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
Authors: Yhim Ho-Young , Kim Kihyun , Kim Jin Seok , Kang Hye Jin , Kim Jeong-A , Min Chang-Ki , Bae Sung Hwa , Park Eunkyung , Yang Deok-Hwan , Suh Cheolwon , Kim Min Kyoung , Mun Yeung-Chul , Eom Hyeon Seok , Shin Ho Jin , Yoon Hwi-Joong , Kwon Jung Hye , Lee Jae Hoon , Kim Yang Soo , Yoon Sung-Soo , Kwak Jae-Yong 
Published: October 2019

Abstract
Abstract 1990

Introduction:
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 2nd ASCT might be a feasible and effective treatment modality in some pts. However, these studies contained small number of pts with 2nd ASCT and did not compare with outcomes of salvage therapy using novel agents. Thus, the aims of this study are to investigate outcomes of 2nd ASCT in pts relapsed after front-line ASCT and identify the impact of 2nd ASCT compared to modern systemic therapy in the novel agent era. To minimize the heterogeneity between the 2 groups, matched-pair design was chosen.

Methods:
The data of 48 pts between 1998 and 2010 with 2nd 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 2nd 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 2nd ASCT were matched to 144 pts with systemic chemotherapy.

Results:
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.
2nd 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 2nd 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 2nd 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 2nd 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.

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

Disclosures:
No relevant conflicts of interest to declare.