20 Years of Transplant Program in Multiple Myeloma - a Single Centre Experience
Authors: Minarik Jiri , Faber Edgar , Raida Ludek , Szotkowski Tomas , Bacovsky Jaroslav , Pika Tomas , Skoumalova Ivana , Krhovska Petra , Zapletalova Jana , Papajik Tomas , Scudla Vlastimil 
Published: October 2019

Abstract
Aims: The aim is to present the results of 20 years of autologous stem cell transplant (ASCT) program in multiple myeloma (MM) at our site.
Patients and methods: Since 1997 till 2017, a cohort of 348 patients underwent ASCT at the Department of Hemato-Oncology of the University Hospital Olomouc. Altogether 274 were 1st ASCT, 62 were 2nd transplants, the rest were tandem or third ASCT. The patients had standard baseline characteristics, including age, gender, immunoglobulin and light chain type, Durie-Salmon (DS) and International Staging System (ISS).
The induction regimens for 1st ASCT included VAD (vincristin, adriamycine, dexamethasone) in 34%, THAL in 15%, BTZ based regimens in 34%, the rest (17%) were combined polychemotherapeutic regimens. The re-induction regimens before 2nd ASCT included CAD (cyclophosphamide, adriamycine, dexamethasone) in 27%, BTZ in 31% and THAL based regimens in 18%, other patients (24%) had LEN based regimens, polychemotherapy or no re-induction. 163 patients (47%) had maintenance, mostly interferon based (25%), conventional chemotherapy based (9%) or THAL based (7%), and 53% of patients had no maintenance.
We assessed response rates, ie the rate of complete remission (CR), very good partial remission (VGPR), partial remission (PR), minimal response (MR), stable disease (SD), progressive disease (PG) and overall response rate (ORR) based on International Myeloma Working Group (IMWG) criteria. The survival measures of individual treatment lines were assessed by means of progression free survival (PFS). We assessed the efficacy of ASCT with respect to treatment line, pre-transplant and post transplant response achieved (day+100), and with respect to DS and ISS as well as to treatment modality used for induction and maintenance.
For statistical estimation we used Kaplan-Meier curves, Log rank test (Mantel-Cox), Post-hoc tests according to Dunn, Pearson ChiSquare test, Fisher´s Exact Test, Kruskal-Wallis test, and McNemar-Bowker Test.
Results: The response rates after 1st ASCT were following: CR 32,1%, VGPR 26,5%. PR 34,8%, MR and SD 3% and PG 3,4%. Median PFS after 1st ASCT was 35 months and it corresponded to the depth of treatment response: CR 48 months, VGPR 36 months, PR 33 months, MR and SD 13 months, PG 9 months, p<0,0001. Pre-transplant responses showed a trend towards better outcomes with deeper responses but beyond statistical significance (p = 0,077). Advanced DS stage correlated with worse PFS (stage I 58 months, stage II 42 months, stage III 31 months). Patients under age 59 years tended to have slightly better PFS (37 vs 34 months, p = 0,078).
Both pre and posttransplant responses were significantly better after novel drugs than conventional chemotherapy, still, there was no statistically significant difference in PFS. None of the maintenance (chemotherapy, interferon, THAL-based) lead to a better PFS. There were very few patients treated with BTZ, LEN or ixazomib maintenance precluding valid statistical analysis. There were no differences in either responses or PFS with regard to treatment line but there were only 19 patients not having ASCT as their first regimen.
The response rates after 2nd ASCT were as follows: CR 26,7%, VGPR 13,3%, PR 38,3%, MR+SD 8,3% and PG 13,3%. Median PFS after 2nd ASCT was 20 months, decreasing with inferior responses (CR 34,8 months, VGPR 22,5 months, PR 33,1 months, MR and SD 18,8 months, PG 6,6 months p<0,0001). There were no differences in PFS with respect to either ISS, DS stage or re-induction regimen. Patients transplanted in their first relapse tended to have better PFS than in later relapses.
Conclusion: The use of ASCT is still the gold standard in MM. Regardless of treatment line, it achieves significant outcomes. Novel drugs induce deeper pre-transplant responses, still, the major advantage against conventional chemotherapy is in the speed of response and absence of severe adverse events, enabling more patients to reach ASCT. Maintenance therapy accounts for better survival, however, this is true only for novel drugs (such as bortezomib, lenalidomide) whereas older modalities including interferone, post-transplant chemotherapy, steroids or thalidomide do not possess such activity. The second ASCT is comparable to to current treatment modalities in relapsed MM with fair post-transplant outcomes as well as PFS, with high rate of complete responses.
Supported by the grant IGA-LF-2018-004 andMH CR - RVO (FNOl, 00098892).

Disclosures
No relevant conflicts of interest to declare.