Third Autologous Salvage Transplant at Late Myeloma Relapse Is Associated with Favourable Overall Survival and Contributes to Improvement of Exhausted Bone Marrow Function
Authors: Strifler Susanne , Hilgendorf Inken , Kleber Martina , Röllig Christoph , Mügge Lars-Olof , Teleanu Maria-Veronica , Kragl Brigitte , Einsele Hermann , Knop Stefan 
Published: October 2019

Abstract
Background High-dose chemotherapy followed by autologous stem cell transplant (ASCT) has been the mainstay of first-line treatment in multiple myeloma for nearly two decades. As the majority of patients (pts.) will experience relapse, we continuously are in need of effective salvage strategies such as the era of the “novel agents” is offering. The “next generation” compounds such as pomalidomide or carfilzomib significantly improve prognosis. However, virtually all drug combinations need to be delivered continuously through (subsequent) disease progression, thereby contributing to exhaustion of bone marrow function. This in turn leads to compromised full-dose treatment, which would be necessary to conquer refractory disease. Given these challenges and considering a long interval since the initial exposure to melphalan (Mel) a further autotransplant seems reasonable. Whether a third autotransplant still is effective in patients who have initially received tandem ASCT and may overcome therapy-induced exhausted bone marrow function is unclear. Therefore, we assessed the outcomes of pts. receiving a third melphalan-based salvage ASCT (ASCT3).
Methods We queried the databases of six German myeloma centres for cases that were offered a third autotransplant after uniform melphalan-based tandem ASCT as part of their first-line therapies.
Results 55 pts. with a median age of 58 years at diagnosis (range, 36 – 72) and of 63 (range, 38 – 77) at ASCT3 were identified. ASCT3 was performed at a median of 63 (range, 14 – 355) months (mos.) from myeloma primary diagnosis and a median interval from initial tandem autotransplant of 51 (range, 5 – 131) mos. Median progression-free survival (PFS) from primary tandem transplant had been 23 mos. (range, 4 – 94). 45 pts. (82%) had either received bortezomib and/or lenalidomide, and 37 pts. both. Eleven pts. had been double refractory and 23 pts. at least had been refractory to one of the novel agents prior to their 3rd transplant. In 45 cases cytogenetic analysis had been available, of which 9.1% could be classified as ”high-risk” (17p13 del, t(4;14), t(14;16), amp1q21, del1p). At ASCT3, median administered Mel-dose had been 100mg/m2 (range, 30-200). 50 pts. received autografts, which had been harvested at first-line treatment while 5 pts. had successfully undergone additional stem cell mobilisation. Median number of re-infused CD34+ cells was 3.0 (range, 0.4 – 15.7) x 10exp6/kg body weight with all patients achieving stable engraftment. A remarkable improvement of platelet count (PLT) and haemoglobin (Hb) within 3 mos. of ASCT3 could be achieved. PLT improvement occurred in 53% and Hb improvement (when compared to pre-ASCT3 values) in 64% of pts. Beyond that, overall response rate (partial response (PR) or better) was 59% with 8 pts. (15%) achieving CR, 6 pts. (11%) VGPR and an additional 18 pts. (33%) PR, respectively. 23 pts. (42%) suffered from grade 3 non-hematologic toxicities and in one case a grade 4 toxicity was documented. Non-relapse mortality (NRM) within 3 mos. after ASCT3 was 5%. Median PFS after ASCT3 was 6 mos. for the whole group and 2 mos. for the group with “high risk” cytogenetics (p=0,06), respectively, whereas median OS (30 mos.) was identical. In case of double-refractory myeloma, PFS did not differ significantly (3 mos. vs. 7 mos., p=0.35) whereas there was a significant difference in median OS (12 mos. vs. 35 mos., p=0.002) in comparison with non-refractory pts., respectively.
Conclusions Our analysis indicates that salvage ASCT at late relapse is feasible and associated with a 6 mos.’ additional PFS interval but also contributes to improved hematopoietic function. Pts. may thus tolerate further conventional lines of treatment what is suggested by an OS of 30 mos. In addition, ASCT offers a substantial treatment-free interval when compared to either “next generation” novel drug. In this series, unfavourable cytogenetics were associated with a trend for worse PFS but not OS outcomes, meanwhile being double refractory was linked with clearly inferior OS. Interestingly, median duration of storage of their autografts of 52 mos. (range, 1 – 154) did not impair engraftment after salvage transplant.

Disclosures
No relevant conflicts of interest to declare.