Between November 1998 and January 2005, a total of 77 patients with MM were treated with ASCT at the Asan Medical Center. All patients had adequate stem cell collection and met all the eligibility criteria of the ASCT protocol including age ≤70 yr and adequate cardiopulmonary and hepatic functions. At study entry, the exclusion criterion was poor performance status, as shown by an Eastern Cooperative Oncology Group (ECOG) score ≥3. All patients gave informed consent.

The study population was divided into two groups based on MM subtype: patients with IgD MM (8 patients); and those with other MM subtypes (69 patients).

Prior to ASCT, patients had received one to two lines of treatment, while 88% of the cases had received only one regimen of chemotherapy. Most patients were treated with VAD (vincristine, adriamycin, and dexamethasone) (67 patients, 87%) or VAD like regimen (6 patients, 8%), while four patients (5%) had received MP (melphalan, prednisone) as first-line treatment. At the time of transplant, 22% of patients were in CR. The vast majority had achieved a partial response (PR) with previous chemotherapy regimens, while 7 (9%) of them had stable disease. The median time interval between diagnosis and transplant was 5.6 months (range: 1.8-83.5 months). Of the patients, 13 (16.9%) had a second transplant; 4 of these had a planned second ASCT in CR and 9 were autografted after relapse or progression of their disease.

Peripheral blood stem cells were collected during 1-3 consecutive leukaphereses, following high-dose cyclophosphamide 4 g/m², i.v., with subsequent lenograstim at 10 µg/kg/day from day 3 to the last day of leukapheresis. The concenturation of circulating peripheral blood hematopoietic progenitor cells (HPCs) were monitored daily, and when HPCs become 5 cells/µL, autologous stem cell harvest was performed (14). Peripheral blood stem cell were harvested with a target concentration of 10.0×10⁶ CD34+ cells/kg.

High-dose chemotherapy was performed 3 and 2 days before stem cells infusion (day -3 and day -2). High-dose chemotherapy comprised melphalan 100 mg/m² iv infusion for 30 min on each of theses two consecutive days (total 200 mg/m²). Stem cells were infused on day 0. Subcutaneous lenograstim treatment 5 µg/kg/day was started on day 1 and continued until the absolute neutrophil count was measured as ≥1,000 cells/µL on two consecutive days. The second ASCT was performed within 3-9 months of the first ASCT in all patients who had second ASCT except one, for whom the interval was 4 yr. The second ASCT was performed following the same procedure as the first ASCT.

At the time of ASCT, staging was performed according to the Southwest Oncology Group (SWOG) staging system (15) and the 2005 International Staging Sytem (ISS) guidelines (16). The European Group for Blood and Marrow Transplant (EMBT) criteria were modified for assessing disease response (17). CR was defined as absence of monoclonal Ig from the serum and/or urine as shown by immuno-fixation analysis and less than 5% plasma cells on bone marrow aspirate (and biopsies, if performed). Patients were considered to be in PR if there was at least a 50% reduction in the serum M-protein concentration and a reduction in the level of Bence-Jones proteinuria by greater than 75% reduction or to less than 0.2 g/24 hr. No change was defined as no change or a reduction in paraprotein levels of less than 50%. Progressive disease (PD) was defined as a confirmed >25% increase in the serum paraprotein concentration compared with the level at the time of the best response, an increase in Bence-Jones proteinuria to more than 1.0 g/24 hr, or other unequivocal signs of disease progression, such as hypercalcemia, progressive skeletal disease, or soft tissue plasmacytoma. Relapse was defined as the reappearance of paraprotein in the serum of patients who achieved CR and an increase of greater than 25% in the serum paraprotein concentration, or other unequivocal signs of disease progression such as hypercalcemia or the development of new extramedullary disease for patients who did not achieve CR. Patients were considered to be in continued CR or continued PR if the CR/PR status attained after the induction chemotherapy was continued after ASCT.

Patient responses were first evaluated 4 weeks after ASCT. Protein electrophoresis and immuno-fixation analyses of serum and/or urine were performed. If CR was achieved, the patient was evaluated every month for the first 2 months, then three times at 2 month intervals, and every three months thereafter. If CR was not achieved initially, the patient was evaluated every month until CR was achieved. At each follow-up visit, the patient's clinical history was recorded and he or she underwent a physical examination, complete blood count, platelet count, and liver function tests, and serum and/or urine protein electrophoresis analyses. If relapse or progression was confirmed, the decision of whether to perform further therapy was at the discretion of the participating physicians.

