligible for stem-cell transplant (such as the elderly) is still debated. Studies presented at the American Society of Hematology 2011 annual meeting showed that maintenance therapy can delay disease progression, although an overall survival (OS) advantage is not yet evident.
Lenalidomide Maintenance Doubles PFS
The value of continuing lenalidomide therapy in elderly (median age, 71 years),
“What is really changing in the treatment paradigm is the concept of continuing treatment, moving from a fixed treatment to one incorporating continuous therapy….Continuous treatment adds about 10 months of remission duration in elderly patients. While no survival advantage has been shown, 3 years overall survival projected at 70% is certainly a good outcome,” Dr Palumbo noted.
MM-015 tested 3 treatment regimens. Two groups received induction therapy consisting of melphalan, prednisone, and lenalidomide (MPR): the first group (N = 152) received maintenance therapy with lenalidomide (MPR-R) on days 1 through 21 until progression; the second group (N = 153) received no continuous therapy after induction with MPR. A third group (N = 154) received only melphalan and prednisone (MP) as induction therapy and no maintenance.
Responses were significantly greater with the 3-drug combination, mainly in response to the effect of maintenance therapy, Dr Palumbo said.
Lenalidomide maintenance significantly extended progression-free survival (PFS), from 14 months with MPR and 13 months with MP to 31 months with MPR-R. “You get a doubling in PFS when you use continuous treatment,” he noted.
In a landmark analysis of all patients, continuous therapy with lenalidomide resulted in a 66% reduction in the risk of progression (P <.001). “The advantage of maintenance was present in all patients, independent of age, grade, prognosis, and so forth,” he said.
At a median follow-up of 41 months, however, no impact was yet seen on OS, which at 4 years was 59% with MPR-R and 58% with both MPR and MP. “But don’t forget that the average survival has been around 3 years,” Dr Palumbo pointed out.
Increase in Secondary Cancers
However, secondary cancers, although still rare, were observed in association with lenalidomide, especially hematologic malignancies, he reported. The incidence rates per 100 patient-years were 3.04 with MPR-R, 2.57 with MPR, and 0.98 with MP.
Dr Palumbo argued that the increased risk of secondary cancers was far outweighed by lenalidomide’s benefit in delaying progression, and he noted that there was the “impression” of predisposing factors at baseline. “The risk of progression is 10 to 15 times higher than the risk of dying of a second cancer,” he said.
The major toxicity was neutropenia, which was grade 4 in 30% of patients; grade 4 thrombocytopenia occurred in 5% of patients. Maintenance therapy, however, did not contribute to toxicity. “Even in the frail elderly, toxicity is acceptable,” Dr Palumbo said.
Bortezomib-based maintenance regimens also represent an attractive platform on which to optimize myeloma treatment, according to María-Victoria Mateos, MD, Hospital Clinico Universitario, Salamanca, Spain, who spoke on behalf of the Spanish Myeloma Group (GEM/Pethema).
Providing background, Dr Mateos noted, “Thalidomide maintenance has been shown to improve PFS in all trials, but the OS benefit is not as clear. Lenalidomide maintenance has been shown to double PFS but without an OS benefit. And maintenance with thalidomide plus bortezomib has been shown to significantly improve PFS, but no OS benefit has yet been seen.”
“So the rationale for maintenance therapy is to achieve the best response, maintain this response, and improve its quality, to achieve prolonged PFS, and finally, OS,” she said.
In the GEM2005MAS65 trial, 260 elderly patients (median age, 71 years) received induction therapy with bortezomib and MP (VMP) or with bortezomib, thalidomide, and prednisone (VTP), after which 178 received 1 of 2 possible maintenance regimens: bortezomib plus thalidomide (VT) or bortezomib plus prednisone (VP). They did not compare outcomes with those of patients who did not receive maintenance therapy.
Investigators previously reported no difference in the overall response rate between VMP (80%) and VTP (81%) and in the complete response rate (20% and 27%, respectively). The current study assessed whether maintenance therapy would upgrade the response rate, with a favorable toxicity profile, and confer a benefit in PFS and OS.
Maintenance therapy consisted of bortezomib 1.3 mg/m2 administered every 3 months plus thalidomide 50 mg daily and prednisone 50 mg every 2 days for as long as 3 years.
In the whole population, after a median of 20 months of maintenance, the rate of complete responses increased from 24% after induction to 42% after maintenance. The rate was slightly higher in the VT maintenance arm than in the VP arm (46% vs 39%, respectively), Dr Mateos reported.
At 46 months of follow-up, median PFS was slightly higher with VT—39 months versus 32 months with VP; this result was not influenced by the induction regimen, she said. OS has not been reached with VT maintenance; at 5 years 69% of patients in this arm were still alive versus 60% with VP; the median OS with VP was 60 months.
Only the 20% of patients with high-risk cytogenetics did not benefit from maintenance. Neither maintenance regimen could overcome the poor prognosis of this group, whose median PFS was 26 months and median OS was 50 months.
Toxicity was very low with maintenance therapy. VT was associated with a higher rate of peripheral neuropathy than VP (9% vs 3%, respectively); however, in all but 1 patient, the neuropathy was worsening, not emergent.