Source: Ned Tijdschr Geneeskd  |  Posted 5 years ago

By Chris Berrie

AMSTERDAM, THE NETHERLANDS -- June 21, 2006 -- The combination of bortezomib (Velcade), melphalan, prednisone, and thalidomide (V-MPT) is a promising regimen for patients with relapsed or refractory myeloma, according to researchers who presented an open-label, phase 2 study here at the 11[^]th[] Congress of the European Hematology Association (EHA).

Principal investigator Antonio Palumbo, MD, chief, myeloma unit, department of haematology, University of Torino, Azienda Ospedaliera S. Giovanni Battista, Torino, Italy, presented the study on June 17[^]th[] on behalf of the Italian Multiple Myeloma Network (GIMEMA).

Recently, various combinations provided by the addition of bortezomib or thalidomide to dexamethasone and melphalan/prednisone regimens for patients with refractory multiple myeloma showed increased rates of response and event-free survival with acceptable safety profiles.

Dr. Palumbo indicated that the rationale for evaluating the V-MPT combination in patients with advanced myeloma was that they might provide further synergistic effects. His team therefore designed their phase 2 study to evaluate the safety and tolerability and the efficacy of the V-MPT combination in patients with advanced myeloma.

Patient with measurable disease were eligible for enrollment if had 1 or 2 prior treatment regimens, Karnofsky performance status greater than or equal to 60%, platelets greater than or equal to 75,000/mm[^]3[], and creatinine clearance greater than or equal to 20 mL/min. Patients with greater than or equal to grade 2 peripheral neuropathy were excluded.

All patients received oral melphalan 6 mg/m[^]2[] on days 1 to 5, oral prednisone 60 mg/m[^]2[] on days 1 to 5, and thalidomide 100 mg/day continuously from day 1. In addition, patients were divided into 3 cohorts, in which they received bortezomib IV bolus at 1.0 mg/m[^]2[], 1.3 mg/m[^]2[] or 1.6 mg/m[^]2[] on days 1, 4, 15, and 22. This treatment cycle was administered every 35 days.

Thirty patients were recruited into each of the 3 bortezomib treatment groups (n = 10, for each), with the overall baseline patient characteristics showing: median age, 66 years; isotype: immunoglobulin (Ig) G, 67%; IgA, 17%; BJ, 17%; median beta[_]2[]-microglobulin, 3.4 mg/L. Prior lines of treatment were as follows: 1, 47%; 2, 53%. Prior treatment was conventional chemotherapy (33%), thalidomide-based regimen (30%), stem cell transplantation (67%). Median time from diagnosis was 33 months.

Dose-limiting toxicities (DLTs) were also recorded, in terms of the occurrence of any grade 3/4 nonhaematological toxicities, grade 4 neutropenia > 1 week, or any grade 4 haematological toxicity, except neutropenia.

After a median of 6 V-MPT cycles, 67% of the full patient cohort achieved an objective response (complete, 17%; partial, 50%); 17% also achieved minimal response, while 7% had stable disease and 7% showed progressive disease. Thus, 83% of the patients achieved at least a minimal response.

The most common grade 1/2 toxicities were infection, fatigue, peripheral neuropathy, and constipation. Grade 3/4 events were mainly haematological, with neutropenia (43%), thrombocytopenia (67%), and anaemia (33%). Serious adverse events highlighted as DLTs showed no specific trends across the increasing bortezomib dosing, with grade 4 thrombocytopenia being most common (13%).

Grade 3/4 infections were also of some concern (33%), although after prophylaxis with acyclovir no events were seen, Dr. Palumbo said.

This combination of V-MPT is indeed feasible; it has a reasonable safety profile and is more effective that MPT alone, Dr. Palumbo said.

"What is interesting in particular here is that the amount of cytoreduction in these relapsed patients [with V-MPT] is quite similar to the amount of cytoreduction we have with MPT alone, but at diagnosis -- this is telling us something," he noted.

The researchers are progressing onto a phase 3 trial to further define this 4-agent approach, he said.

The study was sponsored by Orthobiotec and Johnson & Cilag, with drugs supplied by Pharmion.

[Presentation title: Combination of Bortezomib, Mephalan, Prednisone and Thalidomide (V-MPT) in Advanced Myeloma: a Phase 2 Clinical Trial. Abstract 0729]