Maintenance Therapy with Lenalidomide Doubled Remission Time

VBCM - Meeting Highlights - ASH 2010

Young patients with multiple myeloma (MM) often receive high-dose therapy with autologous stem-cell transplantation (ASCT). Residual disease inevitably leads to relapse, and a research aim has been to determine ways to prevent this. In 2 phase 3 studies, maintenance therapy with lenalidomide resulted in a doubling of the time to disease progression.

CALGB 100104
Updated results of the CALGB 100104 trial, now with 18 months’ follow-up on 460 patients, were presented by Philip L. McCarthy, MD, Roswell Park Cancer Institute, Buffalo, NY. The study team randomized 570 patients to lenalidomide (10 mg/day, with dose reduction or titration allowed) or placebo after ASCT (and a variety of induction regimens).

Time to disease progression (or death) was significantly better in the maintenance arm (42.3 months) compared with placebo (21.8 months), although overall survival (OS) remained similar. The lack of difference may be because most placebo recipients were allowed to receive lenalidomide when the study was unblinded. Of 100 placebo-treated patients, 86 started treatment with lenalidomide when the trial was unblinded.

Of 211 lenalidomide-treated patients, 46 had disease progression or died compared with 95 of the 229 placebo recipients (P <.001). This yielded a 60% reduction in the risk of progression with lenalidomide maintenance, Dr McCarthy reported.

Lenalidomide prolonged time to progression or death in patients with high and low beta-2-microglobulin levels (indicating disease risk) and in patients with previous thalidomide or lenalidomide induction therapy.

No significant OS advantage has been observed, although a trend favored maintenance, with 13 deaths in the lenalidomide arm and 24 in the placebo arm (P <.052).

“Some hematologic toxicity was observed, but it was not severe,” he noted. In the lenalidomide arm, grade 3 hematologic events were observed in 31% of patients versus 7% with placebo, and grade 4 events occurred in 14% versus 4%, respectively (P <.001).

IFM 2005-02 Supports Maintenance Lenalidomide
Updated analysis of the IFM 2005-02 trial, reported by Michel Attal, MD, Hospital Purpan, Toulouse, France, also supported lenalidomide maintenance in patients with MM.

The study included 614 patients aged < 65 years who were randomized post-ASCT to receive consolidation with lenalidomide (25 mg/d, 21 days/month, for 2 months) followed by maintenance with either lenalidomide (10-15 mg/d) or placebo until relapse. After the first preplanned interim analysis, with a median follow-up of 24 months, the study was unblinded because of the superiority of the lenalidomide arm. The final analysis was performed with a median follow-up of 34 months from randomization.

Consolidation with lenalidomide improved the very good partial response rate, and maintenance with the drug improved progression-free survival (PFS). Median PFS was 24 months with placebo and 42 months with lenalidomide, for a very significant 50% reduction in risk of disease progression.

“There was about a 50% reduction in the risk of progression in all subgroups,” he said. “Today, deaths have only been observed in the high-risk patients. Maintenance treatment with lenalidomide was not associated with resistance of the disease at time of progression. The median interval between progression and death was similar in both arms at 12 months,” Dr Attal said. “With the current follow-up, the 5-year postdiagnosis overall survival remains extremely high (81%) and similar in the 2 treatment groups.”

Maintenance treatment with lenalidomide was well tolerated, with treatment interruptions no higher in the active arm.

Concerns Over Second Malignancies
Attendees at ASH 2010 welcomed the findings of prolonged remission with lenalidomide maintenance, but some specialists expressed concern over the finding of an excess number of new malignancies in the lenalidomide arms of the CALGB and IFM trials.

In the CALGB study, 25 new malignancies were reported—3 in the lenalidomide group (1 in a patient treated for breast cancer) and 2 in the placebo arm. A total of 15 malignancies occurred among the 231 patients receiving lenalidomide and 6 among the 229 receiving placebo. The exact types of cancers were not detailed, except for cases of acute myeloid leukemia/myelodysplastic syndrome (AML/MDS).

In the IFM trial, hematologic malignancies have been diagnosed in 10 patients receiving lenalidomide versus 2 receiving placebo; nonhematologic cancers have been diagnosed in 6 patients versus 1 patient, respectively.

Remarking on the CALGB results, Dr McCarthy said, “We don’t know how these patients were treated. We know they all got a big dose of the alkylating agent, but we cannot say anything specific. We will have to see if this holds up as something significant.”

Thierry Facon, MD, of the Hospital C. Huriez, Lille, France, pointed out that the numbers of malignancies are very small and that AML/MDS has long been observed in MM.

In a December 6, 2010, report on this topic (www.reuters.com/article/2010/ 12/06/celgene-idUSN062081432010 1206), Brian Gill, a spokesman for Celgene (lenalidomide maker) said it is known that about 8% of patients with MM who are alive after 2 years are at risk for developing a second cancer, and induction therapy greatly increases this risk. He maintained that the occurrence seen in these studies falls within the expected range.

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Last modified: May 20, 2015
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