Bortezomib in Combination with Dexamethasone for Relapsed Multiple Myeloma.

Single agent bortezomib treatment at the dosage and schedule published by Richardson (2003) stabilizes disease in nearly 60% of patients with relapsed, refractory multiple myeloma (MM). However, only 35% of patients achieve an objective (≥ minor) response (MR). Dexamethasone adds to clinical anti-myeloma activity of bortezomib by inducing 18% responses in patients with either stable or progressive disease on bortezomib alone. In an attempt to improve disease response, we evaluated a primary bortezomib/dexamethasone combination in patients with multiple myeloma in ≥ 2nd untreated or refractory relapse. Eligible patients were 18–80 years old, had an ECOG performance status of 0 – 2 and adequate renal, hepatic, pulmonary and cardiac function. Pre-existing peripheral neuropathy ≥ grade 2 or neuropathic pain of any grade were exclusion criteria. However, we made no restrictions in terms of pretreatment blood counts. Fifteen consecutive patients with relapsed multiple myeloma (9/15 with ≥ 2nd untreated and 6/15 with refractory relapse; 71% with a chromosome 13 deletion) were scheduled to receive bortezomib 1.3 mg/m² IV days 1, 4, 8, 11 q 3 weeks for up to 8 cycles in combination with dexamethasone 20 mg PO once daily on the day of bortezomib injection and the day thereafter. Treatment was withheld for nonhematologic adverse events (AE) ≥ grade 3 and reinitiated at a 25% lower dose after resolution. Treatment was not stopped for myelosuppression of any grade if interim response evaluations precluded myeloma progression as the cause of cytopenia. One patient (7%) achieved a complete response, 10 (67%) a partial response, and 1 (7%) a MR resulting in an overall response rate (≥ MR) of 80% (9/9 with ≥ 2nd untreated and 3/6 with refractory relapse; EBMT/IBMTR/ABMTR criteria). Responses occurred after a median of 3 weeks and were independent of conventional prognostic parameters. Importantly, 8/10 patients with a chromosome 13 deletion achieved a ≥ PR. Adverse events, mainly myelosuppression (34% grade 3/4 neutropenia; 47% grade 3/4 thrombocytopenia), neuropathy (grade 2/3/4 20%/7%/0%) and fatigue (grade 2/3/4 20%/13%/20%), were manageable. There was no case of neutropenic infection or thrombocytopenic bleeding. Two patients suffered herpes zoster. The percentage of transfusion dependent patients decreased from 44% during the 1st treatment cycle to 23% and 11% after the 2nd and 3rd treatment cycles, respectively. Even non-responders did not experience cumulative hematologic toxicity. After a median follow-up of 5 months, median event free and overall survival were not reached. Five out of 15 patients were non-responders (n=1) or had experienced disease progression (n=4). Notably, 2 patients with sustained paraprotein and bone marrow remission (confirmed by biopsy) had extramedullary disease progression, pointing to a bone marrow restricted response to bortezomib in MM. This study indicates that bortezomib can be given safely even in patients with poor bone marrow reserve, who would not have been candidates for the SUMMIT trial. Though the remission rate was high, remissions often were not durable. This fact underlines the need for consolidating treatment and evaluation of bortezomib combinations with other anti-myeloma agents.