Allogeneic stem cell transplantation for multiple myeloma: is there a future?

Transcription

1 Bone Marrow Transplantation (2016), Macmillan Publishers Limited All rights reserved /16 REVIEW Allogeneic stem cell transplantation for multiple myeloma: is there a future? B Dhakal 1, DH Vesole 2 and PN Hari 1 Despite remarkable progress in survival with the availability of novel agents, an overwhelming majority of patients with multiple myeloma (MM) relapse and the curability of MM remains limited. Genetically defined high-risk MM represents a subgroup with an aggressive disease course despite novel agents. Allogeneic hematopoietic cell transplantation (allo-sct) is a potentially curative option in MM that has several advantages including a tumor-free graft, and the potential for sustained immune-mediated disease control. However, historically high treatment-related mortality (TRM) and conflicting reports from prospective studies in the United States and European Union have limited the utilization of this modality. Meanwhile, newer preparative regimens, planned maintenance strategies and improvements in supportive care have led to a decline in TRM and better survival in recent years. The allo-sct platform also provides additional options of immunotherapy at relapse including donor lymphocyte infusions, immunomodulatory drug maintenance and withdrawal of immune suppression. In this article, we provide an in-depth review of literature for allo-sct and other immunotherapy options, as well as the authors approach to using allo-sct in MM. Bone Marrow Transplantation advance online publication, 4 January 2016; doi: /bmt INTRODUCTION In the era of novel antimyeloma agents, autologous stem cell transplantation (ASCT) and subsequent effective salvage therapies at the time of relapse, there has been significant improvement in the survival of patients with multiple myeloma (MM). 1 For transplant-eligible patients, the typical treatment sequence includes induction therapy combining a proteasome inhibitor (PI) with dexamethasone and either an immunomodulatory agent or an alkylating agent (e.g. cyclophosphamide) for 3 4 cycles followed by ASCT. 2 Thereafter, there are a number of options including: observation, a planned second ASCT, consolidation followed by maintenance or maintenance alone. The incidence of complete remission, even to the extent of minimal residual disease, can be achieved in over 50% of the patients. 3 5 Despite this marked improvement in response with this approach, the vast majority of patients relapse and require second-line and subsequent therapies. The available options include retreatment with the initial regimen, assuming efficacy and tolerability, and subsequently the more recently approved drugs including carfilzomib, pomalidomide, panobinostat and so on, and monoclonal Abs. 6,7 Ultimately, despite effective salvage regimens, multidrug resistance ensues and the patients succumb to progressive MM. Thus, although we are approaching MM being considered a chronic disease, it remains an incurable disease despite advances in these treatment modalities. Immunotherapy, excluding the proven graft-versus-myeloma (GVM) effect from alloreactive T cells administered in conventional stem cell allografts, is an attractive option yet it remains in its early development. Recent efforts to generate activated chimeric Ag receptor T lymphocytes (CAR T cells), a technology with proven efficacy in B-cell malignancies expressing CD19, is just being developed in MM to other potential targets. 8 Cellular therapy is perhaps the most underutilized but may be the most potent mechanism of action for disease control in MM. Currently, there is clear evidence of cures in MM with allogeneic transplant (allogeneic hematopoietic cell transplantation (allo-sct)) as documented by older myeloablative preparative regimens, immunosuppressive agent withdrawal and/or donor lymphocyte infusions (DLIs). 9,10 However, the role of allo-sct remains controversial owing to reports of varying benefit and the associated high transplant-related mortality (TRM). 11,12 Despite these concerns, interest persists in striving for a curative therapy for an incurable malignancy. We propose an additional concept that, even if not curative, allo-sct may improve overall survival (OS) as compared with ASCT, again striving for a chronic disease state for those individuals who are not cured. In this article, we provide an in-depth review of literature supporting allo-sct in MM and provide guidelines for who should be considered for this treatment approach. MYELOABLATIVE CONDITIONING Allotransplant preceded by classic myeloablative conditioning therapy was explored for MM in the late 1980s through the mid-1990s. These early data can be extracted from the transplant registries: the European Bone Marrow Transplantation (EBMT), International Bone Marrow Transplantation Registry and the Fred Hutchinson Cancer Center registry A most consistent finding with the use of myeloablative conditioning was high TRM of 40 60% (Table 1). Early TRM in the EBMT report was ~ 45%, 14,15 with deaths mainly due to infection, GVHD and regimen-related toxicities. In a subsequent study, EBMT compared the patients who received transplants between 1983 and 1993 with those who received transplants 1 Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI, USA and 2 Division of Hematology/Oncology, Georgetown University, Washington, DC, USA. Correspondence: Dr PN Hari, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. phari@mcw.edu Received 24 September 2015; revised 11 November 2015; accepted 14 November 2015

2 2 Table 1. Allogeneic stem cell transplantation in multiple myeloma with myeloablative conditioning Reference Total allo patients Trial setting Conditioning cgvhd TRM (%) OS PFS EBMT registry Relapse/refractory patients Cy/TBI, BuCy, N/R 45 Median OS, 26 m N/R MelTBI Hutchinson Cancer 144 Relapse/refractory BuCyTBI, CyTBI 27% 49 11% at 15 y 8% at 15 y registry 13 S Postinduction biological assignment based on sibling match donor Mel/TBI N/R 53 N/R N/R HOVON Postinduction biological assignment based on sibling match donor CyTBI+/ idarubicin 30% 34 Median OS, 25 m Median PFS, 18 m Abbreviations: Bu = busulfan; cgvhd = chronic GVHD; Cy= cyclophosphamide; EBMT = European Bone Marrow Transplantation; HOVON-24 = Haemato- Oncology Foundation for Adults in the Netherlands-24; m = months; Mel = melphalan; N/R = not reported; OS = overall survival; TRM = treatment-related mortality; y = years. between 1994 and 1998, showing a decrease in TRM from 46 to 30% at 2 years with better patient selection earlier in the disease course with chemotherapy-sensitive disease. 