The results of a recent Phase 2 clinical trial comparing four Velcade-based combination therapies in newly diagnosed multiple myeloma patients show that a four-drug combination containing Velcade, Revlimid, cyclophosphamide, and dexamethasone led to similarly high response rates as the three-drug regimens, but resulted in a higher rate of side effects.

“We were hoping to see more activity at the same level of toxicity as the three-drug combination, but the result was similar efficacy at higher toxicity,” said Dr. Shaji Kumar of the Mayo Clinic in Rochester, Minnesota, and lead investigator of the study. “Clearly, as the study showed, more is not necessarily better.”

However, Dr. Kumar added, “I think we should continue to work on novel combinations of drugs working through different mechanisms in order to identify better ways to treat these patients.”

Based on their findings, Dr. Kumar and his colleagues concluded that the combinations of Revlimid ^[1] (lenalidomide), Velcade ^[2] (bortezomib), and dexamethasone ^[3] (Decadron) (commonly referred to as RVD or VRD) as well as Velcade, cyclophosphamide ^[4] (Cytoxan), and dexamethasone (commonly referred to as VCD or CyBorD) are preferred in clinical settings and should be further assessed in larger Phase 3 trials.

“The trial reinforces prior observations that these two regimens are very effective and should be considered as part of the treatment armamentarium,” said Dr. Kumar.

Previous clinical studies have demonstrated the strong anti-myeloma activity of RVD and CyBorD, which have overall response rates of up to 100 percent, and complete response rates of about 40 percent. Additionally, a recent retrospective study comparing multiple initial therapies in newly diagnosed patients showed CyBorD to be slightly more effective than Revlimid-dexamethasone and Revlimid-cyclophosphamide-dexamethasone (see related Beacon ^[5] news).

Based on these findings, the researchers sought to evaluate a four-drug regimen involving Revlimid, Velcade, cyclophosphamide, and dexamethasone (abbreviated as RVCD) in newly diagnosed myeloma patients and compare the response rates and survival outcomes to those for RVD and CyBorD.

According to Dr. Shaji, “This [four-drug regimen] was a logical combination to study given that patients continue to relapse with either of the three-drug regimens. The question was whether we could achieve a deeper remission state that would translate to a better outcome.”

A total of 140 newly diagnosed myeloma patients with a median age of 61 years were enrolled in the study between June 2008 and September 2009. The participants were initially randomly divided into three treatment groups receiving RVCD, RVD, or CyBorD. Following an interim analysis, a fourth treatment arm was introduced with a modified dosing of CyBorD.

All patients could receive a maximum of eight three-week cycles of induction (initial) therapy and could opt to receive a stem cell transplant after four cycles.

Every patient received 1.3 mg/m m² of Velcade on days 1, 4, 5, and 11 and 40 mg of dexamethasone on days 1, 8, and 15. Patients on the RVCD regimen also received 15 mg of Revlimid on days 1 through 14 and 500 mg/m² of cyclophosphamide on days 1 and 8. Those in the RVD group received 25 mg of Revlimid on days 1 through 15. Lastly, patients in the CyBorD group received 500 mg/m² of cyclophosphamide on days 1 and 8. Patients in the modified-CyBorD group received an additional dose of 500 mg/m² cyclophosphamide on day 15.

Following induction therapy, patients received a maintenance regimen of 1.3 mg/m² of Velcade on days 1, 8, 15, and 22 of four six-week cycles.

Patients received a median of six treatment cycles. Eighty-seven percent of patients completed four or more cycles of initial treatment and were evaluated for response. Of these patients who were eligible for a stem cell transplant, 45 percent from the RVCD group, 44 percent from the RVD group, 28 percent from the CyBorD group, and 53 percent from the modified-CyBorD group underwent a transplant.

Across all treatment cycles, the overall response rate (partial response or better) was 88 percent in the RVCD group, 85 percent in the RVD group, 75 percent in the CyBorD group, and 100 percent in the modified-CyBorD group. According to the researchers, the response rates for the three-drug combinations are comparable to those from prior studies.

The one-year progression-free survival rate was 86 percent in the RVCD group, 83 percent in the RVD group, 93 percent in the CyBorD group, and 100 percent for the modified-CyBorD group.

The one-year overall survival rate was 92 percent for the RVCD group and 100 percent for all three of the groups that received a three-drug combination.

More RVCD patients (79 percent) experienced at least one drug-related severe or life-threatening side effect than patients receiving RVD (60 percent), CyBorD (71 percent), or modified CyBorD (61 percent).

In addition, the RVCD group experienced a higher rate of blood-related side effects, including low white blood cell counts (44 percent for RVCD, 10 percent for RVD, 30 percent for CyBorD, and 24 percent for modified CyBorD) and low platelet counts (15 percent for RVCD, 12 percent for RVD, 12 percent for CyBorD, and 0 percent for modified CyBorD). 

Other common side effects affecting all treatment groups included fatigue, diarrhea, pneumonia, and peripheral neuropathy (pain or tingling in the extremities).

The share of patients who discontinued treatment due to side effects was highest in the RVCD group (21 percent, compared to 19 percent in the RVD group, 12 percent in the CyBorD group, and 6 percent in the modified-CyBorD group).

For more information, please see the study in the journal Blood ^[6] (abstract).