A Phase 2 trial of Hycamtin, cyclophosphamide, and melphalan showed that the drug combination is a safe and effective treatment regimen for patients with relapsed and refractory multiple myeloma or patients in first remission. The combination, followed by stem cell transplantation, resulted in an overall response rate of 85 percent and a four-year overall survival rate of 66 percent, making this drug combination comparable in efficacy to treatment with melphalan alone.

High-dose melphalan (Alkeran) is the standard conditioning treatment for multiple myeloma patients who will receive an autologous stem cell transplant. Previous studies have shown that melphalan treatment elicits favorable complete response rates and overall survival. However, the possibility of achieving even better responses was investigated in this study by combining melphalan with other therapeutic agents: Hycamtin (topotecan), which inhibits the replication of DNA in cancer cells, and cyclophosphamide (Cytoxan), which works similarly to melphalan to slow or stop growth of cancer cells.

The study evaluated the safety and efficacy of the Hycamtin-cyclophosphamide-melphalan (HCM) combination in 60 patients with relapsed or refractory multiple myeloma or patients in first remission. HCM was administered intravenously over the course of six days preceding an autologous stem cell transplant.

The overall response rate for the HCM combination was 85 percent: 12 percent of participants achieved complete response, 32 percent very good partial response, and 30 percent partial response. Among the remaining participants, 13 percent had stable disease, and one patient progressed.

Very good partial response and complete response rates were higher in patients who underwent autologous stem cell transplantation within 12 months of their myeloma diagnosis; 68 percent of these patients achieved at least a very good partial response, whereas patients who received stem cell transplants more than 12 months after diagnosis achieved at least a very good partial response rate of 32 percent.

Additionally, very good partial response and complete response rates were higher in patients who achieved at least partial response to HCM therapy before stem cell transplantation. Of those who achieved this preliminary partial response, 63 percent went on to achieve very good partial response or complete response after transplantation. Of those who did not achieve an initial partial response, 31 percent achieved very good partial response or complete response after transplant.

After a median follow-up period of 32 months, the median progression-free survival time was 18.5 months. Five years after the completion of the study, 60 percent of the patients were still alive, and 33 percent were in remission.

Serious blood-related side effects were high, with all patients experiencing low white blood cell counts and low platelet counts. Most other side effects were mild and manageable; the most common were mucositis/stomatitis (inflammation and ulceration of the mouth and digestive tract, 65 percent), nausea (58 percent), and diarrhea (42 percent).

In comparison, past trials have shown that single-agent high-dose melphalan has a complete response rate of 22 to 44 percent, a progression-free survival time of 18 to 30 months, and a median overall survival time of five years, making the HCM combination comparable to, but not an improvement over, melphalan alone.

HCM yielded a lower complete response rate (12 percent) than the standard melphalan regimen, which may be due to a lower melphalan dose used in the combination treatment. Increasing the melphalan dose in HCM could raise the complete response rate, but at the risk of increasing side effects as well.

The side effects of HCM and high-dose melphalan were not directly compared in this study. Dr. Muzaffar Qazilbash of the University of Texas MD Anderson Cancer Center and an investigator of the study explained that side effects were comparable with only a small difference. “Subjectively we felt that the HCM regimen was slightly more toxic in terms of mucositis, diarrhea, and abdominal discomfort than melphalan alone,” said Dr. Qazilbash.

The HCM regimen is also administered over a course of six days, whereas the standard high-dose melphalan treatment is administered over one or two days. Therefore, the HCM treatment would likely be more costly and require longer hospital stays than the standard melphalan treatment.

Aside from complete response rates and treatment times, HCM is comparable to the standard melphalan regimen in terms of overall response rates, progression-free survival rates, and overall survival. However, researchers suggest that a Phase 3 trial directly comparing HCM to high-dose melphalan will be necessary in order to truly determine which treatment regimen is more beneficial.

“Until we can show unequivocal superiority of [HCM] or another regimen, melphalan should remain the standard of care,” suggested Dr. Qazilbash.

For more information, please see the study in Bone Marrow Transplantation (abstract).