16 Similarly, early TRM in the International Bone Marrow Transplantation Registry and the Hutchinson center was 40% and 49%, respectively. 17 The actuarial survival for EBMT patients was 28% at 7 years, 14 for International Bone Marrow Transplantation Registry it was 35% in patients with good performance status and 21% for the Hutchinson center but with the apparent plateaus on survival curves indicative of curative potential. A retrospective study from EBMT comparing ASCT and allo-sct showed that there was a trend for better OS at 1 year in the allo-sct group (P=0.09), but with higher TRM in the group (41% vs 13%). 18 Two prospective trials have compared ASCT with myeloablative allo-sct. The US Intergroup trial (S9321) of early vs late ASCT had a third option that allowed patients with matched siblings ( o55 years) to undergo allo-sct using an ablative regimen of melphalan and TBI. 19 The mortality in this arm was high ~ 53%, resulting in the closure of this arm of the study. The OS rates were identical at 39% for ASCT and allotransplant after 7 years of follow-up, with PFS of 15% vs 22% in the ASCT vs allo-sct arms but with a plateau in the allotransplant cohort that was not evident in the ASCT cohort. The Haemato-Oncology Foundation for Adults in the Netherlands-24 (HOVON-24) study showed TRM of more than 30% with inferior PFS and OS in patients who underwent T-cell-depleted myeloablative allo-sct after cyclophosphamide/tbi conditioning. 20 The consensus opinion was that although allo-sct may be potentially curative in sub-populations of patients achieving a sustained remissions and plateau in survival, due to the high TRM with myeloablative conditioning, myeloablative preparative regimens were abandoned. NON-MYELOABLATIVE/REDUCED-INTENSITY CONDITIONING The advent of newer non-myeloablative and reduced-intensity conditioning (RIC) approaches offered the prospect of reducing TRM for allo-sct in MM. 21,22 Thus in the 2000s, more patients received allotransplant using RIC regimens, usually with melphalan mg/m 2 with or without other agents. 23 A CIBMTR (Center for International Blood and Marrow Transplant Research) analysis demonstrated a major practice switch to nonmyeloablative and RIC-based allo-sct with concomitant reduction in the number of myeloablative allografts performed in the years compared with the two preceding 5-year intervals. 24 RIC allowed for an expansion in patient eligibility with older MM (but o65 years because of Medicare restrictions) patients receiving allo-sct and increasing numbers of allo-sct performed after autologous transplant in a tandem autologous allogeneic sequence. Interestingly, OS after allo-sct did not improve over time since the decline in TRM was negated by an increase in relapse risk in later years. Several phase II studies were reported using the strategy of an initial autologous transplant followed (usually 3 6 months later) by non-myeloablative transplant. The rationale was to uncouple maximal tumor cytoreduction from high-dose melphalan achieved in ASCT from the immune-mediated benefits of the allo-sct approach. Early studies suggested that for newly diagnosed patients after induction, with the tandem ASCT-allo-SCT approach, excellent short-term (24 month) outcomes could be achieved with TRM ranging from 11% (for related donor grafts) to 26% (for unrelated donor grafts). 21,25,26 Long-term results of upfront tandem ASCT-allo-SCT protocol from the Seattle group indicated a post allotransplant complete response (CR) rate of 60% and TRM of 18% at 5 years. 27 The median event-free survival (EFS) was 3 years and the median time to progression was 5 years. Five-year OS and EFS were 64% and 36%, respectively. The GITMO (Gruppo Italiano Trapianti di Midollo) experience in 100 newly diagnosed patients who received tandem ASCT-allo-SCT was similar. Although CR rates increased to 53% after allotransplant, median EFS was only 37 months. 28 The lack of an apparent cure with ongoing late relapses was disappointing in both studies. Allotransplant for MM in the upfront setting Several randomized trials (Table 2) have attempted to evaluate tandem ASCT-allo-SCT approach vs tandem ASCT in the upfront transplant setting using non-myeloablative preparative regimens. 29,30 In 2007, Bruno et al. 31 described the outcomes of 245 patients, o65 years old, biologically assigned (on sibling donor availability) to allo-sct vs a second tandem ASCT after initial induction. 31 Eighty patients with an HLA-identical sibling were assigned to 200 cgy (Gray) TBI-based allotransplant, whereas 82 patients without an HLA-identical sibling were assigned to receive a second ASCT. Overall, 58 and 46 patients completed the tandem ASCT-allo-SCT and the tandem ASCT programs with CR rates of 55% vs 26% and TRM of 10% and 2%, respectively. The initial findings of an improved OS and EFS were confirmed in an update of this study. With a median follow-up of 7 years, the median OS was not reached (P=0.02) and PFS was 39 months (P=0.02) in the 58 patients who received an allo-sct, whereas OS was 5.3 years and EFS 33 months in the 46 who received tandem ASCT. 32 In those achieving CR after allotransplant, 53% were in continuous complete remission compared with 19% for CR following tandem ASCT. This was the first randomized study that showed an advantage for allo-sct over ASCT in MM and indicated that CR achieved after allotransplant was durable with a plateau in OS. However, the main problem with this study was that the melphalan doses were variable and not optimal to see optimal Bone Marrow Transplantation (2016), Macmillan Publishers Limited

