Results of several studies investigating Revlimid main­te­nance ther­a­py for mul­ti­ple myeloma will be presented at this year’s American Society of Hema­tol­ogy (ASH) annual meeting, which starts later this week.

Today’s article previews the results of the key Revlimid main­te­nance studies that will be presented at the meeting, drawing on findings pub­lished in the meeting abstracts.  Some of the study results, it should be noted, will be updated during the presentations at ASH this week and early next week.

The results to be presented at ASH are unlikely to settle the ongoing debate about the role of Revlimid main­te­nance ther­a­py in the treatment of multiple myeloma.

The debate was spurred by diverging results from three major clinical trials investigating the potential bene­fit of Revlimid main­te­nance ther­a­py (see related Beacon news).

All three trials found that main­te­nance ther­a­py with Revlimid increases pro­gres­sion-free survival.  However, only one of the three studies found that Revlimid main­te­nance leads to longer overall survival.

Updates will be presented at the ASH meeting for the two studies that did not show an overall survival ben­e­fit for Revlimid main­te­nance -- the French IFM 2005-02 trial and the European MM-015 trial.  Both of these studies continue to show no overall survival benefit to Revlimid main­te­nance.  (An update regarding the third study, the U.S. CALGB 100104 trial, was presented at the International Myeloma Workshop earlier this year; see related Beacon news.)

There also will be an update at the ASH meeting about a newer study that likewise is investigating Revlimid main­te­nance ther­a­py.   Thus far, this Italian and Israeli study has found that Revlimid main­te­nance provides both a pro­gres­sion-free and overall survival benefit.

Several of the ASH studies related to Revlimid main­te­nance ther­a­py also provide insights rele­vant to dis­cus­sions about the role of stem cell trans­planta­tion in the treatment of multiple myeloma.  In three of the studies discussed below, stem cell trans­planta­tion as consolidation ther­a­py improved outcomes compared to in­ten­sive, Revlimid-based consolidation ther­a­pies.  However, side effects also were typically more common among patients who underwent stem cell trans­planta­tion in these studies.

In addition, one of the studies summarized below may draw attention to the possibility of using prednisone together with Revlimid during main­te­nance ther­a­py.  The study shows that the addition of prednisone to Revlimid main­te­nance ther­a­py improved pro­gres­sion-free survival versus main­te­nance with Revlimid alone, without increasing side effects.  Results from a separate study to be presented at ASH (abstract) also may shed light on the impact of adding prednisone to Revlimid main­te­nance ther­a­py; however, maintenance ther­a­py-related results for that study are not yet available.

Revlimid Maintenance After Stem Cell Transplantation: Follow-Up Analysis From The IFM 2005-02 Trial

Perhaps the most important Revlimid main­te­nance presentation to be made at this year's ASH meeting will be an updated analysis of the French IFM 2005-02 trial (abstract). The Phase 3 trial investigated the efficacy of Revlimid (lenalidomide) main­te­nance ther­a­py after stem cell trans­planta­tion in 614 newly diagnosed multiple myeloma patients.

After initial treatment and stem cell trans­planta­tion, half of the patients received Revlimid as daily main­te­nance ther­a­py, while the other half received a placebo until disease pro­gres­sion or onset of severe side effects.

As of May 2013, the median follow-up time was 70 months from diagnosis.

The five-year pro­gres­sion-free survival rate was significantly higher for patients receiving Revlimid main­te­nance (42 percent) than for patients who received a placebo (18 percent).

However, patients receiving Revlimid main­te­nance ther­a­py had shorter second pro­gres­sion-free survival – time from pro­gres­sion after first-line ther­a­py to pro­gres­sion after second-line ther­a­py or death.

Specifically, the median second pro­gres­sion-free survival time was 10 months for patients receiving Rev­li­mid main­te­nance ther­a­py, compared to 18 months for patients who received a placebo.

The five-year overall survival rates were similar for the Revlimid main­te­nance ther­a­py group (68 percent) and the placebo group (67 percent).

