Four Cycles of Standard Bortezomib and Dexamethasone Produce Significant Overall Response Rates In Patients with Relapsed/Refractory Multiple Myeloma

Bortezomib (B) is a reversible proteasome inhibitor approved by FDA for relapsed/refractory multiple myeloma (MM) patients (pts) in second and higher lines of therapy. The standard regimen includes i.v. injections of B 1.3 mg/m² on days 1, 4, 8 and 11 in a 21-day cycle. The addition of dexamethasone (D) 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12 increases responses as well as the toxicity of the treatment. Generally accepted protocol is to give up to 8 cycles of the treatment. In this abstract we describe preliminary results of open-label, Phase II clinical trial employing only 4 cycles of standard B+D regimen in order to improve safety and evaluate efficacy.

Patients with relapsed/refractory MM who had at least one previous therapy qualified for the trial. In the study they were treated with 4 cycles of standard B+D regimen followed by B maintenance. Patients who achieved complete response (CR) by Blade/EBMT criteria within 4 cycles received up to 2 additional cycles of standard B+D and then were followed closely off study. Those who had partial response (PR) or stable disease (SD) were placed on maintenance therapy with B 1.6 mg/m² i.v. injections on days 1,8,15,22 on 36-days cycle until progression of the disease (PD), development of unacceptable toxicity or decision to stop treatment. Patients with PD were taken of the study. A bone marrow biopsy and aspirate with cytogenetics evaluation were done at the start of the treatment and at the time of CR, PD or decision to stop treatment. MM disease assessment was done with each 21- or 36-day cycle. Thirty eligible and evaluable pts are planned to participate in the study. Primary objective of the study is to evaluate overall response rate (PR + CR). A two-stage accrual design is used in order to allow study to be terminated early, should preliminary results indicate poor activity of the regimen.

Results: Fifteen relapsed/refractory MM pts were evaluable in this first analysis. Mean age was 67.2 years (range 51–84). Eleven pts were males and four females. Sixty percent (9/15) of them were IgG kappa MM, 13.3% (2/15) had IgG lambda and lambda light chain disease, respectively and other 2 had IgA kappa and IgA lambda MM, one each. Mean beta-2-macroglobulin level was 9.3 mg/L (range 2.4–79). Most of the patients (13/15) were stage II (7 pts) and III (6 pts) by International Staging System (ISS, 2005). Cytogenetic studies were available in 13 out of 15 pts. Twelve pts had normal findings and one pt was hyperdiploid. Number of previous lines of treatments was 1.7 (range 1–6). Almost all pts (13/15) had received one of the immunomodulators (thalidomide or lenalidomide), one pt was treated with B and one had autologus peripheral stem cell transplant. After 4 cycles of standard B+D, 9/15 (60%) pts responded to the treatment (20% CR and 40% PR). Three pts (20%) had SD and another 3 (20%) had PD. Eight pts continued maintenance treatment with once-a-week B and received 1–35 cycles. There were no additional responses during the maintenance phase. The most common grade (Gr) 3/4 hematological side effects were thrombocytopenia (40% of pts) and anemia (6.6%). Non-hematological Gr 3/4 toxicities were neuropathy (13.3%), infections (6.6%) and fatigue (6.6 %). Median time to progression and overall survival are presently evaluated.

Although results of this Phase II study are very preliminary, treatment with reduced number of standard twice-a-week B+D cycles seem to result in significant overall response rates and very good tolerability in the group of pts with advanced relapsed/refractory MM. It is worth mentioning that 86% of pts were previously treated with immunomodulators. In addition, maintenance with weekly B seems to be very well tolerated and one of the pts is treated for more than 4 years without major complications.

Al-Janadi:EPIC: Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees. Srkalovic:EPIC: Speakers Bureau; Physicians Connect: Speakers Bureau.