One trial was of a combination of carfilzomib, Revlimid, and dexamethasone, whcih was highly effective and well tolerated in newly diagnosed myeloma patients. Another was  cyclophosphamide(Cytoxan), thalidomide, and dexamethasone – known as “CYCLONE” – is tolerable and effective in newly diagnosed multiple myeloma patients. The phase II part of the study included 24 patients who faield an autologosu transplant, with a median age of 65 years. All patients received 20 mg/m² of carfilzomib on days 1, 2, 8, 9, 15, and 16 of the first 28-day cycle, and 27 mg/m² of carfilzomib in subsequent cycles. Moreover, all patients received 300 mg/m² of oral cyclophos­phamide on days 1, 8, and 15; 100 mg of oral thalidomide daily; and 40 mg of oral dexamethasone on days 1, 8, 15, and 22 of each cycle. After four cycles of treatment, 29 percent achieved a complete response, 46 percent a very good partial response, and 21 percent a partial response.

Another Phase 1/2 study was conducted in France.  The results show that a frontline combination of carfilzomib, melphalan (Alkeran), and prednisone is tolerable and effective in newly diagnosed myeloma patients over the age of 65. The maximum tolerated dose of carfilzomib was defined as 36 mg/m². at thsi time, 43 patients had been treated on the phase II of the study, and 35 patients, with a median age of 74 years, were evaluated for response.

After a median of eight cycles of treatment, 89 percent of patients responded to the treatment regimen, with 3 percent achieving a complete response, 40 percent a very good partial response, and 46 percent a partial response. The progression-free survival was 81 percent and overall survival was 94 percent after a median follow-up of one year.

These are all remarkable results for multiply treated myeloma patients.

Two posters defiend single agents activity. One analyzed outcomes of 228 patients (86 percent) who were either intolerant or refractory (resistant) to Velcade as well as Revlimid or thalidomide (referred to as “double refractory/intolerant”) and a subgroup of 44 patients (17 percent) who were refractory to all classes of myeloma treatments.  This includes alkylators such as melphalan, anthracyclines such as doxorubicin (Adriamycin), corticosteroids such as dexamethasone, immunomodulatory agents such as Revlimid and thalidomide, and proteasome inhibitors such as Velcade. The results show that patients refractory to prior myeloma therapies had responses overall response rates of 23 percent overall, 21 percent for those who were double refractory/intolerant, and 20 percent for those refractory to all classes of myeloma therapies. Responses lasted 7.8 months for the entire study group, 7.4 months for the double refractory/intolerant group, and 7.8 months for those refractory to all classes of treatment. Anotehr poster presented results of a Phase 1/2 clinical trial on the safety and efficacy of carfilzomib as a replacement therapy for Velcade in patients who progressed while taking Velcade-containing regimens. Early results of the study suggest that carfilzomib is an effective and tolerable replacement for Velcade in these patients.

The study included 27 patients who had received a median of six previous lines of therapy, with a median of 2.5 of those containing Velcade.  After progression, patients continued on their same treatment regimens, except intravenous carfilzomib was given in place of Velcade.

Twenty-two of the patients were evaluated for a response after a median of three cycles of carfilzomib therapy.  The overall response rate was 51 percent, with 23 percent of patients achieving a complete response, 5 percent a very good partial response, and 23 percent a partial response. The median progression-free survival time was 9.8 months.

Other studies are still ongoing. For example, one combination study is: NCT01346787, Carfilzomib, Cyclophosphamide and Dexamethasone In Newly Diagnosed Multiple Myeloma Patients (CCD). The purpose of this study is to determine whether the association of Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) as induction treatment is safe and provides benefits in patients with newly diagnosed Multiple Myeloma (MM). There is also a combination study that adds thalidomide.

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This is a relatively unpublished regimen, although it is in extensive use at University of Arkansas. In general, conditioning regimens have been established on the basis of phase II studies; there are only a few comparative studies of different conditioning regimen. This Super-BEAM regimen is ahead of the “curve” and should be considered experimental. Very little has been published on it as of yet and we await more.

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