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C. Greil et al.
did not reveal any significant differences (P=0.766 and P=0.065, respectively) (Table 4), but suggested that QoL under allo-SCT improved rather than deteriorated.
The R-MCI worsened from the time point of allo-SCT to the last follow up in 48% (22 of 46) of the examined patients, whereas the score improved or was unaffected in 26% each (52%). However, a decrease was caused only by aging and age-related impaired renal function in 59% (13 of 22). Only 27% (6 of 22) of the patients with decreased R-MCI after allo-SCT showed signs of (mostly moderate) GvHD. In 14% (3 of 22), the general condition was wors- ening due to occurrence of an independent illness (stroke, second malignancy, LKM1-positive autoimmune hepati- tis). Interestingly, only 45% (10 of 22) reached CR in this cohort, whereas 58% (7 of 12) of the group with improved R-MCI were in CR at the last follow up, indicating the influence of disease activity on the patients’ QoL. The cohort was too small to allow further statistical analyses.
We also assessed each of the 5 risk factors within the R- MCI and their changes upon allo-SCT separately (see Table 4 and Figure 4).
Discussion
Allo-SCT has been conducted in a large group of patients diagnosed with MM at our academic center, especially in relapsed/refractory situations in heavily pre-treated patients, mostly showing high-risk disease due to cytoge- netic analysis and/or ISS. We observed a high ORR of 70%, with a median PFS of 14.2 months and a median OS of 39.2 months. Of note, only a moderate rate of high-grade GvHD occured. Survival was even better in patients with sufficient response to induction therapy (median OS, 65.0 months), and best in those treated within the first-line ther- apy (median OS not reached), independently of the time point of allo-SCT. As survival curves reached a plateau, and late relapses rarely occurred, a possible long-term survival or even cure may be presumed for a subgroup of MM patients. There was no statistically significant difference in survival when comparing patients transplanted in first-line with standard risk and those with high, poor or ultra-high- risk cytogenetics according to the actual IMWG- consensus.30 Similar findings have been obtained in previ- ous trials mostly distinguishing patients with or without detection of deletion 13q14,22 both results suggesting that high-risk cytogenetics may be overcome by allo-SCT.8,9,32–34
Available data from prior retrospective trials on allo-SCT in MM are inconsistent due to divergent therapeutic con- cepts and heterogeneous cohorts.4,35 Thus, comparison of survival and toxicity data is challenging.
For patients transplanted in first-line due to a high-risk constellation, mostly following a prior auto-SCT in terms of a tandem concept, the median OS reported in different studies ranges between 34 months and not reached; the best OS has been achieved with a long follow up, as in our analysis.9-12,36 For the cohort with relapsed/refractory dis-
ease, a median OS of 13-24 months was recorded in differ- ent trials,17,37 with our result of 21.6 months lying in the upper range of these values. Our PFS data were superior for patients with allo-SCT in first-line therapy with a median of 47.7 months compared to 19-35 months reported in the literature.9-12,36 The median PFS reached in our cohort of relapsed/refractory patients was also quite high with 9.6 months compared to 7-10 months in previous studies.17,37
The therapy-associated toxicity at our center, with a cumulative incidence of NRM of 13.4% in two years after allo-SCT performed as first-line treatment, was compara- ble to the rates of 11-16% found in published trials.10,12,36 We observed a relatively low NRM in relapsed/refractory MM with 10% in two years, contrary to prior analyses with rates of 11-43%.15–18,38-40 Accordingly, the incidence of cGvHD was comparatively low, with detection of cGvHD of any grade in 36%, whereas cGvHD was observed in 32- 66% of patients in other cohorts.8,10,12,14,36,40
In order to make an objective assessment of comorbidi- ty and therapy-associated restrictions, we analyzed the R- MCI and its single risk factors over time. The median R- MCI of our allo-SCT cohort was 4 at ID, but improved remarkably to 3 at the assessment right before allo-SCT and at the last follow up. Formally, this increase implicates a risk-group shift from intermediate-fit (R-MCI 4-6) to fit- ter patients (R-MCI 0-3),24 bearing in mind that patients had aged by almost a decade with a substantial age-related deterioration in renal function, which even under-estimat- ed the improvement in patients' QoL. These findings sug- gest that QoL under allo-SCT can indeed improve or at least may not necessarily be impaired, most probably as a consequence of treatment response, as a reduction in ill- ness-induced limitations may outweigh therapy-associated impairment.
Taken together, our data suggest that allo-SCT may enable long-term survival and a potential cure in a carefully selected subgroup of MM patients with tolerable toxicity under appropriate supportive therapy. RIC allo-SCT should preferentially be performed within clinical trials. However, it may be considered individually in younger patients with good performance status and high-risk dis- ease in the initial course of therapy. Such an approach has the potential of achieving a significantly better survival,35 especially in the context of novel agents and immunother- apy approaches,41 and could improve rather than impair QoL, as shown with our R-MCI subanalyses. MRD-guided immunotherapy with DLI, IMID, PI and monoclonal anti- bodies may significantly improve outcome even more.8,9,42,43 Our long-term retrospective single-center study may help to further evaluate the impact and redefine the role of allo-SCT in patients with MM in a rapidly changing treatment scenario. Future prospective trials should be designed with combinations of new drugs that allow pro- found cytoreduction before allo-SCT and that can enhance the efficacy of GvM through immunomodulatory effects after transplantation, thus leading to long-term disease control and survival even in high-risk MM patients.
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