3 Table 2. Allogeneic stem cell transplantation in multiple myeloma with reduced-intensity/non-myeloablative conditioning in upfront setting 3 Reference N total N allo Trial setting Conditioning cgvhd allo-hct TRM OS PFS Conclusion Bruno et al /58 Post-induction biological assignment based on matched sibling donor IFM /65 Parallel prospective studies limited to high-risk disease Rosinol et al /25 Limited to patients not in CR after a first ASCT Knop et al. 96 EBMT-NMAM /126 Limited to patients with 13q by FISH, unrelated donor grafts in 60% 357/108 Post-induction biological assignment based on matched sibling donor BMT CTN 710/226 Post-induction biologic assignment based on matched sibling donor HOVON Not strictly a randomized study donor vs no donor analysis of HOVON-50 MEL ASCT followed by TBI 2 Gy vs MEL doses mg/m 2 followed by Flu-BU+ATG allotransplant vs Flu-MEL allotransplant vs ASCT followed by Flu-MEL vs MEL 200 ASCT followed by Flu TBI 2 Gy vs followed by TBI 2Gy allotransplant vs followed by TBI 2 Gy allo-hct 32% 10% Median 80 vs 54 mo (P=0.01) 42% 11% Median 34 vs 48 mo (P=0.07) 66% 16% Median NR vs 58 mo (P=0.9) N/R 12% Median NR at 49 mo 54% 13% 8 yr OS 49% vs 39% (P=0.03) 54% 11% 3 yr OS 77% vs 80% 64% 16% 6 yr OS 55% in both groups Median 35 vs 29 mo (P=0.02) Median 19 vs 22 mo (P=0.58) Median 20 vs 26mo (P=0.4) Median 34.5 vs 22 mo (P=0.005) 8 yr PFS 22% vs 12% (P=0.02) 3 yr PFS 43% vs 46% 6 yr PFS 28% (donor group) vs 22% (no donor group) Clear benefit for allotransplant in intention to treat donor vs no donor analysis 30% did not complete allotransplant. No benefit to allotransplant in this study Higher CR rate after allotransplant but no survival benefit Largest trial in high-risk patients and with unrelated donors. Del17p subgroup with OS benefit Allotransplant with lower risk of relapse and improved PFS. Benefit for higher-risk del13 subset No benefit to allotransplant in this study No benefit to having a related donor but allotransplant was by center preference. Relapse lower for those with donors Abbreviations: Allo-HCT = allogeneic hematopoietic cell transplantation; ASCT = autologous stem cell transplantation; ATG = antithymocyte globulin; BMT CTN= Blood and Marrow Transplant Clinical Trials Network; BU = busulfan; cgvhd = chronic GVHD; EBMT = European Bone Marrow Transplantation; Flu = fludarabine; Gy = Gray; HOVON = Haemato Oncology Foundation for Adults in the Netherlands; MEL = melphalan; mo = months; N/R = not reported; OS = overall survival; yr = years. results of tandem ASCT, and further problems are that patients drop out mainly in the ASCT arm. Other prospective randomized studies have demonstrated discordant results. The BMT CTN (Blood and Marrow Transplant Clinical Trials Network) 0102 multicenter trial in the United States compared tandem ASCT with tandem ASCT-allo-SCT approach based on matched sibling donor availability. 33 The patients were randomized to tandem ASCT or ASCT-allo-SCT on the basis of availability of HLA-matched sibling donor. Two cohorts were studied: standard risk and high risk, as defined in 2001, by an elevated β2-microglobulin and chromosome 13 deletion by metaphase karyotype. The conditioning regimen for each ASCT was melphalan 200 mg/m 2 ; the conditioning for the allotransplant was 200 cgy of TBI. A total of 710 patients were enrolled: 625 standard-risk (436 tandem ASCT and 189 ASCT/allo-SCT) and 85 high-risk (48 tandem ASCT and 37 ASCT/allo-SCT) patients. The dropout rate was 16% in the ASCT group and 17% in the ASCT/allo-SCT group. In the standard-risk cohorts, the two arms were similar for the primary end point of 3-year PFS (46% vs 43%, P=0.67) and OS (80% vs 77%, P=0.19) in tandem ASCT vs ASCT/allo-SCT, respectively. The TRM was 4% and 11%, respectively. In the high-risk cohort, again no benefit was observed between groups: 3-year PFS (33% vs 40%, P=0.74) and 3-year OS (67% vs 59%, P=0.46) in tandem ASCT vs ASCT/allo-SCT, respectively. The cumulative incidence of GVHD was high with 26% grade 3 4 acute and 47% chronic GVHD (cgvhd) at 1 year after allotransplant. There was a trend towards improved PFS (6 months, P=0.012) in patients who developed cgvhd. In contrast, the EBMT network completed a trial with a similar design with completely opposite results. The conditioning regimen was melphalan 200 mg/m 2 for ASCT and TBI 200 cgy and fludarabine 30 mg/m 2 for 3 days for allo-sct arm. With a median follow-up of 8 years, the PFS and OS for the tandem ASCT-allo-SCT was superior to the tandem ASCT group; PFS was 22% vs 12% (P=0.027), and the OS was 49% vs 36% (P=0.030), respectively, favoring tandem ASCT-allo-SCT. 34,35 Relapse was lower in the allo-sct cohort (60% vs 82%, P=0.0002), although TRM was 12% in this cohort vs 3% in the ASCT cohort. In patients with the high-risk deletion, 13 chromosome abnormality by FISH, PFS and OS favored the allo-sct cohort 21% vs 5%, P=0.026 and 47% vs 31% (P = 0.154), respectively. Interestingly, in this study, patients who relapsed/progressed following allo-sct had a significantly higher OS compared with the patients who relapsed after tandem ASCT. There was also no difference in the outcomes in those patients who developed cgvhd. The GVM effect is thought to have had a major role in this phenomenon. The Italian Bone Marrow registry data of 196 patients with MM receiving an unrelated donor transplant showed a significant improvement in OS for patients with cgvhd (hazard ratio, 0.55). 36 In another single institution study, development of cgvhd was associated with favorable OS and PFS further substantiating the importance of GVM effect Macmillan Publishers Limited Bone Marrow Transplantation (2016), 1 9

4 4 Allotransplant for MM in relapsed setting Retrsopective studies. A number of retrospective studies have reported the feasibility of allo-sct in MM. The outcomes of a second ASCT (N=137) were compared with those of a salvage allograft (N=152) after non-myeloablative and RIC conditioning from 1995 to 2008 in the CIBMTR registry; 3-year PFS and OS for the allo-sct cohort were 6% and 20%, respectively. These outcomes were inferior to those observed for the autotransplant cohort (12% and 46%, respectively) with higher 1-year non-relapse mortality (NRM) (13% vs 2%). 38 In another study, 169 consecutive patients who had relapsed after ASCT and had undergone HLA typing immediately after relapse were analyzed. The 2-year PFS was higher in the donor allo-sct group 42% vs 18% (P=0.0001) with similar OS (54% vs 53%), possibly due to short follow-up, whereas TRM was 22% vs 1% in the allo-sct vs ASCT. 39 de Lavallade et al. 40 showed that patients with relapsed MM who underwent RIC allo-sct had a significantly better EFS compared with patients without a transplant (46% vs 8%, respectively, at 3 years); however, TRM was 33% in the allo-sct group. Michallet et al. 41 reported an EBMT registry study on allo-sct in MM, which included 7333 patients who were transplanted between January 1990 and December The 1588 patients who received an allo-sct after a single SCT showed a 5-year PFS and OS of 26% and 33%, respectively, whereas the 930 who received it after failing a double ASCT showed a 5-year PFS and OS of 24% and 29%, respectively, and the 296 transplanted with an allo-sct after at least three autografts a 5-year PFS and OS of 15% and 23%, respectively. 