Several investment bank reports published this week have heightened concern about a potential link between Revlimid and second cancers in multiple myeloma patients.  The reports have unnerved investors to such a degree that the stock of Celgene, Revlimid’s manufacturer, is down almost nine percent since the middle of last week.

Apprehension about Revlimid (lenalidomide) and secondary cancer first surfaced in December during the American Society of Hematology (ASH) annual meeting.  At the meeting, results were presented from three trials studying long-term Revlimid use.  All three trials showed more cases of second cancers in the Revlimid arms as compared to the placebo arms.

In a conference call last week with Wall Street analysts, Celgene executives reported that, since December, the company has carried out several in-depth analyses of Revlimid patient data.  All the analyses indicate that patients taking Revlimid are not at a higher-than-expected risk of developing second cancers.

Celgene also announced during the conference call, however, that Revlimid maintenance therapy might be discontinued in the French IFM 2005-02 trial to allow researchers to analyze  subsets of the participants and to test re-treatment of patients who relapsed.  The IFM trial is one of the three trials that sparked concern about a potential Revlimid cancer link at the December ASH meeting.

It was additional information about the IFM trial that rang alarm bells on Wall Street this week.  The new information is just as important, however, for myeloma patients and physicians who treat multiple myeloma.

On Wednesday, a Merrill Lynch report described information the investment bank received from “a leader within the IFM cooperative.”  The report said that, of the 20 second cancers observed among patients in the Revlimid maintenance arm of the IFM trial, five “were of an unexpected type rarely observed in this disease setting (3 Hodgkin’s lymphoma / 2 acute lymphocytic leukemia), and all five were observed after 24 months of treatment” with Revlimid.

Merrill Lynch also was told by the investigator it interviewed that the IFM decided to stop Revlimid dosing in its trial because the group believes “the rare cancers were linked to Revlimid exposure, and that it is prudent to discontinue remaining patients in the study" since they all have received at least two years of Revlimid therapy.

Many of the points made in the Merrill Lynch report were expanded upon and supplemented by additional information released on Thursday in a report by Bernstein Research’s Geoffrey Porges.

Based on interviews with IFM researchers, Porges confirmed that the group has decided to discontinue Revlimid treatment in the trial.  “The IFM believes that [the risk of second cancers] increases with increased duration of exposure to Revlimid, and for that reason is instructing all investigators with patients still taking Revlimid to stop dosing.”

Porges went on to write, “Further analysis of the IFM study suggests that the rate of [second] malignancies was comparable to that in the control arm in the first 24 months of [Revlimid] treatment and only started to increase disproportionally at the end of the study.”  These conclusions were drawn by IFM investigators after thorough follow-up with the physicians who treated patients in the control arm of the trial.  The follow-up was done to ensure the IFM has complete information about the frequency of second cancer in both the Revlimid and control arms of the trial.

In the IFM trial, 307 patients were in the Revlimid maintenance arm, and 20 of those patients developed second cancers.  The control (placebo) arm also had 307 patients, but only three patients in that arm developed second cancers.

Bernstein’s Porges noted that, based on their data, IFM researchers believe that most of the progression-free-survival benefit of Revlimid “seems to be occurring during the first 18-24 months and the incremental benefit obtained after that may not justify an increased risk of secondary malignancies.”

In addition to the IFM trial, there were two other trials that reported data at the ASH meeting suggesting a link between Revlimid and second cancers: the U.S.-based CALGB trial, and the international MM-015 trial.

It is not yet clear whether investigators in these other two trials will follow the IFM lead and halt Revlimid dosing of their patients.  Some investment bank analysts believe this could happen. Representatives from Celgene, however, told The Myeloma Beacon in a telephone interview Friday that they have no indication this is likely to happen.

Indeed, one Wall Street analyst wrote The Beacon that there is “clearly … a separation between the French and other investigators.  IFM thinks this is real, significant, and should justify limiting duration of Revlimid; U.S. and other investigators think it’s minor, unclear, and does not justify limiting duration.”  The analyst went on to write that “both camps agree that some duration of maintenance should be routine.  It’s just a question of how long.”

The latter point is underscored by an important statement in the Bernstein report.  Despite the incidence of second cancers in the Revlimid arm of the IFM trial, the report notes, the IFM considers “the benefit of immediate Revlimid maintenance to be overwhelming.”

A similar position was voiced by Dr. Paul Richardson of the Dana Farber Cancer Institute in Boston in an email to The Beacon about the Revlimid controversy.  When asked whether recent developments have changed his views about long-term Revlimid therapy, Dr. Richardson said “No. The risk appears small, and the benefit from Revlimid is big.”

Dr. Richardson does wonder, however, whether there may be negative interactions between Revlimid and drugs myeloma patients often receive when they undergo stem cell transplants.  The transplant-related treatments may damage the DNA in patient cells, but this effect may not be substantial enough on its own to cause secondary cancers. Revlimid may interact with the damaged DNA in a way that, in a small number of patients, causes second cancers to develop.

Celgene representatives told The Beacon on Friday that detailed analyses of the CALGB, IFM, and MM-015 trial data will be completed in the coming months, and results of those analyses will be presented at important myeloma meetings in May and June of this year.

Another ongoing study, called MM-020, also will help determine the optimal duration of Revlimid therapy.  This study will compare Revlimid plus dexamethasone (Decadron) until progression, Revlimid plus dexamethasone for 18 four-week cycles, and combination therapy with melphalan (Alkeran), prednisone, and thalidomide.  Results are expected in late 2012.