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Tandem transplantation for multiple myeloma
acute GvHD, led to early discontinuation in 87% of the patients. In a Phase II CIBMTR trial on 30 patients,55 the use of lenalidomide was feasible if given at lower doses. A lower toxicity profile of lenalidomide maintenance was also reported by Kroger et al. in relapsed patients after an autograft and rescued with a myeloablative allograft.56
Importantly, a synergy between new drugs and graft- versus-myeloma effects with a far safer toxicity profile has been described in the relapsed setting, suggesting that allo- geneic-HCT and new drugs may be complementary. In our study, the median duration of survival of 7.8 years from the first relapse/progression among patients who achieved a response to salvage treatments supports this concept. These findings have been confirmed by two other recent reports.57,58 An update of an Italian study focused on the role of “new drugs” in long-term clinical outcomes.57 Median OS from first relapse was 7.5 years in the autologous/allogeneic group and two years in the tan- dem autologous group (P=0.01). Htut et al. compared the post-relapse OS after autologous/allogeneic HCT versus tandem autografts in patients reported to CIBMTR between 2000 and 2010.58 Six-year post-relapse OS was significantly better in the autologous/allogeneic group as compared with the tandem autografts group, 44% versus 35%, respectively (P=005). Taken together, these findings suggest a synergy between new agents and the donor- derived immunological milieu.
The current role of allografting in multiple myeloma is controversial though the procedure is still used at many centers. Prospective studies were designed before agents with potent anti-myeloma activity became readily avail- able. However, despite the recent introduction of very effective pharmacological therapies, there remains a sub- set of high-risk patients accounting for about 10-15% of new diagnoses, whose dismal prognosis is further com- pounded when early relapse (within 18 months from first- line treatment) is observed.59,60
The negative impact of adverse cytogenetics on clinical outcomes was not overcome by allogeneic HCT in our series. More aggressive plasma cell clones may have escaped graft-versus-myeloma effects after non-myeloab- lative 2 Gy TBI. Instead, the impact of certain high-risk cytogenetics was partly neutralized by graft-versus-myelo- ma effects in a study by Kröger et al.61 on 73 patients treat- ed with autologous HCT followed by reduced-intensity melphalan 140 mg/m2 plus fludarabine, where no signifi- cant differences in PFS between patients with del(17p13) and/or t(4;14) and those without these abnormalities were observed after a median follow up of six years. A French
trial also showed no differences in clinical outcomes between t(4;14) and non-t(4;14) patients.62 Another study by Rasche et al.63 showed no differences in survival out- comes in patients carrying del(17p), t(4;14) or amp(1q21) as compared to those with normal cytogenetics. We spec- ulated that the incorporation of melphalan 140 mg/m2, as employed in the studies by Kroger and Rasche, in the con- ditioning regimen before allogeneic HCT added more cytotoxicity and might have resulted in superior tumor cell-kill and, therefore, better survival among those with high-risk cytogenetics. Moreover, almost 50% of our patients with adverse cytogenetics did not receive “new agents” as part of induction treatment that, in part, are able to overcome certain high-risk genetic features.64
In summary, our study showed that tandem autolo- gous/minimal intensity allogeneic HCT for MM was safe and characterized by low acute and long-term toxicities. Patients among standard and high-risk categories were able to achieve long-term sustained remissions, while patients with ultra-high-risk disease did not benefit from the tandem HCT. Similarly, patients with progressive dis- ease after autologous HCT failed to respond to allogeneic HCT and succumbed to the disease, suggesting that graft-versus-myeloma effects alone are inadequate to con- trol refractory and high-tumor burden disease states. Allogeneic HCT may be employed as a platform for post- transplant immune-based strategies such as novel immunomodulatory drugs or proteasome inhibitors, CAR T- and N-cell infusions, and bispecific T-cell engagers in selected high-risk populations where prognosis remains poor even in the era of new drugs.65-67
Funding
Research reported in this article was supported by the National Cancer Institute of the National Institutes of Health under award numbers CA078902, CA018029 and CA015704. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, which had no involvement in the in study design; the collection, analysis and interpretation of data; the writing of the report; nor in the decision to submit the article for publication.
Acknowledgments
We wish to thank Michelle Bouvier for study management; Joshua J. Latos, Ethan A. Melville for assistance with data retrieval and Helen Crawford for assistance with manuscript preparation and figure layout/formatting. We also thank the patients who participated on the clinical protocols and the physi- cians, nurses and staff who cared for them.
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