The proportions of patients with a given characteristic were compared with the use of χ² test or Fisher's exact test. Differences in continuous variables were analyzed with the Student's t-test and confirmed with the use of the Mann-Whitney U test. All tests were two-tailed. An event was defined as progression, relapse, or death due to any cause. EFS was calculated for all patients from the date of ASCT. OS was calculated from the date of ASCT to death of the patient or to the date the patient was last known to be alive. Kaplan-Meier curves for EFS and OS were plotted and compared using the log-rank test. Prognostic factors for survival were determined by means of the Cox proportional-hazards model for multivariate analysis, which was performed for significant univariate variables. A p value <0.05 was considered significant. All calculations were performed using SPSS version 12.0 for Windows (SPSS Inc., Chicago, IL, U.S.A.).

A total of 8 patients with IgD MM were identified, accounting for about 10% of the study population. In this study, 36 patients (47%) had IgG MM, 17 patients (22%) had Ig A MM, and 16 patients (21%) had free light-chain MM.

Table 1 shows the base-line characteristics of the 77 patients. The median age of the patients was 51.0 yr (range, 20-68 yr). There were no significant differences in patient characteristics at baseline between the two groups (those with IgD MM vs. those with other MM subtypes). The two groups were specially similar in lines of prior chemotherapy, interval from diagnosis to ASCT, disease status prior to ASCT, and the proportion of patients who had second ASCT, which could have influence on outcomes following ASCT. Forty patients were checked for cytogenetic abnormalities, of whom 24 patients (60%) showed abnormalities. Nine patients had chromosome 13 deletion or hypodiploidy both of which are known to be poor prognostic factors (18).

The treatment-related mortality (TRM) was 3% (2/69 patients) in the group of patient with other MM subtypes. The cause of death was septicemia. There was no treatment-related mortality in the IgD MM group. No patient developed grade III-IV cardiac, pulmonary, renal or liver toxicity (World Health Organization scale), whereas neutropenic fever was present in almost all patients and severe mucositis was observed in a third of the patients.

Table 2 shows the patient responses to ASCT. The overall response rate (CR and PR) was 96%. Specifically, the CR rate was 75% for patients with IgD MM, compared with 58% for patients with other MM subtypes (p=0.81). In the IgD MM group, 5 patients (63%) were in continued CR/PR. In the group of patient with other MM subtypes, 37 patients (54%) were in continued CR/PR.

In this study population, the median follow-up was 17.2 months and the median OS was 39.3 months. In the IgD MM group, the median follow-up was 17.1 months (range, 4.7 to 29.7) from the time of ASCT. The median EFS and OS were 6.9 and 12.0 months, respectively. Of the 6 deaths in this group, all were attributed to MM. In the group of patient with other MM subtypes, the median follow-up was 17.2 months (range, 1.1 to 71.3) from the time of ASCT. The median EFS and OS were 11.5 and 55.5 months, respectively. Of the 21 deaths in this group, 13 were attributed to MM, 7 to infection, and 1 to suicide. Patients in the IgD MM group had significantly shorter EFS (p=0.01) (Fig. 1) and OS (p<0.01) (Fig. 2) compared with patients with other MM subtypes. There were no significant differences in OS and EFS among patients with other MM subtypes (p=0.7 and p=0.9, respectively). The median OS in other MM subtypes was 62.6, 40.0, and 55.5 months, and the EFS was 10.6, 11.2, and 15.0 months for IgG, IgA, and free light chain subtype, respectively.

In patients with chromosome 13 deletion or hypodiploidy, the median OS was 39.3 months.

In this study population, age, performance status, lines of prior chemotherapy, interval from diagnosis to ASCT, hemoglobin, creatinine, and albumin levels at the time of ASCT, and response after ASCT showed no association with either EFS or OS. However, the level of β₂-microglobulin at the time of ASCT was significantly associated with EFS and OS.

OS after ASCT was associated with the SWOG stage at the time of ASCT. The median OS was 62.6 months in patients with SWOG stage 1, 24.5 months in patients with SWOG stage 2, and 31.9 months in patients with SWOG stage 3. In this study, patients with SWOG stage 1 had longer EFS and OS compared with patients with SWOG stage 2 or greater (p=0.173 and p=0.011, respectively).

The median OS was 62.6 months in patients with ISS stage 1, 37.8 months in patients with ISS stage 2, and 23.1 months in patients with ISS stage 3. Differences in EFS and OS among patients with different ISS clinical stages at the time of ASCT were not statistically significant (p=0.78 and p=0.185, respectively).

The results of univariate analysis are summarized in Table 3. Statistically significant prognostic factors for OS in the univariate analyses were SWOG stage 1, IgD subtype, and β₂-microglobulin, whereas the prognostic factors for EFS were only IgD subtype and β₂-microglobulin. The results of multivariate analyses are presented in Table 4. Based on the results of multivariate analyses, the prognostic factors associated with significantly shorter OS were IgD subtype (p= 0.002) and SWOG stage 2 or greater at the time of ASCT (p=0.01), whereas the prognostic factor associated with shorter EFS was only IgD subtype (p=0.023).