The investigators calculated that 2.3 percent of patients receiving Revlimid main­te­nance ther­a­py developed a second cancer each year, compared to the 1.3 percent of patients who received a placebo.

Revlimid Maintenance After Induction Therapy For Older Patients: Updated MM-015 Results

An updated analysis of the European MM-015 trial will also be presented at ASH (abstract). The Phase 3 trial investigated treatment of 459 older newly diagnosed myeloma patients with Revlimid, melphalan (Alkeran), and prednisone as initial ther­a­py followed by Revlimid main­te­nance ther­a­py.

Study participants received one of three treatment regimens.

The first group received initial treatment with melphalan, prednisone, and a placebo and then main­te­nance ther­a­py with another placebo (this regimen is referred to as MP). 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).

Results published last year 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) (see related Beacon news).

The study investigators also looked at a measure of pro­gres­sion-free survival known as "PFS2," which measures the time from when a patient enters the trial to when the patient experiences a second pro­gres­sion.  (This is different, it should be noted, from the "second pro­gres­sion-free survival" discussed in the results of the IFM trial; that measure of pro­gres­sion-free survival is the time from first pro­gres­sion to second pro­gres­sion.)

Results from the current analysis show that median PFS2 was also significantly higher for patients treated with MPR-R (40 months) than for patients treated with MP (29 months). PFS2 for the MPR group was not significantly different than either of the other two groups, but most closely resembled that of the MP group.

However, the trial results did not show that Revlimid main­te­nance ther­a­py significantly improved overall survival. After a median follow-up time of 53 months, the median overall survival was 54 months for the MPR-R group, 52 months for the MPR group, and 55 months for the MP group.

The rate of second cancers was 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.

Revlimid-Melphalan-Prednisone Versus Stem Cell Transplantation Consolidation Therapy Followed By Revlimid Versus No Maintenance Therapy For Young Newly Diagnosed Multiple Myeloma Patients

Researchers will also present results from an Italian and Israeli trial comparing different consolidation and main­te­nance ther­a­pies for 402 young newly diagnosed multiple myeloma patients (abstract).

Initial results of this trial were presented at the American Society of Clinical Oncology annual meeting this summer (see related presentation slide deck, courtesy of Dr. Antonio Palumbo).  At the time, concerns were raised by some myeloma experts about whether the study's design permits meaningful conclusions to be drawn from the study results (see related Beacon news, specifically the discussion of "Stem Cell Trans­plan­ta­tion And Maintenance Therapy").

After initial ther­a­py with Revlimid and dexamethasone, half of the patients in the Italian and Israeli study received consolidation ther­a­py with melphalan, prednisone, and Revlimid (MPR), while the other half received consolidation with two autologous (own) stem cell trans­plants spaced four months apart.

After consolidation ther­a­py, half of the patients in the MPR group and half of the patients in the trans­plant group received Revlimid main­te­nance ther­a­py, while the other half did not receive main­te­nance ther­a­py.

Among patients who received stem cell trans­planta­tion as consolidation ther­a­py, 19 percent achieved a complete response and 33 percent a very good partial response.  Among those who received MPR as consolidation, 13 percent achieved a complete response and 37 percent a very good response.

After main­te­nance ther­a­py, the complete response rate for the trans­plant group improved to 25 percent and the complete response rate for the MPR group improved to 17 percent.

After a median follow-up of 48 months, the median pro­gres­sion-free survival time was greater for patients who underwent stem cell trans­planta­tion (39 months) than for those who received MPR consolidation ther­a­py (24 months).

Median pro­gres­sion-free survival was also greater for patients who received Revlimid main­te­nance ther­a­py (43 months from the start of main­te­nance), compared to no main­te­nance ther­a­py (18 months).

Overall survival was similar for the two consolidation groups, with the five-year overall survival rate being 71 percent for patients undergoing stem cell trans­planta­tion and 62 percent for patients receiving MPR.

However, overall survival from the start of main­te­nance was higher in patients who received Revlimid main­te­nance (80 percent four-year overall survival rate) than in patients who did not (62 percent).

