Significant advances have been made in the treatment of multiple myeloma since the introduction of thalidomide (Thalomid), Revlimid (lenalidomide), and Velcade (bortezomib). Combinations of these “novel agents” have significantly improved response rates and survival rates with better safety profiles than stem cell transplants, leading researchers and patients to ask whether the use of transplants is necessary given the efficacy of the novel agents.

Two studies that are investigating whether novel agents are as effective, or possibly more effective, than an autologous stem cell transplant (ASCT) were presented June 6 at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

The two studies suggest that treatment with novel agents may be as effective as ASCT (in which a patient’s own stem cells are transplanted after chemotherapy), but results of the trials are still preliminary.

Dr. Jean-Luc Harousseau of the Rene Gauducheau Cancer Center in France led a discussion session at ASCO on this topic. He cautioned that it is still too early to abandon the use of ASCT, but he suggested that larger studies with longer follow up would likely provide further support for the replacement of ASCT with novel agents.

“I think the most important point is that upfront autologous transplantation might be useful only in certain subgroups of patients,” said Dr. Harousseau. He advised that studies should be designed to determine which patients would respond to novel agent therapy alone and which would need ASCT.

Results of the first study were discussed in Part 1. Results of the second study are discussed in this article.

Revlimid-Velcade-Dexamethasone Treatment Is Highly Effective In Newly Diagnosed Multiple Myeloma Patients, Even Without ASCT

Dr. Paul Richardson of the Dana-Farber Cancer Center presented interim results of ongoing Phase 1/2 trials for the treatment of newly diagnosed multiple myeloma patients with Revlimid-Velcade-dexa­metha­sone (Decadron), a combination therapy known as RVD. The studies have shown that the combination is highly effective in newly diagnosed multiple myeloma patients and that the regimen is favorably tolerated. The study has also established that RVD may be equally effective given with or without ASCT.

The goal of the Phase 1 trial was to determine the maximum tolerated doses of the drugs in combination. The trial was then expanded in a Phase 2 study to determine the efficacy and safety of the RVD regimen. The researchers also determined the impact of the regimen on stem cell collection and transplant.

A total of 66 newly diagnosed multiple myeloma patients were treated with the RVD regimen. Thirty-five of these patients were enrolled in the Phase 2 study.

Phase 1 established the maximum tolerated dose to be 1.3 mg/m² Velcade, 25 mg Revlimid, and 20 mg dexamethasone.

All patients enrolled in the Phase 2 trial received the established maximum tolerated dose of RVD. Patients received eight three-week cycles of RVD therapy and medication to prevent blood clots and viral infection.

If a patient achieved partial response or better, they could proceed to ASCT or receive maintenance therapy. Forty-seven percent of patients elected to undergo ASCT following RVD treatment.

All patients enrolled in the studies achieved a partial response or better. Overall, 39 percent of Phase 1/2 participants achieved a complete response or a near complete response. Of the 35 patients enrolled in the Phase 2 portion of the study, 57 percent achieved a complete response or a near complete response.

“RVD is highly effective,” said Dr. Richardson. “It is the first regimen to achieve 100 percent response rate or better with remarkably high rates of complete response, near complete response, and also very good partial response.”

Researchers also found patient responses improved with continued therapy. Seventy-five percent of patients achieved improved response between cycles four and eight, and 53 percent improved with treatment beyond eight cycles. The average time to best overall response was 2.1 months.

Furthermore, researchers determined that RVD treatment had no effect on stem cell collection or trans­plan­ta­tion.

The 18-month progression-free survival rate was 68 percent for patients who received ASCT following RVD treatment as well as patients who received only RVD.

During the Phase 1 trial, two patients had dose-limiting toxicities. These toxicities were caused by high doses of dexamethasone. Dr. Richardson noted that “high dose dexamethasone with [Revlimid] is problematic.” Patients receiving high-dose dexamethasone during the Phase 1 trial were, therefore, given reduced doses for cycles five through eight.

The most common side effect was nerve damage in the extremities. Although 80 percent of patients had nerve damage, Dr. Richardson stressed that this side effect was serious in only 2 percent. He stated, “We recognize that this is an important challenge going forward. Nonetheless, it was reversible in almost all patients and manageable with appropriate symptomatic measures, dose reductions, and schedule changes.”

Other severe side effects included low white blood cell counts (23 percent of patients) and low platelet levels (6 percent). There were no treatment-related deaths.

RVD treatment achieved a 100 percent response rate, favorable tolerability, and was as effective without ASCT follow up. Based on these qualities, Dr. Richardson predicted that “RVD may represent the basis of a future standard of care in this disease.”

Ongoing clinical trials are underway to determine ways to improve the quality of response. A larger trial will begin in July to compare the use of the RVD regimen with or without ASCT.

For more information, please see abstract 8016 at the ASCO meeting website.