A split may be developing in the multiple myeloma research community regarding the treatment implications of a possible link between long-term Revlimid use and secondary cancers.

Many researchers are going on record saying the current controversy does not justify any change in the use of Revlimid ^[1] (lenalidomide) as a myeloma therapy.  Other researchers, however, believe the controversy raises important questions that justify more cautious use of the drug.

Concerns about a potential Revlimid-secondary cancer link first emerged at the American Hematology Society annual meeting in December.  At the meeting, results were presented from three trials – the CALGB 100104 trial, the IFM 2005-02 trial, and the MM-015 trial – that showed higher rates of reported second cancers in the long-term Revlimid therapy arms of the trials than in the other arms.

These concerns were heightened last week when it was reported that investigators leading the IFM trial have decided to halt Revlimid dosing of patients in that trial (see related Beacon ^[2] news).

Since then, statements from leading scientists, including ones involved with the three long-term Revlimid therapy trials, suggest the myeloma research community may be dividing into two camps.

In the one camp are researchers who believe the trial results deserve further investigation, but who do not feel the results justify any immediate change in the use of Revlimid as a myeloma therapy.

Representatives of this school of thought include, for example, the investigators running the CALGB 100104 trial.  The lead investigator of the trial, Dr. Philip McCarthy of the Roswell Park Cancer Institute, announced last week that there currently are no plans to alter Revlimid dosing in the cooperative group’s Revlimid maintenance trial (see related Beacon ^[3] news).

In his statement to The Beacon about the group’s decision to continue Revlimid dosing, Dr. McCarthy said “there is not enough data to say conclusively that [Revlimid] is associated with an unacceptable increase in the incidence of solid tumors or hematologic malignancies.”

Dr. Bijay Nair of the University of Arkansas for Medical Sciences also told The Beacon today that he has not changed his views regarding long-term Revlimid therapy.  “We are continuing to use Revlimid for maintenance,” Dr. Nair said, “because the benefit of Revlimid in decreasing the risk of recurrence of myeloma seems to outweigh the small risk of secondary malignancy.”

Dr. Nair’s comments were echoed by a myeloma opinion leader interviewed yesterday by analysts at Citigroup Capital Markets.  In a report summarizing this interview, Citigroup wrote

“Based on available data from the IFM, CALGB, and MM-015 studies, our [opinion leader] believes that the secondary malignancy rates were within the historical rates, but did caution that more data in a larger patient population is needed to be conclusive. He also mentioned there is currently no imbalance of secondary malignancies in studies testing Revlimid with low dose dexamethasone. Thus, the imbalance seen in these Phase 3 studies may be due to melphalan ^[4] [Alkeran], a drug known to cause new cancers, which was used along with Revlimid in those studies.”

The Citigroup report also said that the opinion leader believes the recent IFM decision to halt Revlimid dosing in its Revlimid maintenance trial “was conservative” and “may be due to heightened scrutiny of drug safety in France emanating from recent safety concerns relating to heart toxicities and deaths caused by Mediator, a diabetes drug that was used extensively off-label for weight loss … This controversy was recently given central stage by the French newspaper, Le Figaro, in mid-January.”

In the other camp of myeloma researchers are those who agree that the new trial data deserve further investigation, but who also believe the data reveal trends that, for the time being, justify being cautious with Revlimid as long-term therapy.  The "caution is in order" approach to Revlimid therapy is particularly warranted, these researchers believe, in patients who have undergone stem cell transplants.

Investigators leading the IFM trial would seem to fall into this second camp of myeloma researchers.  Reports based on interviews with IFM investigators indicate the decision to halt Revlimid dosing in the IFM trial was driven by concern that Revlimid may be noticeably increasing the incidence of second cancers in patients who take the drug for longer than two years.

Because the IFM investigators also reportedly believe the main benefit of the drug occurs in the first 12 to 24 months of treatment, they apparently did not feel it prudent to continue Revlimid dosing since all patients in the Revlimid arm of their trial had been treated for at least two years.

Another key myeloma opinion leader also has told The Beacon that he, too, believes caution is in order when it comes to long-term Revlimid therapy.  Earlier this week, Dr. S. Vincent Rajkumar of the Mayo Clinic told The Myeloma Beacon

“Before the finding of second cancers, I stated that post-transplant lenalidomide [Revlimid] maintenance was of unproven value because an overall survival benefit had not been shown. The finding of second cancers reaffirms my position that progression-free survival is not an adequate endpoint for maintenance studies. I do not recommend routine lenalidomide maintenance following stem cell transplantation in clinical practice.”

Dr. Rajkumar’s statement underscores a key concern among researchers in the second, “caution is in order” camp of myeloma researchers.  These researchers do not question all use of Revlimid as long-term therapy.  Indeed, many of the researchers in this camp are quick to emphasize the significant benefit of Revlimid as a myeloma therapy.

Instead, the concern is how long, and sometimes even whether, long-term Revlimid therapy should be given as maintenance therapy to patients who have undergone stem cell transplants.  Long-term Revlimid therapy for patients who have not undergone stem cell transplants is less of a concern at this point.

The IFM investigators appear to believe the risks of Revlimid therapy outweigh the benefits in post-transplant patients once they have undergone 12 to 24 months of Revlimid therapy.  Other researchers, such as the Mayo Clinic’s Dr. Rajkumar, believe it is not justifiable to use Revlimid as routine maintenance therapy in post-transplant patients outside the clinical trial setting.

It is not clear at this point how large the two camps of myeloma researchers are.  Qualitatively, there appear to be more statements from members of the “no reason to be overly concerned” camp.

Yet a not-too-subtle sign that the two camps exist, and that one does not far outweigh the other in size, may be something that has not occurred – that has not appeared in the public record – during the past few days.

Early this week, The Beacon heard from multiple sources that an International Myeloma Working Group consensus statement on the Revlimid-second cancer controversy might be published on Monday.

So far, however, no such statement has been issued.