Three myeloma experts yesterday presented additional clinical trial data on the possible link between Revlimid and secondary cancer in multiple myeloma patients.  All three experts concluded that Revlimid’s benefit as a myeloma treatment outweighs its risks.

The presentations were made at a session of the American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

In a summary talk reviewing the three presentations, Dr. Ola Landgren from the U.S. National Cancer Institute noted that the risk of developing a secondary cancer following Revlimid (lenalidomide) therapy was significantly lower than a myeloma patient’s risk of dying from any cause.

Dr. Landgren added, however, that much is still unknown about these secondary cancers.  Clear answers are still missing because of study limitations and small sample sizes. For this reason, he stressed that physicians should discuss all aspects of treatment, including the development of secondary cancers, with their myeloma patients.

Dr. Landgren also recommended that future research focus on understanding the mechanisms causing secondary cancers, in part to identify which myeloma patients are most likely to develop a second cancer.

The session’s presentations were certainly a vote of confidence in Revlimid, which has been under scrutiny since last December.  It was then that the topic of secondary cancers became an important concern for the myeloma community, after results from several clinical trials showed that treatment with Revlimid may increase a myeloma patient’s risk of developing a secondary cancer.

The U.S. Food and Drug Administration announced in April that it is currently investigating the safety of Revlimid and its chemical cousin thalidomide (Thalomid) (see related Beacon news).   Both Revlimid and thalidomide are marketed in the United States and elsewhere by Celgene Corporation.

Despite the positive tone of yesterday's presentations, it is unclear how many minds the session changed in regard to the Revlimid-secondary cancer controversy.

For example, Dr. Leif Bergsagel of the Mayo Clinic in Scottsdale, Arizona told The Beacon that, in his opinion, “second cancers are an ever increasing problem.”  He believes it “overly simplistic to recommend [Revlimid] maintenance for all comers; there are some patients for whom it may be better to use as maintenance, and others where it is better to use at relapse.”  He agrees with Dr. Landgren that an important goal should be “to figure out which patients truly benefit from [Revlimid] maintenance, and which receive no benefit – or may in fact be harmed.”

Melphalan-Prednisone-Revlimid In Elderly Newly Diagnosed Myeloma Patients

Dr. Antonio Palumbo from the University of Torino in Italy kicked off yesterday’s presentations on Revlimid and secondary cancer.  He first reviewed results of a study that investigated the rate of secondary cancers in 459 newly diagnosed, elderly myeloma patients who were ineligible for stem cell transplants.

In the study, referred to as MM-015, one third of the patients received melphalan (Alkeran) and prednisone (MP), one third received MP in combination with Revlimid (MPR), and the final third received the three-drug combination followed by long-term Revlimid maintenance therapy (MPR-R). The median age of the study participants was 71 years, and the share of high-risk patients (50 percent) in the study was high.

As of February 28, four patients in the MP group had developed secondary cancers, compared to nine patients in the MPR group and 12 in the MPR-R group. The rate of secondary cancers in this study, Dr. Palumbo noted, is similar to rates reported in other studies.

The rate of solid tumors – cancers occurring in organs such as the lung or colon – were very similar across the three treatment groups. The differences were mainly due to the blood-based cancers myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML): one patient in the MP group developed a blood cancer, compared to 5 patients in the MPR group and 7 in the MPR-R group.

Dr. Palumbo pointed out that all patients who had complex chromosomal abnormalities were in the MPR and MPR-R treatment groups. These patients, Dr. Palumbo said, were at significantly higher risk of developing a secondary cancer, which may partly explain the discrepancies in secondary cancers across the three treatment groups.

Dr. Palumbo used the results of the MM-015 to analyze the relative risk of developing a secondary cancer versus disease progression or death in patients undergoing Revlimid maintenance, and concluded that the benefit-risk ratio for Revlimid is favorable.

