A Phase 1 study found the four-drug combination of Revlimid-Velcade-dexamethasone-cyclophosphamide (RVCD) to be safe and effective in newly diagnosed, previously untreated multiple myeloma patients.

These results suggest that adding cyclophosphamide as the fourth drug in the treatment therapy may be just as or more effective than traditional two- and three-drug combinations. The study also determined that 500 mg/m² cyclophosphamide, the highest dose tested, could safely be used in the RVCD drug combination.

Previous studies have shown that three-drug combinations can be very effective, including the Revlimid (lenalidomide)-Velcade (bortezomib)-dexamethasone (Decadron) (RVD) combination as well as cyclophosphamide and dexamethasone in combination with Revlimid or Velcade. In this study, researchers combined all four of the above mentioned drugs in hopes of further advancing combination therapies and responses to them.

Dr. Shaji Kumar of the Mayo Clinic explained, “The concept of four drug regimens was to examine if the natural history of the disease [could be altered] by producing deeper responses.”

The 25 myeloma participants in the study, all of whom were newly diagnosed and previously untreated, received 100, 200, 300, 400 or 500 mg/m² cyclophosphamide once a week along with maximum RVD doses for eight 21-day cycles. Starting with the lowest dose of cyclophosphamide, a couple of patients were enrolled at each dosage level until participants experienced severe side effects.

Of the 25 patients, 96 percent responded to treatment. Twenty percent achieved a stringent complete response, another 20 percent achieved a complete or near complete response, and 28 percent achieved a very good partial response. These responses are just as strong, or in some cases, stronger, than leading three-drug combination treatments.

The median time to the first response was 49 days, and the median time to best response was 95 days.

The time to disease progression, progression free survival, and overall survival rates have not yet been reached.

There was no significant difference in response that could be determined between groups that received different dosages of cyclophosphamide. “It is difficult to make any conclusions regarding differences between the different doses of cyclophosphamide, since only three to six patients were enrolled at each dose level. However, no obvious differences stood out,” explained Dr. Kumar.

In addition to investigating the efficacy of the RVCD regimen, the safety of the therapy was also determined.
Based on tolerability of the highest dose of cyclophosphamide tested, the researchers recommended that 500 mg/m² cyclophosphamide be used when administered with the RVD combination.

Dr. Kumar explained that raising the dose above 500 mg/m² would have made little-to-no difference in response rates at the expense of a higher rate of side events. “Increasing the dose of cyclophosphamide would not have made much impact on the response rate, but certainly could have compromised the doses of other drugs in terms of common toxicities,” Dr. Kumar stated.

Forty percent of study participants experienced at least one serious side effect. The most common severe side effects were low white blood cell counts (24 percent), peripheral neuropathy (pain or tingling in the extremities, 16 percent), low red blood cell counts (12 percent), low platelet counts (12 percent), and back pain (12 percent).

Two patients required dose reductions: One patient experienced fever and low white blood cell counts, requiring a dose reduction while on 400 mg/m² cyclophosphamide. Another patient developed severe herpes zoster and required a dose reduction while on 500 mg/m² cyclophosphamide.

Eight patients left the study due to side effects and personal decisions to decline further treatment. One patient died during the study due to disease progression.

Dr. Kumar concluded, “The response rates did not seem substantially different between the three and four drug regimens. So, at this point, it is hard to say that a four drug regimen is required. However, novel combinations of multiple drugs with different mechanisms of action should continue to be studied in trials.”

The Phase 2 portion of this study will compare RVCD with RVD and Velcade-cyclophosphamide-dexamethasone.

Further research also needs to address whether high response rates from multi-agent drug regimens lead to improved survival rates.

For more information, please see the study in Nature (abstract).