The results of a recent Phase 2 trial show that the addition of cyclophosphamide to Revlimid and low-dose dexamethasone may result in better responses for previously untreated myeloma patients.

“This [study] provides the efficacy of another regimen for use in patients with myeloma,” said the study’s lead author Dr. Shaji Kumar of the Mayo Clinic in Rochester, Minnesota. “It is a fairly safe combination and is quite efficacious,” he stated in an e-mail to The Myeloma Beacon.

According to the study authors, the combination of Revlimid (lenalidomide), cyclophosphamide (Cytoxan) and low-dose dexamethasone (Decadron) (abbreviated as RCd) is suitable as long-term therapy. They stated that the increased side effects associated with RCd, compared to Revlimid plus low-dose dexamethasone (Rd), were manageable.

Previous studies have shown that cyclophosphamide can improve combination therapies containing thalidomide (Thalomid) or Velcade (bortezomib) in newly diagnosed myeloma patients. They have also shown that cyclophosphamide in combination with Revlimid improves responses in relapsed myeloma patients.

The authors wanted to determine if the addition of cyclophosphamide to Rd therapy would also improve outcomes in newly diagnosed myeloma patients.

The trial included 53 previously untreated myeloma patients. Among these patients, 26 percent were considered high-risk based on chromosomal abnormalities.

Participants were treated with 25 mg Revlimid daily for three weeks, 300 mg/m² of cyclophosphamide on days 1, 8, and 15, and 40 mg of dexamethasone on days 1, 8, 15, and 22 of a 28-day cycle. In an effort to reduce side effects, the last 19 patients enrolled in the study received a lower dose of cyclophosphamide (a flat dose of 300 mg). Treatment was continued for a maximum of 12 cycles.

After four cycles of treatment, 79 percent of patients responded, including 2 percent who achieved a complete response and 28 percent who achieved a very good partial response.  Some patients achieved a higher response after longer treatment; the overall response rate during the study was 85 percent.

Additionally, response rates were similar for patients receiving high- and low-doses of cyclophosphamide (77 percent compared to 84 percent).

The median progression-free survival was 28 months, and overall survival was estimated to be 87 percent two years after diagnosis.

Although high-risk patients typically respond similarly or not as well to treatment as standard-risk patients, high-risk patients in this study had a better overall response rate than the standard-risk patients (93 percent compared to 79 percent). Two-year progression-free survival and overall survival were similar for the two groups.

The authors suggested that high-risk patients may respond better to RCd therapy than to Rd alone.  However, Dr. Kumar explained, “[This combination] does not specifically affect the treatment of high-risk patients. They should continue to get Velcade-based treatments,” which currently is the general recommendation for high-risk patients.

Half of all participants experienced low white blood cell counts, which was also the most common cause for treatment delays. Fatigue was the second most common side effect. Side effects were similar among those who received the high- and low-doses of cyclophosphamide.

Dr. Kumar indicated that growth factors could be included with RCd therapy as a way to prevent low white blood cell counts.

The authors stated that RCd therapy is comparable to a number of other new combination therapies with regard to efficacy in newly diagnosed myeloma patients. A comparison of results from this and previous studies showed that the overall response rate for RCd (85 percent) is higher than for Rd alone (70 percent) and comparable to Velcade, cyclophosphamide, and high-dose dexamethasone combination therapy (88 percent).  Survival rates appear to be similar for the three regimens.

The combination of Revlimid, Velcade, and dexamethasone, however, has produced the highest response rate (100 percent) in newly diagnosed myeloma patients, with around half of those patients achieving a complete or near complete response.

According to Dr. Kumar, it is not yet clear when RCd may be investigated in a Phase 3 trial.

For more information, please see the study in the American Journal of Hematology (abstract).