To further analyze Revlimid’s potential link to secondary cancers, Dr. Palumbo and his colleagues also carried out a retrospective study of nine clinical trials involving 1,798 newly diagnosed myeloma patients. They compared the risk of secondary cancers in patients receiving Revlimid plus a type of anti-cancer drug called an alkylating agent, to the risk of secondary cancer in patients who received an alkylating agent with an anti-myeloma drug other than Revlimid.   Melphalan and cyclophosphamide (Cytoxan) are examples of alkylating agents commonly used in the treatment of myeloma.

Based on the results of this retrospective analysis, Dr. Palumbo concluded that Revlimid when used with melphalan increases the rate of secondary cancers, but Revlimid does not increase second cancers when used with dexamethasone.

“The rate of secondary cancers is low, and the benefit-risk ratio is strongly in favor of continuous Revlimid maintenance,” said Dr. Palumbo.

Clarithromycin, Revlimid, and Dexamethasone In Newly Diagnosed Myeloma Patients

Dr. Adrianna Rossi from the Weill Cornell Medical College and New York Presbyterian Hospital presented the results of a Phase 2 trial that investigated the rate of secondary cancers after six years of follow-up in 72 newly diagnosed myeloma patients treated with clarithromycin (Biaxin), Revlimid, and dexamethasone (Decadron).

Initial results from the study indicated that the combination therapy, abbreviated as BiRD, was very effective against myeloma in this patient population. Fifty-three percent of patients achieved a complete response, 21 percent a very good partial response, and 17 percent a partial response for an overall response rate of 90 percent.

In addition, four years after the start of treatment, 82 percent of the patients enrolled in the study were still alive.

Dr. Rossi reported that 16 percent of the participants developed a second cancer after an average of 31 cycles of Revlimid. The secondary cancers included skin (6), colon (2), prostate (1), pancreas (1), and metastatic melanoma (1). None of patients developed the blood cancers MDS or AML. The secondary cancers were not associated with any risk factors, such as specific chromosomal abnormalities, whether or not the patient received a stem cell transplant, whether or not that patient was still receiving treatment with Revlimid, or patient gender.

Dr. Rossi also reported that the frequency of secondary cancers in this study (2.85 percent per year) was similar to cancer rates in non-myeloma individuals of a similar age (2.1 percent per year). “The rate of second cancers is low and similar to that expected for people of similar age,” said Dr. Rossi.

Dr. Rossi pointed out that there are some limitations to her analysis: the study included a small number of patients, it was a retrospective analysis, and there was no bone marrow surveillance looking for MDS.

Revlimid And Dexamethasone In Relapsed/Refractory Myeloma Patients

Dr. Ruben Niesvizky from the Weill Cornell Medical College wrapped up the session’s presentations of trial results related to Revlimid and secondary cancers.  He presented the results of a study that evaluated the rate of secondary cancers in relapsed/refractory myeloma patients treated with Revlimid and dexamethasone. The researchers retrospectively analyzed the results from two Phase 3 clinical trials comparing Revlimid and dexamethasone in combination with dexamethasone alone.  Treatment in both cases was continued until disease progression.

At a median follow-up time of 48 months, eight cases of secondary cancer (including two cases of MDS) were reported for patients in the Revlimid-dexamethasone arm, compared to two cases of secondary cancer in the dexamethasone-alone arm. No cases of AML were reported in either group of patients.

Time to progression or development of a second cancer was 12.4 months for Revlimid-dexamethasone versus 4.6 months for dexamethasone alone. Taking into account that Revlimid plus dexamethasone significantly extended survival (overall survival of 31 months compared to 24 months) and that older people have a generally higher risk of cancer, Dr. Niesvizky concluded that the observed secondary cancer rates in both treatment arms were comparable to rates expected for the general population.

“Clearly, this does not affect overall survival, and the overall survival benefit remains with continued Revlimid treatment,” said Dr. Niesvizky.

Based on his analysis of the trial results, Dr. Niesvizky believes the benefit-risk ratio for Revlimid remains strongly positive.

For more information, please see abstract 8007 (melphalan-prednisone-Revlimid), abstract 8008 (BiRD combination therapy), and abstract 8009 (Revlimid-dexamethasone) on the ASCO Meeting website.

(Initial reporting for this article was done by Jessica Langholtz.)