One of the key presentations during the recent American Society of Hematology (ASH) annual meeting in New Orleans was one that summarized initial results of a large international Phase 3 clinical trial known as the "FIRST", or MM-020, trial.

The trial results show that continuous administration of Revlimid and dex­a­meth­a­sone improves response rates as well as progression-free and overall survival in newly diagnosed multiple myeloma patients who are older or not eligible for stem cell transplantation.

Specifically, the researchers found that the overall response rate was highest (75 percent) among patients who received treatment with Revlimid ^[1] (lenalidomide) and dex­a­meth­a­sone ^[2] (Decadron) continuously until disease progression, compared to patients who received Revlimid-dex­a­meth­a­sone for a fixed period of 72 weeks (72 percent), and compared to those who received melphalan ^[3] (Alkeran) plus prednisone ^[4] and thalidomide ^[5] (Thalomid) for a fixed 72 weeks (62 percent).

The median progression-free survival was significantly longer for patients who received continuous Revlimid plus dex­a­meth­a­sone (26 months) than those who received Revlimid plus dex­a­meth­a­sone for 72 weeks (21 months) and those who received melphalan plus prednisone and thalidomide (21 months).

In addition, the four-year overall survival was highest for patients who received continuous Revlimid-dex­a­meth­a­sone (59 percent), compared to those who received Revlimid-dex­a­meth­a­sone for 72 weeks (56 percent) and those who received melphalan plus prednisone and thalidomide (51 percent).

Dr. Thierry Facon from the Hospital Claude Huriez in Lille, France, presented the trial results during the plenary session at the ASH meeting. Presentations given during that session are considered particularly note­worthy.

The results of this trial are important because they are expected to lead to official approval of Revlimid as a frontline myeloma treatement.  This, in turn, will allow greater use of the drug for newly diagnosed patients in Europe and other countries where physicians often can only prescribe medications for their approved uses.

In addition, as was pointed out by Dr. Vincent Rajkumar from the Mayo Clinic in his recent column ^[6] for The Beacon, the results of the trial are important because they demonstrate that a "well-tolerated doublet" (two-drug regimen) can prolong survival in older myeloma patients.  The results also lend support, Dr. Rajkumar wrote, for ongoing research into a number of different treatment regimens that use the Revlimid-dex­a­meth­a­sone combination as their basis.

Background

The combination of melphalan plus prednisone and thalidomide is currently approved, and used regularly, in Europe and other parts of the world for the treatment of newly diagnosed multiple myeloma patients who are not candidates for stem cell transplantation.

Revlimid, alone or in combination with other anti-myeloma agents, is often used for the treatment of newly diagnosed patients in the United States.  This is not the case, however, in most other countries, because Revlimid is not officially approved for newly diagnosed myeloma anywhere in the world.

The lack of an official approval for newly diagnosed myeloma creates a substantial barrier to Revlimid's use outside the U.S.  Physicians in many European countries, for example, cannot prescribe a drug outside of a clinical trial for uses other than those that are officially approved.

This is less the case in the U.S., where "off-label" prescribing is legally permitted and widely practiced -- particularly in oncology.

Study Design

The international Phase 3 "MM-020" study – also known as the Frontline Investigation Of Lenalidomide + Dexamethasone Versus Standard Thalidomide ("FIRST") trial – compared the efficacy and safety of Revlimid and dex­a­meth­a­sone to that of melphalan plus prednisone and thalidomide in newly diagnosed multiple myeloma patients who were 65 years and older or not eligible for stem cell transplantation.

The study included 1,623 newly diagnosed multiple myeloma patients from 18 countries.  More than a quarter of the patients were from France, with Canada and Italy together accounting for another quarter of the trial participants.  Less than 4 percent of the patients were from the United States.

The median patient age was 73 years.

Patients were divided into one of three treatment groups.

One third of the patients received 25 mg of Revlimid on days 1 to 21 plus 40 mg of dex­a­meth­a­sone on days 1, 8, 15, and 22 of a 28-day treatment cycle until disease progression.

Another third of patients received the same Revlimid plus dex­a­meth­a­sone dosing schedule for 72 weeks.