41 A small number of single institution comparison have also been performed and are summarized in Table These studies suggest that allo-sct in the salvage setting has lower relapse rates but comparable or inferior survival to salvage ASCT, which is offset by high NRM. Prospective studies. In a prospective multicenter EBMT trial, Kroger et al. 45 investigated the role of allo-sct from unrelated donors in 49 patients who relapsed after a previous ASCT. Conditioning regimen consisted of melphalan (140 mg/m 2 ), fludarabine (90 mg/m 2 ) and rabbit antithymocyte globulin. The overall response rate was 90%, including 40% complete remissions. Cumulative incidence of 1-year TRM was 25%, and was significantly lower in transplants from fully HLA-matched donors as compared with mismatched donors (10% vs 53%, P=0.001). After a median follow-up of 43 months, the 5-year PFS and OS were 20% and 26%, respectively, and were significantly better in patients who achieved post transplant CR (41% vs 7%, P=0.04, and 56% vs 16%, P=0.02). 45 In summary, while allo-sct induces high CR rates and provides superior antirelapse potential compared with ASCT, TRM rates with conventional allo-sct remain prohibitive. In the absence of a clearcut survival advantage across studies and with recent improvements in induction and maintenance therapy, some experts have suggested the death of allo-sct in MM. However, MM is still incurable with novel induction followed by ASCT, and while two randomized studies have shown a survival benefit for allo-sct, other studies have suggested comparable/inferior outcomes to ASCT. It is also notable that these allo-sct trials were conducted in patients who had not received novel therapy-based induction regimens. The discordant results of the randomized trials of allotransplant in upfront therapy of MM are illustrated in Table 2. These trials vary in conditioning regimens used, patient selection, MM risk profile and the use of agents such as antithymocyte globulin, which may reduce the potential for GVM effect. Variability in duration of follow-up may also account for some of the disparity the BMT CTN 0102 trial has much shorter follow-up than the positive trials from Europe. IMMUNOMODULATION Although not specific to MM, the key indicators of the existence of a clinically beneficial graft vs malignancy are the induction of sustained antineoplastic effect by infused allogeneic donor lymphocytes, the association of GVHD with disease responses and lower relapse rates in recipients of unmanipulated (T-cell-replete) allografts compared with those receiving T-cell-depleted grafts or syngeneic grafts. 46 The prospective BMT CTN 0102 study and a retrospective CIBMTR study also found that the occurrence of cgvhd after allo-sct correlated with freedom from progressive MM. 33,47 Other single institution studies have also shown that development of cgvhd is significantly associated with better OS, 37,48 further substantiating the GVM effect. Additionally, in vitro or in vivo T-cell depletion has been associated with higher relapse rates and a need for subsequent DLI after allotransplant. 49,50 However, in a large series of patients with hematological disorders including MM undergoing allo-sct, the presence of GVHD is associated with only modest reduction in relapse risk in MM and AML, suggesting the presence of graft-vs-tumor effect in the absence of GVHD. 51 Similarly, in another study of high-risk relapsed MM patients undergoing allo-sct, OS and PFS were comparable to other studies in the absence of GVHD. 52 There is a report of complete remission in a patient after immunosuppression withdrawal in patient progressing after allo-sct. 9 Other new promising immune therapies include anti-pd1 agents, vaccines and CAR T-cell approaches in MM and monoclonal Abs against CD38. 8,53 56 Table 3. Allogeneic stem cell transplantation in multiple myeloma with reduced-intensity/non-myeloablative conditioning in relapsed setting Reference N NRM/RR PFS/OS Comments Freytes et al. 38 Auto: 137 Allo: 152 Patriarca et al. 39 Auto: 94 Allo: 68 de Lavallade et al. 40 Auto: 13 Allo: 19 Mehta et al. 44 Auto: 42 Allo: 42 Qazilbash et al. 43 Auto: 26 Allo: 14 Wirk et al. 42 Auto: 27 Allo: 19 4%, 91% 15%, 83% 1%, 81% 22%, 48% 0%, 86% 33%, 22% 10%, 72% 43%, 33% 7%, NS 11%, NS 3.7%, NS 5.3%, NS 4%, 29% at 5 yrs CIBMTR analyzes only RIC conditioning multiple lines of therapy 2%, 9% at 5 yrs 18%, 54% at 2 yrs Donor vs no donor analysis on consecutive patients at first relapse after auto-hct 42%, 53% at 2 yrs who had HLA typing 8%, 92% at 3 yrs Donor vs no donor analysis 46%, 93% at 3 yrs RIC conditioning NS, 54% at 3 yrs NS, 29% at 3 yrs 6.8 m, 29 m 7.3 m, 13 m 19 m, 23 m 6 m/, 19 m Multiple lines of therapy Ablative conditioning Case-matched series Retrospective not case controlled RIC conditioning Retrospective only first relapse Multiple conditioning regimens Abbreviations: Auto-HCT= autogeneic hematopoietic cell transplantation; CIBMTR = Center for International Blood and Marrow Transplant Research; m = months; NRM = non-relapse mortality; NS = not stated; OS = overall survival; RIC = reduced-intensity conditioning; RR = relapse rate; yrs = years. Bone Marrow Transplantation (2016), Macmillan Publishers Limited

5 Donor lymphocyte infusion DLIs are able to induce a clinically meaningful GVM effect in some patients relapsing after allo-sct. 57 The first proof of principle was demonstrated by Tricot et al. 58 when a patient progressing after 2.5 months of allo-sct received CD3+ cells per kg, resulting in complete remission for 14 months. However, DLI treatment carries a risk of inducing severe GVHD. 59 In a series of 54 patients, DLI yielded overall and complete response rates of 52% and 17%, and acute GVHD and cgvhd in 57% and 47%, respectively. 60 The median PFS was 19 months, and only six patients had complete remission for 2 years. Disease control from DLI was superior for responders and for those who developed GVHD. Another strategy is the use of preemptive DLI at defined time periods (usually 6 months) or in graded incremental T-cell doses for improving donor-derived T-cell immunity and to convert those with partial to full donor chimerism. 61 An exciting area of research is to use specific donor-derived T cells directed at myeloma-associated Ags such as WT1 or Ags in the cancer testis Ag family. 62,63 In a study by Kroger et al., patients were treated with DLI plus either an immunomodulator or bortezomib if no response after allo-sct. Nineteen patients achieved CR by the EBMT criteria, of which 17 had no evidence of disease by flow cytometric criteria and 15 by molecular analysis. 