A Phase II Study of Bortezomib-Dexametason Followed by High-Dose Melphalan Combined with Bortezomib in Patients Relapsing After High-Dose Melphalan with Autologous Stem Cell Support

The prognosis of multiple myeloma has improved significantly during the last three decades especially in the younger patient who are eligible for high-dose chemotherapy with autologous stem cell support (ASCT). However, in spite of prolonged progression free survival (PFS) the patients will eventually experience treatment demanding relapse. As many of the patients still have stored frozen stem cells, it is a widespread routine to offer another ASCT after re-induction therapy or in some cases directly without induction therapy. Only few reports of the results of ASCT in the relapse setting have been published and all have been retrospective analyses.

It is well known that the time from first ASCT to relapse has an impact on both PFS and on overall survival (OS) after second-line treatment (Alegre et al, 2002, Alvares et al, 2005, Lenhoff et al, 2006). New drugs like bortezomib and lenalidomide have improved the PFS and OS at relapse also in some of the bad-risk patients.

Therefore, we decided to determine the effect of induction therapy with bortezomib and dexamethasone and including bortezomib in the conditioning regimen with high-dose melphalan (HDM) in the relapse setting, which has also been addressed by the French group (Roussel et al, 2011).

Patients formerly treated for multiple myeloma with HDM with stem cell support as first line treatment and who had first symptomatic relapse and had stored more than 2.0 × 10⁶ CD34+ stem cell/ kg body weight. Exclusion criteria. Former treatment with bortezomib.

Prospective non-randomised phase II study. Study treatment. Three courses of bortezomib 1.3 mg/m2 (Velcade®) days 1, 4, 8 and 11 and dexamethasone 20 mg days 1, 2, 4, 5, 8, 9, 11 and 12 (btz-dex) followed by Melphalan (200 mg/m²) on day –2 with bortezomib 1.3 mg/m² days –5 and –2, and reinfusion of more than 2.0 × 10⁶ CD34⁺ stem cells/kg body weight on day 0. Prophylactic treatment for herpes zoster was giving according to local routine. Primary end-point: Comparison of PFS after the first ASCT and the second ASCT with bortezomib included in induction and conditioning at first relapse. Secondary end-points: Toxicity of bortezomib as part of the high-dose melphalan conditioning, response rate of the second ASCT and comparison of time schedule for marrow regeneration (neutrophil- and platelet recovery) in the first and second ASCT. Pre-planned exploratory subgroup analysis of patients with early relapse (within first year) vs. later relapse, different types of relapse.

53 patients relapsing from 3.5 to 112.3 months after initial ASCT (7 patients had received initial tandem ASCT) were included. Four included patients never went forward to ASCT after relapse: one patient died from septicemia shortly after one bortezomib injection, one patient developed respiratory insufficiency after the second btz-dex course and two patients had aggressive progression after the third btz-dex course. The table summarises the results of the 49 patients who completed the ASCT after first relapse. The ratios between the second and first PFS (Hermansen & Gimsing, 2008) were calculated and showed median: 0.9 (range: 0 – 1.77). Detailed safety data will be presented.

Salvage high-dose melphalan with bortezomib and stem cell support after reinduction with btz-dex at first relapse after high-dose therapy with saved frozen stem cells is a safe treatment with high response rate and reasonable long PFS compared to the initial treatment.

No relevant conflicts of interest to declare.