Matched-Pair Analysis Comparing Outcomes of Second Autologous Stem Cell Transplantation and Chemotherapy As a Salvage Therapy in Patients with Multiple Myeloma Who Relapsed After Front-Line Autologous Stem Cell Transplantation

Autologous stem cell transplantation (ASCT) is a standard of care for younger multiple myeloma patients (pts). However, nearly all pts undergoing ASCT will relapse and require salvage therapy. Several investigators have reported 2^nd ASCT might be a feasible and effective treatment modality in some pts. However, these studies contained small number of pts with 2^nd ASCT and did not compare with outcomes of salvage therapy using novel agents. Thus, the aims of this study are to investigate outcomes of 2^nd ASCT in pts relapsed after front-line ASCT and identify the impact of 2^nd ASCT compared to modern systemic therapy in the novel agent era. To minimize the heterogeneity between the 2 groups, matched-pair design was chosen.

The data of 48 pts between 1998 and 2010 with 2^nd ASCT after relapse of front-line ASCT identified from web-based registry (www.myeloma.or.kr) were analyzed. Pts with tandem ASCT or salvage allo-SCT were excluded. The goal of this study was to perform a matched-pair analysis, each patient with 2^nd ASCT was matched to three pts from a cohort of 517 pts treated with systemic chemotherapy after relapse of prior ASCT. The pts were matched for 9 potential prognostic factors: age at relapse (<60 vs ≥60), serum creatinine (sCr) at diagnosis (<2mg/dL vs ≥2mg/dL), ISS (I vs II vs III), serum LDH level (normal vs elevated), cytogenetics (del(13q)/hypodiploidy vs others), Induction therapy at first ASCT (VAD vs novel agents), Conditioning regimen at first ASCT (≤MEL140 vs >MEL140), response to front-line ASCT (≥VGPR vs <VGPR), and time to progression (TTP) since first ASCT (<18months vs ≥18months). At least 8 of these factors should be matched between the four matched pts. Finally, 48 pts with 2^nd ASCT were matched to 144 pts with systemic chemotherapy.

The median age at relapse was 55.5 (range, 33.4–68.5) years and 106 pts (55%) were male. The ISS was I(54, 28%)/II(84, 44%)/III(54, 28%). Serum LDH level was elevated in 133 (69%) and sCr ≥2mg/dL was in 35 (18%). The data of conventional cytogenetic analysis was available in 156 pts (79%). Thirty-three (21%) were abnormal. Of these, 26 pts (79%) had complex chromosomal abnormalities, 15 (45%) del(13q), and 6 (18%) hypodiploidy. One hundred sixty (83%) received VAD as induction therapy for first ASCT. Conditioning regimen for first ASCT was MEL 140–200 mg/m² in 187 (97%). Fifty-six (29%) received maintenance therapy after first ASCT. Response to front-line ASCT was 67 CR (35%), 39 VGPR (20%), 68 PR (35%), 13 MR/SD (7%), 5 PD (3%). The median TTP after first ASCT was 12.0 (range, 1.1–83.8) months, and pts with ≥18 months of TTP after first ASCT were 57 (30%). After matching process, we identified it was successful because the distribution of 9 matching variables and unmatched other variables (ECOG performance status, hypercalcemia, bone lesions) was balanced between 2 groups.

2^nd ASCT conditioning consisted of MEL alone in 45 (94%), the remaining 3 had MEL with busulfan or bortezomib. Only one transplant-related death occurred following 2^nd ASCT. Novel agents used as salvage therapy in their course of disease were bortezomib in 151 (79%), thalidomide in 138 (72%), and lenalidomide in 6 (3%). Thalidomide was less frequently used in the 2^nd ASCT group than the systemic chemotherapy group (58% vs 80%, p=0.016).

With a median follow-up of 55.3 (range, 3.4–140.0) months, the 2^nd ASCT group revealed significantly better progression-free survival (median, 18.0 [95% CI, 15.2–20.8] months vs 9.1 [6.7-11.5] months, p=0.017, respectively) and overall survival (OS; median, 55.5 [46.2-64.8] months vs 25.4 [16.7-34.1] months, p=0.035, respectively) than the systemic chemotherapy group. In multivariate analysis for OS, <18 months of TTP after first ASCT (HR, 2.77; 95% CI, 1.49–5.14), ISS III (HR, 2.04; 95% CI, 1.09–3.82), and salvage systemic chemotherapy (HR, 1.88; 95% CI, 1.09–3.22) were independent prognostic factors for worse OS.

The outcomes of salvage 2^nd ASCT appear superior to those of systemic chemotherapy, even fewer pts in the 2^nd ASCT group received thalidomide. Additionally, 2^nd ASCT was an independent prognostic factor for better OS. Considering current low mortality of 2^nd ASCT, our results might provide a substantial evidence for performing 2^nd ASCT in relapsed myeloma pts and suggest the value of performing a prospective randomized trial comparing 2^nd ASCT and systemic chemotherapy in pts relapsed after front-line ASCT.

No relevant conflicts of interest to declare.