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Submyeloablative total body irradiation‐based conditioning and allogeneic stem cell transplantation in high‐risk myeloma with early progression after up‐front autologous transplantation

Treatment of patients with relapsed multiple myeloma (MM) after autologous stem cell transplantation (autoSCT) remains challenging. According to the consensus statement from the European Society for Blood and Marrow Transplantation (EBMT) and International Myeloma Working Group (IMWG), allogeneic SCT (alloSCT) should be considered as a treatment option in patients with high-risk MM. As there is still no established conditioning regimen in relapsed MM, our present retrospective analysis aimed to investigate a submyeloablative conditioning regimen with total body irradiation (TBI) in patients with early relapse after high-dose melphalan (HDM)/autoSCT. Between September 2009 and December 2017, 32 consecutive patients with high-risk MM were treated with a conditioning regimen with TBI (8 Gy)/cyclophosphamide followed by alloSCT at our institution (Data S1). Progression-free survival (PFS), overall survival (OS) and non-relapse-mortality (NRM) were calculated from date of alloSCT. Baseline patients’ and disease characteristics as well as previous treatments are described in Table SI. Besides early progression from up-front HDM/autoSCT (≤24 months) in all patients, 58 3% had adverse cytogenetics and 79 2% had either International Staging System Stage III and/or elevated lactate dehydrogenase and/or adverse cytogenetics at initial diagnosis. Details on re-induction treatment and response rates prior to alloSCT, engraftment and post alloSCT response rates, maintenance therapy, donor lymphocyte infusions (DLI) and relapse therapies are shown in Table I. The median age at alloSCT was 50 (range 34–64) years. Cumulative rates of very good partial response or better (≥VGPR) and progressive disease (PD) at day +100 post alloSCT were 42 3% and 34 6% respectively. Toxicities during admission for conditioning and alloSCT are listed in Table SII. In all, 15 patients developed acute graft-versus-host disease (aGvHD) of any grade (Table SIII). Chronic (c)GvHD occurred in 18 patients (Table SIII). The median [95% confidence interval (CI)] follow-up from alloSCT was 76 7 [38 8–112 6] months. The median (95% CI) PFS and OS from alloSCT was 9 4 (5 2– 13 7) months and 28 8 (8 0–49 5) months (Fig 1A,B). The PFS/OS were 41%/66% at 1 year, 22%/50% at 3 years and 13%/30% at 5 years. The NRM was 12 5% at 1-/3-years (95% CIs 4–27%) whereas the PD rates were 47% (95% CI 29–63%)/66% (95% CI 46–80%) at 1-/3-years respectively (Fig 1C). In total, 18 deaths were MM-related and four deaths were NRM-related (two patients with multi-organ failure, day +56/+287; one patient with aGvHD, day +67; one patient with sepsis, day +336 post alloSCT). Upon subdivision of the patient cohort in to two time periods from first MM diagnosis (2003–2010 versus 2011–2015), no differences in PFS, OS, PD or NRM were found (Figure S1). Neither cGvHD of any grade until day +180 post alloSCT or ≥VGPR on day +180 post alloSCT or combination of these two factors correlated with favourable PFS/OS (Figure S2). The presented submyeloablative TBI-based conditioning regimen in patients with high-risk MM led to a rather low NRM of 12 5% at 1-/3-years and encouraging OS (66%/50% at 1-/3-years) but efficacy was limited by a substantial number of early PD. Early relapse after HDM/autoSCT is associated with unfavourable disease characteristics and current maintenance treatment strategies after HDM/autoSCT can delay but mostly not prevent progression in this patient population. Our present study provides a focussed approach to treat such a patient population using alloSCT with an acceptable toxicity profile/NRM. Data on such focussed treatment approaches in a specific subgroup of patients with high-risk MM are rare and it is difficult to directly compare our present results to other studies. However, data from the Myeloma Research Council XI trial evaluating the prognosis of patients with early relapse after HDM/autoSCT found a median OS of 26 months, which is comparable to our present analysis. Current approved treatments in medically fit patients with relapsed MM after up-front HDM/autoSCT include mostly triplet combinations with monoclonal cluster of differentiation 38 (CD38) antibodies, next-generation proteasome inhibitors and immunomodulatory agents. These combinations produce deep responses and prolonged median PFS also in patients with high-risk MM, such as daratumumab/lenalidomide/dexamethasone (DRd, 26 8 months). Thus, these approaches challenge treatment including alloSCT but direct comparison of studies is difficult. However, there are general Correspondence