Among patients receiving Revlimid main­te­nance, 8 percent of those in the trans­plant group and 2 percent of those in the MPR group developed second cancers. Among patients not receiving main­te­nance ther­a­py, 6 percent of those in the trans­plant group and 6 percent of those in the MPR group developed second cancers.

Revlimid-Cyclophosphamide-Dexamethasone Versus Stem Cell Transplantation Consolidation Therapy Followed By Revlimid-Prednisone Versus Revlimid Maintenance Therapy For Young Newly Diagnosed Myeloma

Another trial comparing consolidation and main­te­nance ther­a­py options for young newly diagnosed myeloma patients will be presented at ASH (abstract).

The Italian Phase 3 study included 389 newly diagnosed myeloma patients under the age of 65 years.

After initial ther­a­py, half of the patients received consolidation ther­a­py with Revlimid, cyclo­phos­pha­mide (Cytoxan), and dexamethasone (Decadron) treatment (RCD), while the other half received consolidation with stem cell trans­planta­tion.

After consolidation ther­a­py, half of the patients in each of the consolidation groups received main­te­nance ther­a­py with Revlimid and prednisone (RP), while the other half received main­te­nance ther­a­py with Revlimid alone.

Among patients who underwent stem cell trans­planta­tion, the two-year pro­gres­sion-free survival from the start of main­te­nance was 83 percent for patients in the RP group and 64 percent for those in the Revlimid group. Among patients who received RCD consolidation ther­a­py, the two-year pro­gres­sion-free survival from the start of main­te­nance was 64 percent for patients in the RP group and 47 percent for those in the Revlimid group.  However, none of the differences in overall survival were statistically significant.

The rates of severe to life-threatening side effects were higher among patients undergoing stem cell trans­planta­tion than among those receiving RCD, but they were similar in both the RP and Revlimid main­te­nance groups.

At the time of analysis, 2 percent of patients developed second cancers, but the abstract does not specify which anti-myeloma treatments these patients received.

Minimal Residual Disease Monitoring During Revlimid Maintenance Therapy

Researchers at the ASH meeting also will present results of a study looking at minimal residual disease monitoring during Revlimid main­te­nance ther­a­py (abstract).

The study included 50 newly diagnosed myeloma patients who underwent initial and consolidation ther­a­pies similar to those in the previously described study.

Specifically, all patients received initial ther­a­py with four cycles of Revlimid and dexamethasone.

After initial ther­a­py, half of the patients received consolidation ther­a­py with Revlimid, cyclo­phos­pha­mide, and dexamethasone (RCD), while the other half received consolidation with stem cell trans­planta­tion.  Patients had to achieve at least a very good response to their consolidation therapy to be included in the analysis discussed below.

After their consolidation ther­a­py, all patients received maintenance with either Revlimid alone or Revlimid with dexamethasone.  (Patients and physicians apparently could choose which of these two maintenance regimens they wished to use; the study was not intended to compare one versus the other.)

Bone marrow samples were collected at diagnosis, after consolidation, after three and six courses of main­te­nance ther­a­py, and every six months until clinical signs of relapse. The samples were tested for presence of minimal residual disease, measured by the amount of cancerous plasma cells in the bone marrow.

The researchers found that after consolidation ther­a­py, minimal residual disease was not detected in 40 percent of patients, including 52 percent of patients who underwent stem cell trans­planta­tion and 28 percent of those who received RCD.

Among patients who received RCD consolidation ther­a­py, the investigators observed that main­te­nance ther­a­py further increased their quality of response, with the number of residual plasma cells decreasing during main­te­nance ther­a­py.

After an average of 26 months following the start of ther­a­py, 18 percent of patients clinically relapsed. In all of these patients, clinical relapse was preceded by a significant increase in minimal residual disease.

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For information about additional studies that will be presented at ASH, see a list of all myeloma-related ASH abstracts, all abstracts about main­te­nance ther­a­py for myeloma, and other articles in the Beacon's ASH 2013 multiple myeloma preview series.