64 This improvement in CR (21%) by DLI resulted in the improved 5-year PFS and OS. Allo-SCT thus remains a platform for additional immune-based strategies at relapse or to preempt relapse (Table 4). Lenalidomide Lenalidomide (LEN) is a potent antimyeloma agent that also upregulates NK cells and NK T cells, and has been shown to improve time to disease progression and possible OS when used as an ongoing maintenance therapy after ASCT LEN maintenance after allo-sct is attractive as the GVM effect could be augmented by LEN-induced stimulation of the alloreactive lymphocytes and NK cells. In a phase I/II dose-finding study, within a week of LEN treatment, peripheral blood CD4 and CD8 T cells were increased with improved NK cell-derived antimyeloma activity and was followed by a delayed increase in the regulatory T cells. 68 It has also been demonstrated that LEN by promoting T-cell proliferation augments response to a myeloma-specific tumor vaccine. 69,70 These studies suggested that in the post allotransplant setting, LEN may induce disease response and also GVHD. Objective responses to salvage treatment with LEN were noted in 83% of patients (including 29% CR) relapsing after an allotransplant. On LEN therapy, 31% developed or exacerbated an acute GVHD episode, which was significantly associated with an improved antimyeloma response; however, at least one death was attributed to GVHD. 71 The feasibility of LEN maintenance after allotransplant has been evaluated prospectively. The HOVON-76 trial assessed LEN maintenance starting 1 to 6 months after allotransplant for newly diagnosed MM. 72 Unfortunately, 53% developed GVHD with 37% acute GVHD (at a median of 18 days on LEN) and 17% cgvhd, leading to premature discontinuation of therapy in 43% of the patients. The study was discontinued early owing to toxicity. A recent US phase II study (CIBMTR) reported the use of LEN maintenance starting at a median of 96 days post transplant in 30 high-risk patients after allotransplant. 73 The cumulative incidence of MM progression from the start of maintenance was 37% with a low TRM of 11%. Acute GVHD was noted in 37%, whereas PFS and OS at 18 months from the initiation of LEN was 63% and 78%, respectively, suggesting benefit and manageable GVHD risk in this high-risk subgroup. In a study by Kroger et al., 45 maintenance therapy with LEN after salvage allo-sct was started in 33 MM patients. Twenty-four patients started maintenance therapy with LEN at a median dose of 5 mg for a median of six cycles. Cumulative incidence of relapse at 3 years was 42% and the 3-year estimated probability of PFS and OS were 52% and 79%, respectively. 74 Bortezomib The intrinsic antimyeloma activity of PIs and their ability to suppress GVHD, 75,76 without mitigating the GVM effect, makes bortezomib an ideal option for post allotransplant maintenance. Kroger et al. 45 investigated the use of bortezomib for at least two cycles and at a median of 8 months following a RIC allotransplant. 77 In patients with measurable disease, CR was seen in 30, PR in 50% and a minor response was seen in 20% of patients. There was no major increase in GVHD. Caballero- Velázquez et al. 78 evaluated bortezomib within an RIC, and as maintenance postallografting in patients relapsed after a prior autograft. The maintenance treatment consisted of cycles of intravenous bortezomib (on days 1, 8 and 15). Sixteen patients were prospectively enrolled: 9/16 (56%) and 5/16 (31%) achieved CR and PR, respectively. Acute grade III GvHD was observed in 25%. Three-year cumulative incidence of TRM, relapse and OS were 25%, 54% and 41%, respectively. 78 In a study by Nishihori et al., MM patients with a very good partial response or better received fludarabine (30 mg/m 2 4 days intravenously 5 Table 4. Prospective trials of immunomodulators or proteasome inhibitors in allotransplant in MM Reference Intervention N NRM/RR PFS/OS Comment Kroger et al. 45 DLI only: 6 DLI+ImID and/or bortezomib: 24 0%/NS CR pts: 58%/90% at 5 years No CR pts 35%/62% at 5 years 59% CR by the EBMT Criteria CR improved survival 33% Grade II IV GVHD Kroger et al. 64 Lenalidomide 6%/42% 52%/79% at 3 years 28% Grade II IV agvhd Kroger et al. 74 Lenalidomide 30 10%/27% 63%/78% at 18 months 30% agvhd grades II IV 47% of all planned cycles completed Most common dose upon completing study 5 mg QOD Kneppers et al. 72 Lenalidomide NS/NS 61%/94% at 2 years 37% agvhd grades II IV 11% Chronic extensive GVHD Only 10% of patients completed planned therapy Alsina et al. 73 Bortezomib 25%/54% 30%/41% at 3 years 25% Grade III agvhd Caballero-Velazquez et al. 78 Bortezomib as part of conditioning 16.9%/NS 74%/77% at 2 years No post transplant maintenance in most patients Abbreviations: agvhd = acute GVHD; CR= complete remission; DLI = donor lymphocyte infusion; EBMT = European Bone Marrow Transplantation; ImID = immune-modulating drug; MM = multiple myeloma; NRM = non-relapse mortality; NS = not stated; OS = overall survival; pts = patients; QOD = every other day; RM = non-relapse mortality; RR = relapse rate Macmillan Publishers Limited Bone Marrow Transplantation (2016), 1 9

6 6 Table 5. Allogeneic transplant trials registered at Clinical trials.gov for allotransplant in MM Trial identifier Trial setting Status NCT (BMT CTN 1302) Phase II, multicenter double-blind trial that randomizes patients with high-risk MM to ixazomib Not yet recruiting maintenance or placebo days after allogeneic HSCT NCT A phase II, open-label study of bortezomib following non-myeloablative allogeneic stem cell Recruiting transplant in patients with high-risk MM NCT Phase I/II trial on RIC allogeneic transplantation: an optimized program for high-risk relapsed Recruiting patients NCT Phase II trial to assess the PFS and overall survival, as well as the safety and efficacy of Recruiting allogeneic HSCT using a preparative regimen with busulfan, melphalan, fludarabine and ATG, and a T-cell-depleted stem cell transplant from a histocompatible-related or -unrelated donor in patients with relapsed or high-risk MM NCT Allogeneic stem cell transplantation for patients with relapsed/refractory MM: a pilot study using a novel protocol Not yet recruiting Abbreviations: ATG = antithymocyte globulin; BMT CTN= Blood and Marrow Transplant Clinical Trials Network; HSCT = hematopoietic stem cell transplantation; MM = multiple myeloma; RIC = reduced-intensity conditioning. with bortezomib (n=13) and 40 mg/m 2 4 days without bortezomib (n=9) plus melphalan (70 mg/m 2 intravenously 2 days). The risk of moderate to severe cgvhd at 2 years was 46%, but the 2-year PFS was 74.8% comparing favorably with the 52% 2-year PFS seen in similar patients who underwent an allogeneic hematopoietic cell transplantation. 