High-dose Therapy Stem Cell Support Research Articles

Clinical Prognostic Factors in Chemosensitive Multiple Myeloma (MM) Patients Intensified with High Dose Therapy/Stem Cell Support (HDT/SCS): Results of the Spanish Trial (PETHEMA/GEM2000).

Autologous stem cell transplantation (ASCT) has become the standard of care for young MM pts. The analysis of prognostic factors will contribute to identify which pts benefit more from this procedure. However, in this type of analysis it is important that all pts receive uniform treatment, and since primary refractory pts have a different prognosis from pts sensitive to initial chemotherapy, our policy was to use up-front a more intensive treatment approach for the refractory pts. In this report we will focus on the analysis of clinical prognostic factors in sensitive MM pts to induction chemotherapy. The Spanish PETHEMA/GEM2000 trial included untreated MM pts younger than 70 years and consisted on six alternating cycles of chemotherapy VBMCP/VBAD followed by high dose therapy (BuMel or Mel200) supported with ASCT. Pts achieving CR IF- or CR IF+ after the first transplant received maintenance treatment with interferon/prednisone, while pts with a remaining visible M-spike (partial or minimal response) received a second HDT/SCS with CBV (cyclophosphamide, etoposide and BCNU) or a dose-reduced intensity allogeneic transplant if donor is available. Between January 2000 and December 2004, 803 pts were considered to have chemosensitive disease and were transplanted as above described. Median age at time of diagnosis was 59 y (range: 31–70). Baseline characteristics were similar to those previously reported in other series in which young patients were included. Following initial chemotherapy, the response rate was: 13.6% CRIF-, 14% CRIF+ and 60% PR. Response rate increased after HDT/SCS: CRIF-, CRIF+ and PR rates were 38%, 20% and 35%, respectively. Early death rate, occurring during the first two months after ASCT was 3,5% (28 pts). 207 out of 803 pts received a second HDT/SCS. 531 pts (66%) started maintenance therapy after transplant with interpheron and prednisone in most of them (77%). After a median follow-up of 45 months (range: 6–91), the median EFS time for the 803 pts was 45 months (95% CI: 40,5–49,1), defining event as relapse/progression or death; median OS time has not been reached and the estimated 8-year EFS and OS were 30 and 53%, respectively. Univariate analysis identified the following adverse prognostic factors for EFS: age ≥ 59 y, advanced Durie and Salmon stage, advanced ISS stage, Monoclonal component ≥ 30g/l, Hemoglobin (Hb) level < 11 g/dl, creatinine > 1,5 mg/dl, Bone Marrow Plasma cells infiltration ≥ 45%, performance status according to EGOG 3–4, and failure to achieve CR IF- after induction chemotherapy or after the first transplant. The same prognostic factors were identified in the univariate analysis for OS. On multivariate analysis only five variables retained an independent prognostic influence on EFS and OS: age ≥ 59 y (p:0,04), Hb < 11 g/dl p:0,000), advanced ISS stage (p:0,03) and lack of CRIF- after transplant (p:0,000). The three ISS stages could be subdivided into two subgroups using the variables selected in the multivariate analysis. Thus pts who didn't achieve CR IF- after transplantation and had an additional adverse factor (either age or anemia) showed a significant different outcome within the ISS stage I, II and III.

A PETHEMA study of high-dose therapy/stem cell support (HDT), including tandem transplant, in primary refractory multiple myeloma (MM): Identification of two populations with different outcomes

