Maintenance Strategies in Elderly Patients with Myeloma Not Eligible for Transplant

Lenalidomide and Bortezomib Both Prolonged Remission
February 2012 Vol 5, No 1, Special Issue - Multiple Myeloma, Multiple Myeloma

The value of continuous, or maintenance, therapy in pa­tients newly diagnosed with multiple myeloma who are not eligible for stem-cell transplant (such as the elderly) is still debated. Studies presented at ASH 2011 showed that maintenance therapy can delay disease progression, although an overall survival (OS) advantage is not yet evident.

Lenalidomide Extends PFS, Increases Secondary Cancers
The final results of the phase 3 MM-015 trial that investigated the value of lenalidomide in elderly, transplant-ineligible patients, median age 71 years, were presented by Antonio Palumbo, MD, University of Torino, Italy.

“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. Although no survival advantage has been shown, 3 years of OS projected at 70% is certainly a good outcome,” said Dr Palumbo.

MM-015 tested 3 treatment regimens. Two groups received induction therapy consisting of melphalan, prednisone, and lenalidomide (MPR); half (N = 152) of this group was placed on maintenance therapy with lenalidomide (MPR-R), given on days 1 to 21 until progression; the other half received no continuous therapy (MPR); the third group (N = 154) received only melphalan and prednisone (MP) as induction therapy and no maintenance.

Patient responses were significantly greater with the 3-drug combination. “For induction, a 3-drug combination significantly increases response rates, so MPR is better than MP when toxicity is not a problem,” Dr Palumbo said. “But maintenance therapy provides the major difference.”

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, lenalidomide continuous therapy resulted in a 66% reduction in the risk of progression (P <.001). A significant treatment benefit was observed in all subgroups of age, response, and stage. Patients aged ≥75 years had slightly lower benefit, probably because more discontinued treatment and frail patients received less dose intensity.

“The advantage of maintenance is present in all patients, independent of age, grade, prognosis, and so forth,” Dr Palumbo said.
At a median follow-up of 41 months, however, no impact was yet seen on OS, which at 4 years was 59% for MPR-R, 58% for MPR, and 58% for MP as well. “But don’t forget that the average survival has been around 3 years,” he emphasized. A trend toward a survival benefit was observed in the 65- to 75-year-old age-group.

Secondary cancers, although still rare, were observed in association with lenalidomide, especially hematologic malignancies. There were 12 cases of cancer among patients receiving maintenance lenalidomide, and 10 among patients receiving lenalidomide alone in the induction regimen, compared with only 4 among patients who received MP only.

Dr Palumbo argued, however, that the increased risk of second cancers was far outweighed by lenalidomide’s benefit in delaying progression. “There is a 75% to 80% risk of progression, but less than a 5% risk of second primary malignancies,” he said. This was echoed by many specialists at the meeting.

The major toxicities were grade 4 neutropenia in 30% of patients and grade 4 thrombocytopenia in 5% of patients. “But as far as maintenance is concerned, thrombocytopenia and neutropenia rates were very rare. Even in the frail elderly, toxicity is acceptable,” he said.

Bortezomib-Based Maintenance, Low Toxicity
Bortezomib-based maintenance reg­imens also represent an attractive strategy to optimize myeloma treatment, reported Maria-Victoria Mateos, MD, PhD, of the Hospital Clinico Universitario in Salamanca, Spain, on behalf of the Spanish Myeloma Group (GEM/Pethema).

In the GEM2005MAS65 trial, 260 elderly patients (median age, 71 years) received induction therapy with bortezomib, melphalan, and prednisone (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).  

Maintenance therapy included bortezomib 1.3 mg/m2 administered every 3 months plus thalidomide 50 mg/day and prednisone 50 mg every 2 days up to 3 years.

The study did not evaluate outcomes in patients who did not receive maintenance.

Response rates were similar between the regimens: 80% with VMP and 81% with VTP. The current study assessed whether maintenance therapy would upgrade these responses, with a favorable toxicity profile, and might confer a benefit in terms of PFS and OS.

In the whole population, after a median of 20 months of maintenance, the rate of complete response (CR) increased from 24% after induction therapy to 42% after maintenance. After induction, CR rates were similar between VMP and VTP, but slightly more additional CRs were achieved in the VT maintenance arm (46% vs 39%).

At 46-month follow-up, median PFS was slightly higher with VT (39 months vs 32 months with VP), and this was not influenced by the induction regimen. OS has not been reached with VT maintenance, with 69% of patients being alive at 5 years, and 60% alive with VP.

In the 20% of patients with high-risk cytogenetics, neither maintenance regimen could overcome the poor prognosis. Median PFS was 26 months and median OS was 50 months, with no differences seen between the regimens.

“Toxicity was very low with maintenance,” Dr Mateos said. VT was associated with more peripheral neuropathy (9% vs 3%), but in all but 1 patient this was worsening, not emergent, neuropathy.

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