79 More studies are needed to more definitively define the role of post transplant maintenance. In this regard, the BMT CTN has initiated a national US allotransplant study (BMT CTN, 1302, NCT ) for high-risk MM patients either in the upfront setting or in the first chemotherapy-sensitive (at least very good partial response) relapse. This trial incorporates bortezomib in the conditioning regimen with melphalan and fludarabine. Post transplant, patients are randomized to either observation or to the second-generation oral PI (ixazomib) maintenance. The aim of this trial is to mitigate the risk of GVHD using PI without compromising anti-mm effect. KIR mismatch and NK cell-mediated immunity A new and potentially important observation in allo-sct was the lower relapse rate for those patients transplanted with stem cell graft that had KIR-ligand incompatibility, which has so far only been observed in patients with myeloid malignancies. 80,81 There was a significant lower incidence of relapse (P=0.05) despite no difference in OS, TRM and PFS. Furthermore, no severe grade III/IV acute GVHD was observed in the KIR-ligand group in comparison with 10% of the non-kir-ligand group; however, because of the low number of patients, this difference was not statistically significant. Extrapolating the concept of KIR-ligand mismatch in allotransplant, a phase I study was conducted using anti-kir Ab IPH2101 in patients with relapsed/refractory MM using the dose escalation approach. 82 The study showed that the biologic end point of full KIR2D occupancy across the dosing cycle was achieved without dose-limiting toxicity or maximally tolerated dose. There was preliminary evidence of disease stabilization in some patients. This study opens up new door for using anti-kir monoclonal Ab for anti-mm therapy. Other immune therapies Other immune therapies including immune checkpoint blockade, monoclonal Abs, vaccines and CAR T cells have shown promising activity in MM. Based on the extensive preclinical evidence of PD1 expression on T cells from MM, 83 numerous phase I/II dose escalation study using the anti-pd1 agent in MM is being conducted. 54 In one phase II clinical trial, Rosenblatt et al. 70 demonstrate that repeated immunization with a DC-tumor fusion vaccine after ASCT induces myeloma-specific immunity and improves clinical response. 70 Recent study with the immunostimulatory monoclonal Ab elotuzumab in combination with LEN and dexamethasone has shown promising results with 1- year PFS of 68% vs 57% at 1 year (P 0.001). 7 Early pilot studies have shown promising signs of efficacy with the CAR T cells in MM. 8 Future trials will combine these agents both in ASCT and allo-sct settings to further enhance selective anti-mm memory immunity and achieve durable clinical response. Risk stratification in MM Multiple biological factors that influence risk and prognosis in myeloma also inform and influence the choice of therapy to provide a risk-adapted algorithm for patients. 84,85 At diagnosis, all patients should have metaphase karyotyping and FISH performed to differentiate them into high-, intermediate- and standard-risk groups. 86 Even with the incorporation of novel therapies into our treatment algorithms, we have made little impact on the prognosis of intermediate- and high-risk patients. The exception is that the utilization of PIs have modified the prognostic outcome of patients with t(4;14) from high risk to intermediate risk. Minimal improvement has been observed with novel therapies, single or tandem ASCT or the use of allo-sct in this group of patients. Biologically, high-risk MM patients also may acquire new clonal abnormalities and present with rapidly progressing relapses, extramedullary relapses or secondary plasma cell leukemia. 87,88 In the absence of an effective established standard of care, these patients should be enrolled in clinical trials. High risk as defined by msmart guidelines from Mayo Clinic include 17p deletion, t(14:16) or t(14:20) by FISH or high-risk signature by gene expression profiling, 86 whereas International Staging system (ISS) stage II/III along with t(4:14) or 17p deletion by FISH is considered high risk as per the International Myeloma Working Group. 89 A recent study showed that the risk of early MM progression-related death was related to three independent prognostic variables: high lactase dehydrogenase, ISS stage III, t(4:14) and/or 17p deletion by FISH. 90 International myeloma working group recently published a Revised-ISS (R-ISS) for MM based on ISS stage, lactase dehydrogenase and the presence of high-risk chromosomal abnormalities (17p and/or t(4:14) and/or t(14:16)). 91 In this report, the 5-year OS in R-ISS stage I, II and III are 82%, 62% and 40%, respectively, confirming the significance of these three prognostic variables. In a median follow-up of 72 months, Barlogie et al. 92 showed that adding thalidomide upfront to tandem ASCT reduced the hazard of death by 41% in patients with cytogenetically abnormal disease (P=0.008). In a subsequent study, incorporation of bortezomib upfront into tandem ASCT regimen as total therapy 3 showed superior EFS and CR duration in expression profiling-defined highrisk group. 93 Similarly, in HOVON-65/GMMG-HD4 trial, patients with 17p deletion had superior median PFS (P=0.024) and 3-year Bone Marrow Transplantation (2016), Macmillan Publishers Limited

7 OS (P=0.028) with the addition of brotezomib before and after tandem ASCT. 84 In the EBMT-NMAM 2000 study, at a median follow-up of 96 months, 21% of patients with the higher-risk deletion 13 abnormality by FISH receiving tandem ASCT-allo-SCT were progression free compared with 5% in the tandem ASCT group. 35 However, there was no survival benefit in this group in BMT CTN when compared with tandem ASCT. A single center study has shown similar survival in the high-risk group compared with the standard-risk group; 37 this suggests that allo-sct may overcome the negative impact of high-risk disease. WHEN AND WHO DO I REFER FOR ALLOTRANSPLANT? A designation of ultra-high-risk MM is used to characterize patients who have a predicted median survival of 24 months or less. 94 This group includes patients presenting with ISS stage III disease in addition to specific genetic abnormalities such as deletion 17p, Ig heavy-chain gene translocations t(4;14) or t(14;16) and chromosome 1q21 amplification (43 copies). 