The remaining third received 0.25 mg/kg of melphalan on days 1 to 4 plus 2 mg/kg of prednisone on days 1 to 4 and 200 mg of thalidomide on days 1 to 42 of a 42-day treatment cycle for 72 weeks.

Study Results

Response Rates And Survival

The results show that more patients achieved a partial response or better to continuous treatment with Revlimid plus dex­a­meth­a­sone (75 percent) than 72 weeks of Revlimid plus dex­a­meth­a­sone (73 percent) or melphalan plus prednisone and thalidomide (62 percent).

In addition, patients treated with Revlimid plus dex­a­meth­a­sone achieved deeper responses.

Among those treated with Revlimid-dex­a­meth­a­sone continuously, 15 percent achieved a complete re­sponse and 28 percent a very good partial response.  Similarly, 14 percent of those treated with Revlimid-dex­a­meth­a­sone for 72 weeks achieved a complete response and 29 percent achieved a very good partial response.

In comparison, 9 percent of those treated with melphalan plus prednisone and thalidomide achieved a complete response and 19 percent achieved a very good partial response.

The median progression-free survival was significantly longer for those who received continuous Revlimid plus dex­a­meth­a­sone (26 months) than for those who received Revlimid plus dex­a­meth­a­sone for 72 weeks (21 months) and those who received melphalan, prednisone, and thalidomide (21 months).  The differences in progression-free survival became apparent right at the 72-week mark, when two of the groups dis­con­tinued treatment.

Likewise, the four-year overall survival was longest for those who received continuous Revlimid plus dex­a­meth­a­sone (59 percent), compared to those who received Revlimid plus dex­a­meth­a­sone for 72 weeks (56 percent) and those who received melphalan, prednisone, and thalidomide (51 percent).  The difference was statistically significant for continuous Revlimid plus dex­a­meth­a­sone compared to melphalan, prednisone, and thalidomide.

Continuous Revlimid-dex­a­meth­a­sone therapy also seemed to improve progression-free survival versus treatment with melphalan, prednisone, and thalidomide therapy across a wide range of patient subgroups.  The improvement was still seen, for example, in patients above the age of 75, in patients with limited kidney function, and in patients whose disease at diagnosis was at a more advanced stage.

There was, however, one exception.  Melphalan-prednisone-thalidomide therapy offered somewhat better progression-free survival that continuous Revlimid-dex­a­meth­a­sone treatment in patients with high-risk chromosomal abnormalities (t(4;14), t(14;16), or del(17p)).  This difference, however, was not statistically significant.

Side Effects, Including Secondary Cancers

According to Dr. Facon, the side effects of both the Revlimid-dex­a­meth­a­sone and the melphalan-prednisone-thalidomide combinations were as expected and manageable.

The most common side effects of continuous Revlimid-dex­a­meth­a­sone included infections (29 percent), low white blood cell counts (28 percent), and low red blood cell counts (18 percent).

The most common side effects of the melphalan-prednisone-thalidomide combination included low white blood cell counts (45 percent), low red blood cell counts (19 percent), and infections (17 percent).

The overall rate of secondary cancers ^[7] was lower in patients who received continuous Revlimid-dex­a­meth­a­sone (7.0 percent) than in patients receiving Revlimid-dex­a­meth­a­sone for 72 weeks (8.1 percent) and those receiving melphalan-prednisone-thalidomide for 72 weeks (8.7 percent).

There was a noticeable difference, however, in the rate of blood-related secondary cancers across the patient groups.  Blood-related secondary cancers such as leukemia were more likely to occur in the patients treated with melphalan, prednisone, and thalidomide (2.2 percent) than in those treated with Revlimid and dex­a­meth­a­sone (0.4 percent in both those groups).

For more information, please see ASH abstract 2 ^[8].  Also, slides from Dr. Facon's presentation are available on pages 6 through 24 of this investor relations slide deck ^[9] from Celgene, the company that markets Revlimid in the U.S. and elsewhere in the world, and which sponsored the FIRST trial.

For additional ASH-related information, please see the ASH 2013 Myeloma Gateway ^[10].