Reapplication of High-Dose Chemotherapy and Autologous Blood Stem Cell Transplantation as Salvage Treatment for Patients with Relapsed or Refractory Multiple Myeloma – a Single Center Experience.

A wide range of therapeutic options is currently available for the treatment of patients with relapsed or refractory multiple myeloma (MM). For patients treated with a prior high-dose therapy (HDT) followed by autologous blood stem stem cell transplantation (PBSCT) the reapplication of HDT is a widely used salvage strategy. However, data on the use of a second salvage HDT followed by autologous PBSCT is rare, particularly as no randomised studies have been reported in this situation.

In this retrospective study we report on 55 patients with relapsed or refractory MM, who were treated with a salvage HDT between 1997 – 2007 at our institution. Prior therapies consisted of HDT in all patients, thalidomide in 69% and bortezomib in 27% of patients. The median number of prior lines of therapy was 2 (range:1-6) and time from diagnosis to second HDT was in median 45 months. At the time of salvage HDT median age was 56 years (range: 42-69) and ISS stage was 1 in 63% of patients, 2 in 11% and 3 in 16% (not assessable 11%). The median duration of the remission of the last line of treatment was 21 months (range:0-71) with 43% of patients being refractory to their last line of therapy and 57% suffering from relapse.

Induction treatment before reapplication of HDT included conventional chemotherapy, bortezomib and immunmodulatory drugs (IMID) in 56%, 40% and 22% of patients. Conditioning consisted either of melphalan 100mg/m2 on day -3 and -2 (Mel200, 27%), melphalan 140mg/m2 on day -2 and busulphan 3mg/kg/BW on days -6 to -3 (Bu-Me, 38%) or melphalan 100mg/m2 on day -3 and -2 and bortezomib 1.3 mg/m2 delivered day -3 before the infusion of melphalan (Mel200-Vel, 35%). Palifermin and pegfilgrastim were used for supportive care in 36% of patients. After HDT 62% of patients received no maintenance therapy, 27% received thalidomide and 11% interferon alpha until relapse.

Treatment-related mortality was 5% and response rates were as follows: 9% CR, 9% vgPR, 57% PR, 11% MR+SD and 4% PD (5% not assessable). The median event-free (EFS) and overall survival (OS) was 14 and 52 months, respectively. Toxicity was moderate as shown by a median duration of neutropenia (<0.5 × 10E9/l) and thrombocytopenia (<50 × 10E9/l) of 9 (range:5-16) and 14 (range:5-42) days, respectively. Patients needed iv antibiotic treatment for in median 6 (range:0-23) days, parenteral narcotic analgesia for 2 (range:0-15) days and parenteral nutrition for 2 (range:0-21) days resulting in a hospilitation of in median 21 days (range:5-48).

Patients treated with palifermin and pegfilgrastim had a significantly shorter duration of neutropenia (9 vs. 11;p=0.03) with a trend towards less days with parenteral narcotic analgesia (4 vs. 1;p=0.1) and parenteral nutrition (5 vs. 0;p=0.1) as well as a shorter stay in hospital (18 vs 21;p=0.1).

In our group of patients there were no differences in terms of remission rates, EFS and OS or toxicity for patients treated with different kinds of induction treatment (bortezomib vs IMID vs chemotherapy), conditioning regimen (Mel200, Bu-Me, Mel200-Vel) or maintenance therapy (thalidomide vs INF/none). In univariaten analysis long lasting duration of remission after the first transplant, platelet count >140×10E9/l and achievement of CR or PR after salvage HDT were associated with longer EFS, whereas duration of remission after first HDT, platelet count and age >60 years were favourable prognostic factors for OS. In multivariate analysis a duration of remission after prior HDT of less than 12 months was the only adverse prognostic parameter for both, EFS (p=0.002) and OS (p=0.004). Further subgroup analysis showed a significantly (p<0.001) different median EFS and OS for patients with a previous remission duration after the first transplant of 1-12 months (4 and 7 months, respectively), 13-24 months (15 and 41 months) and 25-36 months (15 and 78 months).

Second salvage HDT followed by autologous SCT is an effective treatment option with favourable risk profile for patients with relapsed or refractory MM. The supportive application of palifermin and pegfilgrastim can further reduce toxicity. Still, patients with an early relapse of less than 12 months after their first transplant do not benefit from this treatment modality

Fenk:Celgene: Consultancy, Honoraria, Research Funding; OrhtoBiotec: Honoraria. Kobbe:Celgene: Consultancy, Honoraria, Research Funding; OrhtoBiotec: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding.