Auto-HCT has been regarded as the standard of care for younger myeloma patients [1, 23]. However, much controversy exists about the role and timing of allo-HCT in newly diagnosed MM. Our meta-analysis indicates despite higher CR rates following an auto-allo HCT approach, there is no apparent improvement in OS, whether comparative analysis is performed as per-protocol or on ITT basis. This is likely explained by significantly higher NRM associated with RIC allo-HCT versus a second auto-HCT [RR (95% CI) = 3.55 (2.17-5.80), p < 0.00001]. Accordingly, further improvements in the auto-allo HCT approach will require strategies to significantly reduce NRM and augment anti-myeloma effects. Not surprising, significant cause of NRM in the auto-allo HCT arm resulted from development of acute and/or chronic GVHD in these patients. For instance, in the study by Krishnan et al. eight (13%) of 60 deaths were attributed to GVHD . Similarly, in the study by Rosiñol et al., three (75%) of four cases of NRM were from complications of acute GVHD . This suggests that future treatment strategies aimed at exploiting GVM effects, in auto-allo HCT approach, should avoid exacerbating GVHD at all costs. It is noteworthy that OS benefit with an auto-allo HCT approach is limited to studies using 2 Gy TBI-based conditioning regimens [14, 15], which has led to speculation  that the lack of survival benefit in other studies might relate to use of more intense conditioning which is associated with increased regimen-related toxicity and mortality in those studies [16, 17]. It is important to indicate the largest trial by Krishnan et al.  used 2 Gy TBI conditioning but was also subject to referral bias, and to date has not reported any survival benefit.
Conceptually, auto-allo HCT approach combines the advantage of cytoreduction from HDT from the first autograft with the benefit of adoptive immunotherapy resulting from the donor T cell alloreactivity. Notwithstanding, in the study by Krishnan et al. 22 (37%) of 60 deaths in the auto-allo HCT arm were still due to MM . As a result, future strategies should aim at achieving deeper remissions, namely molecular remissions, or a state of minimal residual disease, prior to moving forward with allografting. This might entail evaluating novel potent therapies during the peri-allografting phase. Moreover, designing more effective regimens for allo-HCT, beyond 2 Gy TBI, is likely necessary to improve outcomes.
In regards to using auto-auto HCT as the control arm for comparison in these studies, one could argue that this approach is not yet considered the standard of care in all patients with newly diagnosed MM. In fact, outcomes from various studies comparing single auto-HCT versus tandem auto-auto approach have been discrepant [7, 24, 25] and a published meta-analysis failed to show OS benefit with tandem autografts .
A major limitation of all studies comparing auto-auto HCT to auto-allo HCT is lack of detailed information about disease/genetic risk stratification. Only one study limited accrual to patients with deletion 13q detectable by FISH . However prognostic significance of 13q deletion detected by FISH as opposed to conventional cytogenetics remains questionable . Whether an auto-allo HCT approach might be beneficial for high-risk MM is not known, and should be further assessed in future trials [27–29]. We were not able to assess if auto-allo HCT approach might be beneficial for high risk myeloma patients as included studies did not report results according to risk categories for all outcomes. An individual patient data meta-analysis would be suitable to answer this question. Furthermore, the results are prone to outcome reporting bias as only three studies reported OS data according to ITT [13, 14, 18] and another study reported data using per-protocol analysis only .
The findings are also somewhat different from the systematic review by Armeson et al. as we excluded a manuscript published by Garban et al. because it aimed at comparing two parallel trials (IFM99-03 and the IFM99-04) which enrolled allograft and autograft recipients separately . The objectives of the IFM99-03 trial were to evaluate the feasibility and NRM of RIC allografting , whereas the primary end point of IFM99-04 was to compare CR rates achieved after the second auto HCT (with or without anti–IL-6 monoclonal antibody BE-8). Additionally, we excluded a cohort of high-risk patients reported by a study by Krishnan et al. because the original aim of this study was to assess progression-free survival among standard-risk patients . The investigators reported only partial data on a smaller cohort of high-risk patients.