Further findings from two clinical studies of Revlimid maintenance thera­py were presented at the 14^th International Myeloma Workshop (IMW) in Kyoto, Japan, earlier this month.

Both studies involved newly diagnosed multiple myeloma patients who received maintenance therapy with Revlimid ^[1] (lenalidomide).

Results from both studies, which were published in the New England Journal of Medicine last May, indicate that Revlimid maintenance therapy significantly increases progression-free survival compared to a placebo (see related Beacon ^[2] news). One of the studies also found that Revlimid maintenance therapy improved overall survival of patients.

Both studies also found that patients who received Revlimid maintenance therapy were at an increased risk of developing secondary cancers, compared to patients who received a placebo.

At the IMW meeting, Dr. Philip McCarthy from the Roswell Park Cancer Institute presented updated results on the efficacy and long-term safety data from the so-called CALGB study.  He reported that patients receiv­ing Revlimid maintenance therapy following stem cell transplantation continue to have better progression-free and overall survival than patients receiving a placebo after transplantation.

Dr. Michel Delforge from the University Hospital in Leuven, Belgium, presented updated long-term safety data from the so-called MM-015 trial.  He reported that Revlimid maintenance therapy continues to be well tolerated by myeloma patients who are ineligible for stem cell transplantation. The latest results show that the rate of new or worsening severe side effects is low.

The updated data from both studies also show that the risk of developing sec­ond­ary cancers continues to be higher in patients receiving Revlimid main­te­nance therapy. However, both studies also show that the risk of pro­gres­sion and death is higher in patients receiving the placebo.

Based on these findings, Dr. Delforge concluded that the benefit-risk profile of Revlimid remains favorable and Dr. McCarthy suggested that the risk of secondary cancers should be evaluated within the context of the risk of disease progression.

Results of a third trial on Revlimid maintenance, the so called IFM trial, were also published in the New England Journal of Medicine last May. However, no updates about that trial were given at IMW.

CALGB Study

The CALGB study is a Phase 3 trial that recruited newly diagnosed patients under the age of 70 from centers across the United States between 2005 and 2009. All patients in this trial received a stem cell transplant following initial treatment.

The patients then received either 10 mg of Revlimid daily or a placebo as maintenance therapy.

In December 2009, an interim analysis showed that patients receiving Revlimid maintenance therapy had significantly better progression-free survival.  Patients in the placebo group were therefore given the option to start taking Revlimid maintenance therapy.

The median time to disease progression was 46 months for patients on Revlimid maintenance, compared to 27 months for those who received a placebo.

The results published last year showed that after a median follow-up of 34 months, fewer patients who received Revlimid maintenance therapy progressed or died compared to patients who received a placebo (37 percent versus 58 percent).

Revlimid maintenance therapy also improved overall survival. After a median follow-up time of 34 months, 85 percent of the patients receiving Revlimid maintenance therapy and 77 percent of the patients in the placebo group were still alive. The estimated three-year overall survival rate was higher for the Revlimid group (88 percent) than the placebo group (80 percent).

Overall, 8 percent of patients receiving Revlimid maintenance therapy experienced secondary cancers, com­pared to 3 percent of patients who received a placebo. Among the Revlimid maintenance group, 4 percent developed blood-related cancers and 4 percent developed solid tumors (excluding non-melanoma skin cancers).

CALGB Updated Efficacy And Safety Data

During his presentation at IMW, Dr. McCarthy reported that after a median follow-up time of 48 months, the median time to progression for patients who received Revlimid maintenance therapy remains longer than the median time to progression for patients in the placebo group (50 months versus 27 months, respectively).

In addition, overall survival continues to be better for patients receiving Revlimid maintenance therapy. The median overall survival has not been reached for patients receiving Revlimid maintenance therapy, com­pared to 73 months for patients receiving a placebo.

The most recent data also indicate that fewer patients who received Revlimid died, compared to patients who received a placebo (19 percent versus 34 percent).

Dr. McCarthy also pointed out that the rate of secondary cancers remains higher in patients who received Revlimid maintenance. Overall, 13 percent of patients who received Revlimid developed a secondary cancer, of which 5 percent developed blood cancers, 5 percent developed solid tumors, and 3 percent developed skin cancers.

Of the patients who received a placebo, 4 percent developed secondary cancers.

Despite the increased risk of second cancers, the results showed that patients who received Revlimid maintenance therapy had significantly longer median time to progression, secondary cancer, or death (47 months versus 27 months, respectively).

Dr. McCarthy stated that further analysis of the CALGB data will focus on identifying any potential associa­tions between genetic changes, side effects, and outcomes as well as evaluating risk factors associated with second cancers.

MM-015

The second study, known as the MM-015 study, was conducted in Europe, Australia, and Israel. Patients who were at least 65 years of age and transplant ineligible were recruited for the study from February 2007 until September 2008.

Patients were divided into three treatment groups.

The first group received treatment with melphalan ^[11] (Alkeran), prednisone ^[12], and a placebo as an initial therapy (MP). These patients subsequently received another placebo as maintenance therapy.

The second group received initial treatment with melphalan, prednisone, and Revlimid, followed by a pla­cebo as maintenance therapy (MPR).

The final group received the same initial treatment as the second group, but also received Revlimid as maintenance therapy (MPR-R).

The results published last May showed that the median progression-free survival was significantly longer for patients in the MPR-R group (31 months), compared to patients in the MPR group (14 months) and the MP group (13 months).

However, unlike the CALGB trial, this study did not show that Revlimid maintenance significantly improved overall survival.

The rate of secondary cancers at three years was 7 percent for patients receiving MPR-R, 7 percent for patients receiving MPR, and 3 percent for patients receiving MP.

MM-015 Updated Safety Data

In his presentation at IMW, Dr. Delforge focused on the long-term safety of Revlimid maintenance therapy.

He described the safety profile of continuous Revlimid maintenance therapy as predictable and manage­able.

He reported that after a median follow-up of 53 months, few new or worsening severe side effects were observed during Revlimid maintenance therapy. The most common were blood-related and included low platelet counts (9 percent), low red blood cell counts (8 percent), and low white blood cell counts (7 percent).

Overall, 18 percent of the patients discontinued treatment due to side effects.

The rate of secondary cancers continues to be higher in patients receiving Revlimid: 11 percent for patients receiving MPR-R, 11 percent for patients receiving MPR, and 8 percent for patients receiving MP.

During the maintenance phase of the study, more patients in the MPR-R group developed secondary can­cers (11 percent), compared to patients in the MPR group (3 percent) and MP group (2 percent). The majority of secondary cancers in the MPR-R group were blood-related cancers, such as acute myeloid leukemia.

According to Dr. Delforge, the four-year probability of developing a second cancer was 13 percent for patients receiving MPR-R, 10 percent for patients receiving MPR, and 4 percent for patients receiving MP.

The four-year probability of disease progression or death, on the other hand, was significantly lower for patients receiving MPR-R (70 percent), compared to patients receiving MPR (93 percent) and patients receiving MP (95 percent).

For more information, please see Dr. McCarthy’s ^[13] and Dr. Delforge’s ^[14] presentation slides, which they have made available for download and viewing as a courtesy to The Beacon’s readers.