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Haematological Profiles Similar With Bortezomib and High-Dose Dexamethasone Treatment in Relapsed Multiple Myeloma: Presented at EHA

By Chris Berrie

AMSTERDAM, THE NETHERLANDS -- June 19, 2006 -- The novel proteasome inhibitor bortezomib has greater efficacy than high-dose dexamethasone (HDdex) and predictable and manageable hematologic adverse events in patients with relapsed multiple myeloma, according to a trial presented here at the 2006 Congress of the European Hematology Association (EHA).

Results of the efficacy update and subset analysis from the international, multicentre, randomized, open-label study was presented on June 17^th by Sagar Lonial, MD, assistant professor, Winship Cancer Institute, Emory University, Atlanta, Georgia, on behalf of the Assessment of Proteasome Inhibition for Extended Remissions (APEX) trial investigators.

Bortezomib has demonstrated efficacy and safety for relapsed and/or refractory multiple myeloma, and as Dr. Lonial indicated, this agent could represent the preferred therapy in this population. However, a high proportion of these patients are difficult to treat, such as the elderly and those with renal dysfunction, and there is the need for correct management of the hematologic adverse effects seen.

While providing an update of the efficacy for bortezomib versus HDdex from the APEX trial, this analysis was designed to characterize the hematologic profiles of these patients, as stratified by age and renal function.

Inclusion criteria for the APEX trial were relapsed multiple myeloma following 1 to 3 prior lines of therapy; measurable disease (as M-protein or plasmacytoma); and haematologic profile within 14 days prior to day 1 of cycle 1 that included platelet count greater than or equal to 50x 10⁹/L and haemoglobin greater than or equal to 7.5 g/dL, both without transfusion support, within 7 days, and an absolute neutrophil count of greater than or equal to 0.75x 10⁹/L without colony-stimulating factors.

The treatment design provided for initial randomisation of the 669 patients enrolled for induction with either bortezomib (n = 333), as 8 cycles of 1.3 mg/m² IV push on days 1, 4, 8 and 11 every 3 weeks, or dexamethasone (n = 336), as 4 cycles of 40 mg by mouth on days 1 to 4, 9 to 12 and 17 to 20 every 5 weeks. This was followed by maintenance of either bortezomib, as 3 cycles of 1.3 mg/m² IV push on days 1, 8, 15 and 22 every 5 weeks, or dexamethasone, as 5 cycles of 40 mg PO on days 1-4 every 4 weeks.

As Dr. Lonial indicated, this provided equivalent total treatment durations for the 2 arms (273 and 280 days, respectively).

Baseline patient and disease characteristics according to the bortezomib and HDdex arms were, respectively: median age, 62.0 versus 61.0 years; male 56% versus 60%; IgG/IgA/IgD/IgM, 60/23/2/<1% versus 59/24/1/0%; 1 prior line of treatment, 40% versus 35%; Karnofsky performance score greater than or equal to 70%, 94% versus 95%; median serum beta₂-microglobulin, 3.7 versus 3.6 mg/L.

Updated APEX efficacy data demonstrated an improved response rate of 43% for bortezomib, with 18% for HDdex. These were seen as 9% complete, 7% near-complete and 34% partial responses for bortezomib, and <1%, <1% and 17% for HDdex.

Patients who received bortezomib as second-line therapy had a higher response rate compared with those receiving more than one prior line (51% vs 37%, respectively). "They showed significant improvement in the early relapse subset as well for this single agent therapy in the relapsed/refractory setting," Dr. Lonial said.

Baseline hematologic status was similar both by age subgroup and by treatment arm. However, there was a difference in baseline hemoglobin levels for patients who had renal dysfunction, with creatinine clearance of less than 30 mL/minute, although there was no significant difference in neutrophil or platelet counts at baseline.

Hematological toxicities during treatment were similar by age, although there was a tendency towards neutropenia in the <60-year age group. When classified according to renal function, there were again no significant variations in toxicity rates, although there was a trend for a slightly higher rate with bortezomib, Dr. Lonial said.

He also noted that while hemoglobin levels increased in both treatment arms over the course of the study, with a clearer trend seen for bortezomib, neutropenia associated with bortezomib was transient and cyclical. Similarly, the incidence of anemia was similar between treatment arms, with blood transfusion frequency dropping and hemoglobin increasing with both therapies.

Thrombocytopenia was seen to be cyclical, with significant recovery towards baseline during the rest period of each cycle. Mean platelet counts increased with time with both treatments, while the number of patients requiring platelet and blood transfusions decreased after peaking within the first 2 cycles.

Even though there was thrombocytopenia with bortezomib therapy, the incidence of significant bleeding events was similar between the 2 treatment arms. There were, however, 2 patients in the HDdex arm who died as a result of significant bleeding events.

This analysis demonstrated that hematologic adverse events with bortezomib are both predictable and manageable Dr. Lonial stressed, while age and renal function have no effects on the incidence of these hematologic toxicities.


[Presentation title: Haematological Profiles With Bortezomib or High-Dose Dexamethasone Treatment in Relapsed Multiple Myeloma: Phase 3 APEX Trial. Abstract 0492]

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