P53 Deletion Yields High Response Rates but Rapid Progression and Poor Overall Survival in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation.

Abstract

Background: The p53 deletion has been documented to confer poor prognosis in patients with multiple myeloma (MM) treated with either conventional chemotherapy or autologous stem cell transplant (ASCT). However, it is not clear whether primary drug resistance and/or rapid relapse account for these adverse outcomes.Objective: Evaluate the impact of the p53 deletion in patients who have undergone ASCT for MM on baseline features, response to initial therapy, progression free survival and overall survival post ASCT.Method: Retrospective review of all patients undergoing ASCT for MM at our institution from January 2000 to July 2007.Results: 31 patients with the p53 deletion intended for ASCT were identified. Four patients did not undergo transplant: 2 patients had plasma cell leukemia (PCL) and died within 4 months of diagnosis, 1 patient had primary refractory disease to all therapy and died in 1 year, and 1 patient's stem cells could not be collected. The 28 who underwent transplant had a median age of 52 (range 30–76) and 20 (78%) were male. Immunoglobulin subtype was IgG in 14 (52%), light chain in 10 (36%), IgA in 1 (4%), IgD in 1 (4%) and non secretory in 1 (4%). 23 pts (85%) had bony disease. ISS stage was as follows: 13 (52%) stage I, 6 (24%) stage II, and 6 (24%) stage III. Seven patients presented with PCL. All patients were treated with dexamethasone based induction chemotherapy (alone or VAD), with 6 patients also receiving thalidomide. Pre-transplant status after induction therapy was 0 CR, 22 PR (92%), 1 MR (4%) and 1 SD (4%). All patients were conditioned with high dose melphalan 140–200mg/m2. There was one patient who died within 100 days of transplant. Overall responses after completion of ASCT, compared with diagnosis, in evaluable pts (n=22) included 1 CR (5%), 19 PR (86%), 2 MR (9%). Median progression free survival (PFS) for this cohort was 16.9 months (95%CI 9.1–22.3) and median overall survival (OS) was 48.2 months (95%CI 11.3–67.2) post transplant. This is considerably shorter when compared to the full cohort of MM pts transplanted at our institution during the same timeframe (n= 706): median PFS 24.4 months and median OS 76.6 months post transplant.Conclusions: Patients with the p53 deletion have a high incidence of plasma cell leukemia (29%), but most respond well to induction therapy and ASCT. However, the duration of response is short (16.9 months), nearly 8 months less than our overall results with ASCT. Furthermore, median overall survival post transplant is only 4 years, over 2 years shorter than the median of 6.4 years observed in all ASCT patients. ASCT is less effective therapy in patients with this poor prognostic marker; development of novel therapeutic regimens, including targeting p53 dysregulation pathway, may be required to improve the clinical outcome in this subset of MM.