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Velcade-Melphalan And Double Stem Cell Transplant Combination Is Feasible In Treatment-Resistant Myeloma Patients

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Published: Apr 13, 2012 1:03 pm

The results of a recent Phase 1/2 study suggest that a combination of Velcade and melphalan followed by two back-to-back stem cell transplants is active and well-tolerated in multiple myeloma patients who failed to respond to their initial therapy or who have plasma cell leukemia, a highly aggressive form of myeloma.

Although the response and survival rates for this regimen did not improve upon those for previously tested regimens, the study authors contend that further studies of this novel Velcade-melphalan combination should be conducted to better understand the synergistic properties of these agents.

According to Dr. Ken Shain, from the Moffitt Cancer Center and one of the study’s investigators, trials have already been started to further investigate the combination’s efficacy for both autologous (self) and allogeneic (donor) transplants.

“There are on-going clinical research protocols using the conditioning [preparative] regimen of Velcade and melphalan for autologous transplantation in patients with chemotherapy-responsive multiple myeloma. There is also a protocol incorporating Velcade to allogeneic transplantation in multiple myeloma. Direct comparison of this regimen against the standard high-dose melphalan is planned,” said Dr. Shain.

High-dose chemotherapy followed by stem cell transplantation is a standard treatment option for multiple myeloma patients. Melphalan (Alkeran) is a common chemotherapeutic agent used to remove cancerous cells from a patient's bone marrow prior to transplantation.

Previous studies have shown that Velcade (bortezomib) causes myeloma cells to become more responsive to melphalan, suggesting that these two agents could have an additive anti-myeloma effect and lead to better outcomes after stem cell transplantation (see related Beacon news).

Based on these findings, researchers at the Moffitt Cancer Center in Tampa, Florida, sought to evaluate the safety and efficacy of varying doses of Velcade plus melphalan as a conditioning regimen in patients with aggressive forms of myeloma.

“This trial was intended to introduce Velcade early on to those patients with refractory or resistant disease to control myeloma better and to hopefully sensitize inherently resistant myeloma cells to melphalan,” said Ken Shain.

A total of 34 multiple myeloma patients with a median age of 55 years were enrolled in the study between June 2005 and February 2009. Eligible patients had no prior exposure to Velcade and either failed to respond to their initial therapy or had plasma cell leukemia.

All patients were initially treated with 1.3 mg/m2 of Velcade, known as salvage therapy, on days 1, 4, 8, and 11 of two 21-day treatment cycles. Following this regimen, patients received melphalan and Velcade prior to stem cell transplantation, known as conditioning therapy.  All patients received 100 mg/m2 of melphalan, administered once per day for two consecutive days, followed by treatment with Velcade immediately after the second dose of melphalan. Patients received either 0.7 mg/m2, 1.0 mg/m2, or 1.3 mg/m2 of Velcade.  Previously collected stem cells were re-infused into the patients' bodies three days after the completion of the conditioning regimen.

Between 75 and 105 days after the first transplant, patients underwent a second conditioning regimen, using the same dosage and schedule as the first conditioning regimen, followed by a second transplant.

After completing two cycles of Velcade salvage therapy prior to the first transplant, 37 percent of the evaluated patients demonstrated at least a partial response, including 3 percent who achieved a complete response.

Three-quarters (74 percent) of the patients proceeded to the conditioning regimen followed by stem cell transplantation, and 65 percent underwent two transplants.

Three months after their last transplant, patients demonstrated an overall response rate of 84 percent, including 20 percent who achieved a complete response, 24 percent a very good partial response, and 40 percent a partial response.  At the time of their best response, 36 percent of patients achieved a complete response.

After a median follow-up time of four years, median progression-free survival was 15 months from the first dose of Velcade.  Among patients who received at least one stem cell transplant, median progression-free survival after the first transplant was also 15 months.

Median overall survival was 35 months from the first dose of Velcade.  For those who went on to receive at least one stem cell transplant, median overall survival was 40 months from the time of their first transplant.

According to Dr. Shain and his colleagues, these results are comparable to those of earlier studies investigating stem cell transplants in a pretreated population, which showed median progression-free survival times of 18 months to 30 months, and median overall survival times of less than 60 months. Additionally, these prior studies showed overall response rates of 70 percent to 92 percent and complete response rates of 16 percent to 40 percent.

The maximum dose of Velcade (1.3 mg/m2) was well tolerated, thus no maximum tolerated dose was determined.

Common severe side effects following Velcade salvage therapy included low platelet counts (13 percent), low white blood cell counts (10 percent), anemia (10 percent), and pneumonia (3 percent). A third of the patients experienced mild peripheral neuropathy, which is characterized by pain, tingling, and numbness in the extremities.

For more information, please see the study in the British Journal of Haematology (abstract).

Photo by IndyDina and Mr. Wonderful on Flickr – some rights reserved.
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