8021 Background: It has been claimed that patients with primary refractory myeloma benefit from early HDT. However, the reported series have 2 shortcomings: 1) patients with “unresponsive-progressive disease” vs those “non-responding-non progressing” were not analyzed separately and 2) some included patients had MR or even PR according to the EBMT criteria. Aim: Response and survival after early HDT in the two populations of truly primary refractory MM Methods: From Oct 1999 to Dec 2004, 829 patients with MM received 6 cycles of VBMCP/VBAD and at least one transplant. 79 of the 829 patients were refractory to VBMCP/VBAD. These resistant patients were scheduled to receive a tandem transplant, the first with Bu-12/MEL-140 or MEL-200 and the second “autologous” with CVB or “allo- RIC” (if donor available) with Fluda/MEL-140. Response and progression were defined by the EBMT criteria. Results: 32 of the 79 primary refractory patients had progressive disease under the initial chemotherapy while 47 were “unresponsive, non-progressive”. The prognostic features, including cytogenetics, were similar in both groups. 70% of the patients responded to the first HDT (CR/nCR 8%, PR 48%, MR 13%). 37 patients were given a second transplant (26 “auto”, 11 “allo”). 41% who received a second “auto” up-graded their response (CR 9%, PR 14%, MR 18%) while 42% who underwent “allo-RIC” increased their response (CR 28%, PR 14%). Median survival of the whole series was 3 years. Patients progressing while on therapy had a shorter survival than the “no-change” group (median 2 yrs vs not reached, p=0.00002). Finally, the 47 “non-responsive, non-progressors” patients had similar survival than the 718 with chemosensitive disease intensified with HDT. Conclusions: 1) HDT in patients with primary refractory MM results in a low CR rate, 2) patients progressing while on initial therapy have a short survival despite the intensive approach and 3) patients with “non-responding, non-progressive” disease have similar survival than chemosensitive patients. Whether this good outcome is due to the impact of HDT or to the natural history of a more indolent disease remains to be determined. No significant financial relationships to disclose.

High-Dose Therapy/Stem Cell Support (HDT), Including Tandem Transplant, for Primary Refractory Multiple Myeloma (MM): Results from the Spanish Myeloma Group (PETHEMA/GEM) in 49 Patients.

It is assumed that patients with primary refractory myeloma are the most likely to benefit from early HDT. In four series the CR rate was between 8 and 40% and the overall survival ranged from 4 to 6 years. However‚ the number of patients with progressive disease vs those with “stable disease” was not given in published series. The aim of our study was to investigate the efficacy in terms of response up-grading and survival of early HDT in patients with primary refractory myeloma. From October 1999 to December 2003 patients with MM younger than 70 years were given 6 courses of VBMCP/VBAD chemotherapy. Patients with refractory disease were scheduled to receive a tandem transplant‚ the first procedure intensified with busulphan-12 mg/kg-/melphalan-140 or melphalan-200 and the second with the CVB -cyclophosphamide‚ etoposide and BCNU- or with a dose-reduced intensity “allo” conditioned with fludarabine/melphalan-140‚ depending on sibling donor availability. Response and progression were defined according to the EBMT criteria. Forty-nine patients with primary refractory disease were identified. Twenty patients showed progression after their initial chemotherapy while 29 patients had “non-responding‚ non-progressive disease”. Eighty percent of the patients achieved some degree of response after the first autologous transplant (CR or near-CR: 8%‚ PR: 56%‚ MR: 16%) while 10% did not respond and 10% died from the procedure. Twenty-four patients were given a second transplant (autologous: 17‚ allogeneic: 7). Forty-six percent of the 17 patients who received a second autologous transplant upgraded their response (CR: 6%‚ PR: 17%‚ MR: 23%) while 41% had progressive disease or “no-change” and 13% died from the procedure. Three of the seven patients who underwent a dose-reduced intensity “allo” responded (2 CR‚ 1 PR) while two had progressive disease and two died from transplant-related complications. The median survival of the whole series of 49 patients was 32 months. Patients who had progressive disease after the initial chemotherapy had a significantly shorter survival than those who showed “non-responsive‚ non-progressive disease” (median 21 months vs. not reached‚ p=0.003). Finally‚ patients with “non-responding‚ non-progressive disease” had similar survival than those with chemosensitive disease intensified with HDT in the GEM trial.Conclusions.A high-dose therapy approach in patients with primary refractory myeloma results in a high overall response‚ but the CR rate is low‚patients with progressive disease to the initial chemotherapy have short survival despite intensive therapy‚ andpatients with “non-responding‚ non-progressive disease” have similar survival than chemosensitive patients.Whether the good outcome of the latter patients is mainly due the effect of HDT or to the natural history of a more indolent disease remains to be determined.