The past two decades witnessed major advances in treatment of multiple myeloma (MM), including introduction of high-dose therapy (HDT) (chemotherapy or chemoradiotherapy), autologous hematopoietic cell transplantation (auto-HCT), and other effective therapies including immunomodulatory drugs or proteasome inhibitors, namely bortezomib [1–5]. These new chemotherapeutic agents when used in combinations, have led to improvement in survival and a higher frequency and better quality of response; but have not translated into cure of this disease [3, 4].

The concept of ″total therapy″ treatment approach for patients with newly diagnosed MM, using multi-agent induction regimens, tandem auto-auto HCT, and post-transplantation maintenance resulted in progressive increase in proportion of patients achieving complete remission (CR) [6]. The Intergroupe Francophone du Myelome (IFM) demonstrated that tandem auto-auto HCT improves overall survival (OS) among patients with myeloma, particularly if a very good partial response (VGPR) is not achieved after undergoing the first auto-HCT [7]. A meta-analysis by our group showed that tandem auto-auto HCT versus single auto-HCT in previously untreated MM results in improved response rates, but not improved OS [8].

Badros et al. demonstrated the feasibility of offering reduced-intensity conditioning (RIC) allogeneic (allo)-HCT as a salvage strategy in 31 patients with relapsed MM [9]. Seventeen (55%) of 31 cases had received at least two auto-HCT and 17 (55%) had progressive disease at time of allografting [9]. Despite these adverse clinical features, 19 (61%) patients achieved CR or a near CR, with the 100-day and overall non-relapse mortality (NRM) of 10% and 29%, respectively [9]. This suggests a beneficial graft-versus-myeloma (GVM) effect mediated by alloreactive donor T-cells is capable of disease control, even in MM refractory to HDT. Gahrton et al. compared outcomes of patients who received allo-HCT for relapsed MM during 1983–1993 and 1994–1998 showing improvement in NRM and OS for patients allografted during the later time period [10]. The authors speculate that earlier time to allografting (10 months versus 14 months), for patients transplanted during the later time period, probably contributed to this beneficial effect [10]. Similar results were recently reported by Kumar et al., where 1 year OS post allo-HCT improved in three successive eras (1989–1994, 1995–2000, and 2001–2005) and increased interval between time of MM diagnosis and allografting was found to be an independent adverse prognostic factor for OS [11].

Combining benefits of cytoreductive-therapy from HDT and auto-HCT with adoptive immunotherapy (from allo-HCT) forms the basis of auto-allo HCT treatment strategy in patients with MM. Conflicting results, however, have been noted when an auto-allo HCT approach has been compared to an auto-auto HCT strategy. A recent systematic review on the same issue was performed by Armeson et al. [12] However, this systematic review is limited by inclusion of an inappropriate study, in our opinion. That is, this systematic review included the study by Garban et al. which was not a true randomized controlled trial but rather represents comparisons from two parallel trials (IFM99-03 and IFM99-04) that enrolled allograft and autograft recipients separately. Most importantly, the systematic review by Armeson et al. did not attempt to evaluate the methodological quality of included studies, which is the one of the key reasons to conduct a systematic review. Assessment of risk of bias in the systematic review process provides explanations on whether the observed findings are indeed the effect of the intervention or as a result of bias. Accordingly, we performed a systematic review of published studies comparing auto-auto HCT with auto-allo HCT in patients with newly diagnosed MM that addresses all the issues that were not addressed in the systematic review by Armeson et al.

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 [13]. Similarly, in the study by Rosiñol et al., three (75%) of four cases of NRM were from complications of acute GVHD [17]. 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 [14] 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. [13] 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 [13]. 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 [8].

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 [16]. However prognostic significance of 13q deletion detected by FISH as opposed to conventional cytogenetics remains questionable [26]. 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 [17].

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 [12]. The objectives of the IFM99-03 trial were to evaluate the feasibility and NRM of RIC allografting [19], 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 [13]. The investigators reported only partial data on a smaller cohort of high-risk patients.

Efforts at identifying particular subgroups of patients with MM, based on prognostic clinical, biological, cytogenetic and genetic risk factors, which are likely to benefit from an auto-allo HCT approach is necessary to help refine the role of this approach in MM. At the present, totality of evidence suggests that an auto-allo HCT approach for patients with newly diagnosed myeloma should not be offered outside the setting of a clinical trial.

Parts of this manuscript have been presented as an oral presentation at the Annual Meeting of the European Group for Blood and Marrow Transplantation 2012 (Abstract 520).