A Phase I/II National, Multi-Center, Open-Label Study of Bortezomib Plus Melphalan and Prednisone (V-MP) in Elderly Untreated Multiple Myeloma Patients.

For more than 25 years, melphalan and prednisone has remained as the gold standard treatment for elderly multiple myeloma (MM) patients. Bortezomib has shown significant activity with manageable toxicity in refractory/relapse MM patients. Moreover, in vitro synergy has been reported when bortezomib is combined with cytotoxic agents such as melphalan.

Aim: To define the appropriate dose of bortezomib in combination with MP and to analyse the efficacy of V-MP in untreated MM patients ≥ 65 years old.

Methods: This is a dose escalation study with two sequential dose levels (Ph 1) and expansion of the cohort at the MTD by 60 patients to further refine estimates of efficacy (Ph 2). In the first cohort, bortezomib (1mg/m²) was administered as a iv bolus to 6 consecutive patients on days 1,4,8,11,22,25,29 and 32 followed by a 10 day rest period in combination with oral melphalan, 9 mg/m^2, and prednisone, 60mg/m^2, once daily on days 1 to 4. In the 2^nd cohort, bortezomib was administered at 1.3mg/m². MTD was defined as that dose level below which 2/6 patients had a DLT.

Patients: 12 patients have been enrolled to date - 6 in cohort 1 and 6 in cohort 2.

Results: Toxicity has been manageable. The first cohort at 1 mg/m² has completed at least two 6-week treatment cycles. There was no DLT in the first cycle. The 2^nd cohort has enrolled 6-patients at a dose of 1.3 mg/m² but none has completed the first cycle yet.

In the first cohort, there was one patient with grade 3 neutropenia (ANC = 0,668) observed at Cycle 1 Day 25. During the second cycle, there were no patients with grade 4 therapy-related toxicity and only one grade 3 adverse event (neutropenia) was observed. The most common grade1 or 2 toxicities were nausea, vomiting, rash, constipation, diarrhea, fever, herpes zoster infection, anorexia, neutropenia, anemia and thrombocytopenia. Ocular neuropathic pain (grade 2) developed de novo in 1 patient during the first cycle; one dose of bortezomib was held and the adverse event resolved with analgesic treatment in 4 days. Treatment was continued at a dose of 0,5 mg/m² at D11 and D22. After this date, bortezomib at 1.0 mg/m² was restarted. The second cohort is in the first 6-week cycle at present, so observations are limited. One serious adverse event (pulmonary embolism and probably septic shock with death) was observed in this cohort in a patient at day +11. He had normal WBC. Two grade 3 adverse events (leucopenia and neutropenia) were observed in one patient. Other grade 1 or 2 toxicities are similar to those observed in the first cohort.

Regarding response, after two cycles of treatment, in the first cohort, 3 out of the 6 patients have experienced >50% reduction in M-protein (two with > 75% reduction) and the others three have experienced either a minor response (1) or stable disease (2). In the second cohort, response data are not available at this time.

Conclusion:The combination of V-MP is well tolerated at standard doses of MP with bortezomib 1 mg/m² with no DLTs in 6-patients. Bortezomib (1.3 mg/m²) is being explored in the second 6-patient cohort in order to define the MTD. So far, no patient has developed DLT. Rapid M-protein responses have been seen. Results will be updated and presented for the 2nd cohort.