84,90,94 In a recently published R-ISS staging, this would fall into R-ISS stage III with a 5-year OS and PFS of 40% and 24%, respectively, only. 91 In a prospective study of 73 patients treated with ASCT followed by allo-sct, a review in high-risk patients showed similar remission rate, PFS, OS and relapse rate when those with del(17p)/t(4;14) were compared with the non-del(17p)/t(4;14) patients, and identified the achievement of molecular complete remission as the major factor for outcome. 95 In a prospective randomized study by Knop et al., 96 patients with newly diagnosed MM were randomized to either ASCT-allo-SCT from an HLA-matched related or unrelated donors (with fludarabine/melphalan conditioning) or tandem ASCT. At 49 months of follow-up, median PFS (P=0.002) and OS was superior (P=0.011) for the allo-sct in the highest risk subgroup with del 17p and del 13q abnormality. Since the outcomes for high-risk MM remain poor despite the best available standard therapies (OS of months), promising initial data suggest that allo-sct should ideally be explored in this subset. In this subgroup of patients, the adverse risk benefit ratio for allo-sct over standard therapies is balanced by the lack of efficacy of standard approaches. In such uncommon situation of a patient with ultra-high-risk MM, allo-sct is reasonable as long as patients are aware of their unfavorable prognosis and are willing to accept the risks of allo-sct. Given the dismal outcome with the current modalities in this group, a number of studies are being conducted looking into the incorporation of novel agents: carfilzomib and pomalidomide; siltuximab, adoptive immunotherapy (Th1/Tc1 immunotherapy) either during induction or as maintenance is being considered. Similarly, a number of allo-sct studies are also being conducted in these patients, one of which is BMT CTN 1302, which is a multicenter phase II, double-blind placebo-controlled trial of ixazomib (oral PI) maintenance after allo-sct for highrisk MM. CONCLUSION Given the lack of consistent survival benefit, in both newly diagnosed and relapsed MM, use of allo-sct in MM should be restricted to well-designed clinical trials and not considered the standard of care. However, in patients with high-risk MM, with such a poor long-term prognosis, allo-sct is a strong consideration as part of their initial course of therapy or in first chemotherapy-sensitive relapse. At this time, the number of studies for allo-sct in MM is registered in clinical trials (Table 5). These studies are trying to answer questions of effectiveness of this method either by itself or in combination with other novel agents. Future The success of allogeneic stem cell transplantation in MM, although limited, suggests an important role of immune-based therapies in the treatment armamentarium. In the future, with improving risk stratification tools, MRD detection methods and the availability of the results from current trials, we will have an even better understanding on timing and patient selection for this modality. We anticipate that it will remain an important curative intent option for a minority of high-risk patients. On the other hand, we believe that, emerging cellular- and Ab-based immune therapies will have a major role in the treatment of MM in both the upfront and relapsed setting. The results of monoclonal Abs directed at the CD38 Ag and immune check point proteins, CAR T cells and vaccines are likely to revitalize immune therapy for MM in general. At this time, there is considerable interest in integrating newer novel agents such as ixazomib in maintenance after allogeneic transplant. Combination of allotransplant with immune therapies and the newer novel agents will most likely be the next generation of allogeneic transplant trials. In November 2015, the Centers for Medicare and Medicaid Services in the United States signaled their intention to approve MM as an approved transplant indication for allogeneic hematopoietic cell transplantation; in the setting of an appropriate clinical trial for the medicare age population (generally 65 years). These developments suggest an evolving role of allo-sct in MM and the challenges in determining who, how and with what agents. CONFLICT OF INTEREST The authors declare no conflict of interest. REFERENCES 1 Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008; 111: Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004; 351: Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 2012; 120: Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352: Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010; 11: Wang M, Martin T, Bensinger W, Alsina M, Siegel DS, Kavalerchik E et al. Phase 2 dose-expansion study (PX ) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood 2013; 122: Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med 2015; 373: Masters GA, Krilov L, Bailey HH, Brose MS, Burstein H, Diller LR et al. Clinical cancer advances 2015: Annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol 2015; 33: Libura J, Hoffmann T, Passweg J, Gregor M, Favre G, Tichelli A et al. Graft-versusmyeloma after withdrawal of immunosuppression following allogeneic peripheral stem cell transplantation. Bone Marrow Transplant 1999; 24: Lokhorst H, Einsele H, Vesole D, Bruno B, San Miguel J, Perez-Simon JA et al. International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma. J Clin Oncol 2010; 28: Barlogie B, Shaughnessy J, Tricot G, Jacobson J, Zangari M, Anaissie E et al. Treatment of multiple myeloma. Blood 2004; 103: Hunter HM, Peggs K, Powles R, Rahemtulla A, Mahendra P, Cavenagh J et al. Analysis of outcome following allogeneic haemopoietic stem cell transplantation for myeloma using myeloablative conditioning evidence for a superior outcome Macmillan Publishers Limited Bone Marrow Transplantation (2016), 1 9

8 8 using melphalan combined with total body irradiation. Br J Haematol 2005; 128: Bensinger WI, Buckner CD, Anasetti C, Clift R, Storb R, Barnett T et al. Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. Blood 1996; 88: Gahrton G, Tura S, Ljungman P, Blade J, Brandt L, Cavo M et al. Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol 1995; 13: Gahrton G, Tura S, Ljungman P, Belanger C, Brandt L, Cavo M et al. Allogeneic bone marrow transplantation in multiple myeloma. European Group for Bone Marrow Transplantation. N Engl J Med 1991; 325: Gahrton G, Svensson H, Cavo M, Apperly J, Bacigalupo A, Bjorkstrand B et al. Progress in allogenic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: a comparison between transplants performed and at European Group for Blood and Marrow Transplantation centres. Br J Haematol 2001; 113: Durie BG, Gale JP, Klein JP et al. Allogeneic transplants for multiple myeloma: an IBMTR analysis. Proc Am Soc Clin Oncol 1995; 15: Bjorkstrand BB, Ljungman P, Svensson H, Hermans J, Alegre A, Apperley J et al. Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective case-matched study from the European Group for Blood and Marrow Transplantation. Blood 1996; 88: Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol 2006; 24: Lokhorst HM, Segeren CM, Verdonck LF, van der Holt B, Raymakers R, van Oers MH et al. Partially T-cell-depleted allogeneic stem-cell transplantation for first-line treatment of multiple myeloma: a prospective evaluation of patients treated in the phase III study HOVON 24 MM. J Clin Oncol 2003; 21: Kroger N, Schwerdtfeger R, Kiehl M, Sayer HG, Renges H, Zabelina T et al. Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma. Blood 2002; 100: Giralt S, Aleman A, Anagnostopoulos A, Weber D, Khouri I, Anderlini P et al. Fludarabine/melphalan conditioning for allogeneic transplantation in patients with multiple myeloma. Bone Marrow Transplant 2002; 30: Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 2009; 15: Kumar S, Zhang MJ, Li P, Dispenzieri A, Milone GA, Lonial S et al. Trends in allogeneic stem cell transplantation for multiple myeloma: a CIBMTR analysis. Blood 2011; 118: Kroger N, Shimoni A, Schilling G, Schwerdtfeger R, Bornhauser M, Nagler A et al. Unrelated stem cell transplantation after reduced intensity conditioning for patients with multiple myeloma relapsing after autologous transplantation. Br J Haematol 2010; 148: Maloney DG, Molina AJ, Sahebi F, Stockerl-Goldstein KE, Sandmaier BM, Bensinger W et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003; 102: Rotta M, Storer BE, Sahebi F, Shizuru JA, Bruno B, Lange T et al. Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting. Blood 2009; 113: Bruno B, Rotta M, Patriarca F, Mattei D, Allione B, Carnevale-Schianca F et al. Nonmyeloablative allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo. Blood 2009; 113: Lokhorst HM, van der Holt B, Cornelissen JJ, Kersten MJ, van Oers M, Raymakers R et al. Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study. Blood 2012; 119: ; quiz Rosinol L, Perez-Simon JA, Sureda A, de la Rubia J, de Arriba F, Lahuerta JJ et al. A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood 2008; 112: Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 2007; 356: Giaccone L, Storer B, Patriarca F, Rotta M, Sorasio R, Allione B et al. Long-term follow-up of a comparison of nonmyeloablative allografting with autografting for newly diagnosed myeloma. Blood 2011; 117: Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E III et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol 2011; 12: Bjorkstrand B, Iacobelli S, Hegenbart U, Gruber A, Greinix H, Volin L et al. Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up. J Clin Oncol 2011; 29: Gahrton G, Iacobelli S, Bjorkstrand B, Hegenbart U, Gruber A, Greinix H et al. Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study. Blood 2013; 121: Passera R, Pollichieni S, Brunello L, Patriarca F, Bonifazi F, Montefusco V et al. Allogeneic hematopoietic cell transplantation from unrelated donors in multiple myeloma: study from the Italian Bone Marrow Donor Registry. Biol Blood Marrow Transplant 2013; 19: Donato ML, Siegel DS, Vesole DH, McKiernan P, Nyirenda T, Pecora AL et al. The graft-versus-myeloma effect: chronic graft-versus-host disease but not acute graft-versus-host disease prolongs survival in patients with multiple myeloma receiving allogeneic transplantation. Biol Blood Marrow Transplant 2014; 20: Freytes CO, Vesole DH, LeRademacher J, Zhong X, Gale RP, Kyle RA et al. Second transplants for multiple myeloma relapsing after a previous autotransplant-reduced-intensity allogeneic vs autologous transplantation. Bone Marrow Transplant 2014; 49: Patriarca F, Einsele H, Spina F, Bruno B, Isola M, Nozzoli C et al. Allogeneic stem cell transplantation in multiple myeloma relapsed after autograft: a multicenter retrospective study based on donor availability. Biol Blood Marrow Transplant 2012; 18: de Lavallade H, El-Cheikh J, Faucher C, Furst S, Stoppa AM, Coso D et al. Reduced-intensity conditioning allogeneic SCT as salvage treatment for relapsed multiple myeloma. Bone Marrow Transplant 2008; 41: Michallet M, Sobh M, El-Cheikh J, Morisset S, Sirvent A, Reman O et al. Evolving strategies with immunomodulating drugs and tandem autologous/allogeneic hematopoietic stem cell transplantation in first line high risk multiple myeloma patients. Exp Hematol 2013; 41: Wirk B, Byrne M, Dai Y, Moreb JS. Outcomes of salvage autologous versus allogeneic hematopoietic cell transplantation for relapsed multiple myeloma after initial autologous hematopoietic cell transplantation.jclinmedres2013; 5: Qazilbash MH, Saliba R, De Lima M, Hosing C, Couriel D, Aleman A et al. Second autologous or allogeneic transplantation after the failure of first autograft in patients with multiple myeloma. Cancer 2006; 106: Mehta J, Tricot G, Jagannath S, Ayers D, Singhal S, Siegel D et al. Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft? Bone Marrow Transplant 1998; 21: Kroger N, Sayer HG, Schwerdtfeger R, Kiehl M, Nagler A, Renges H et al. Unrelated stem cell transplantation in multiple myeloma after a reduced-intensity conditioning with pretransplantation antithymocyte globulin is highly effective with low transplantation-related mortality. Blood 2002; 100: Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED. Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation. N Engl J Med 1981; 304: Ringden O, Shrestha S, da Silva GT, Zhang MJ, Dispenzieri A, Remberger M et al. Effect of acute and chronic GVHD on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma. Bone Marrow Transplant 2012; 47: Mir MA, Kapoor P, Kumar S, Pandey S, Dispenzieri A, Lacy MQ et al. Trends and outcomes in allogeneic hematopoietic stem cell transplant for multiple myeloma at mayo clinic. Clin Lymphoma Myeloma Leuk 2015; 15: e2. 49 Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood 2006; 107: Alyea E, Weller E, Schlossman R, Canning C, Webb I, Doss D et al. T-cell--depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect. Blood 2001; 98: Stern M, de Wreede LC, Brand R, van Biezen A, Dreger P, Mohty M et al. Sensitivity of hematological malignancies to graft-versus-host effects: an EBMT megafile analysis. Leukemia 2014; 28: Smith E, Devlin SM, Kosuri S, Orlando E, Landau H, Lesokhin AM et al. CD34-selected allogeneic hematopoietic stem cell transplantation for patients with relapsed, high-risk multiple myeloma. Biol Blood Marrow Transplant 2015; pii: S (15)00573-X (e-pub ahead of print). Bone Marrow Transplantation (2016), Macmillan Publishers Limited