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Editorials
declined through treatment, indicating that performance status, and accordingly quality of life, was improved by treating the underlying disease. In those patients whose condition deteriorated, such a deterioration was from decreasing renal function and increasing age, and only in a minority was this due to complications from the allogeneic HCT, such as chronic GvHD.
Six prospective trials examined the role of allografting compared with autologous HCT alone.12-21 Substantial dif- ferences in inclusion criteria and treatment schemas partly contributed to conflicting outcomes. While most of these trials demonstrated an improved PFS in the allogeneic cohort, in only two studies did this response also translate into a longer OS. Similarly, a meta-analysis of published clinical trials containing 1192 newly diagnosed patients who received tandem auto-auto and 630 who underwent tandem auto-non-myeloablative allogeneic HCT showed that the CR rates were higher in the auto-allo group, but there was no survival advantage in the first three years.22 Of note, the survival advantage in the auto-allo group, reported in two of the published comparative studies, became statis- tically significant after a follow up of at least three years. All these studies were conducted prior to the routine imple- mentation of novel drugs into induction therapy; treatment of relapsed disease following HCT varied and was not taken into consideration when analyzing survival rates.
Today, there is remarkable heterogeneity in the use of allogeneic HCTs for patients with myeloma among differ- ent countries, and even institutions, and few ongoing clini- cal trials are studying how to improve allogeneic HCT strategies in myeloma or clarify its role. Trends in the use of HCT in myeloma were published in a large evaluation of the European Group of Blood and Marrow Transplantation (EBMT) over a 25-year period that examined a total of 3405 myeloma patients given allogeneic HCT either as an upfront treatment, within an upfront autologous-allogeneic HCT concept or as salvage treatment after a failed autolo- gous HCT.23 It was demonstrated that allogeneic HCT is currently mostly used as salvage therapy for myeloma patients after at least one autograft rather than within an intensified upfront induction-auto-allo approach. Similar to the studies by Maffini et al. and Greil et al., the EBMT analy- sis demonstrated that OS rates in the first few years follow- ing allogeneic HCT were comparable with novel induction strategies involving new drugs and high-dose chemothera- py with autologous HCT; however, also in the EBMT dataset, long-term survival was observed in more than 20% of patients given allogeneic HCT. Again, patients receiving allogeneic HCT within an upfront auto-allo tandem approach achieved better outcomes, but even later trans- plants, usually in progression or relapse following autolo- gous HCT, resulted in encouraging long-term outcomes with 25% survivor rates at ten years.
In the light of the studies by Maffini et al. and Greil et al., and those by other groups, the abandonment of allograft- ing, as some have suggested, appears rather premature even in newly diagnosed myeloma patients. The two reports draw particular attention to the long-term follow up with potential cure in subsets of patients. Reasons to re-examine the role of allogeneic HCT for patients with myeloma in controlled clinical trials are as follows.
• Today, validated tools are available to identify patients
at high risk in whom OS and PFS are very poor even in the era of new drugs, including the R-MCI,11 the revised International Staging System by the International Myeloma Working Group,24 cytogenetics, etc. For this patient subset, new effective treatments are urgently needed. The negative prognostic impact of high-risk cytogenetics appeared to be partly neutralized by graft-versus-myeloma activity in two recent studies.15,25
• Patient preparation, including the achievement of a deep response prior to HCT, has significantly improved over the past decade by incorporating second and third gen- eration proteasome inhibitors, IMIDs, monoclonal antibod- ies, and histone deacetylase inhibitors. Patients may, there- fore, be in better condition (as many of them have not been exposed to toxic chemotherapy), have improved organ function, and be in deeper remission of the disease prior to HCT. These factors all optimize the baseline setting for an allogeneic HCT, reducing treatment-related toxicity, mor- bidity, mortality, and providing time for graft-versus-myelo- ma activity to be established.
• The role of the combination of new drugs with graft- versus-myeloma activity has never been systematically explored in this incurable disease. This may partly be attrib- uted to the limited current interest on cell therapy strategies in myeloma. New drugs and graft-versus-myeloma activity are not mutually exclusive and their synergy has clearly been shown in relapsed patients.
In conclusion, despite the recent dramatic improvement in survival, the overwhelming majority of myeloma patients invariably relapse. Given the potentially curative effect of graft-versus-myeloma activity, the role of allograft- ing should become a matter of sound scientific debate in the myeloma community. Combinations of allografts with potent anti-myeloma agents pre- and post-HCT should be examined in young high-risk and/or early relapsed patients for whom life expectancy is currently very poor. Modern MRD monitoring tools may guide individual treatment decisions and thereby further improve long-term outcomes.
References
1. Greil C, Engelhardt M, Ihorst G, et al. Allogeneic transplantation of multiple myeloma patients may allow long-term survival in carefully selected patients with acceptable toxicity and preserved quality of life. Haematologica. 2018;104(2):370-379.
2. MaffiniE,StorerBE,SandmaierBM,etal.Longtermfollow-upoftan- dem autologous-allogeneic hematopoietic cell transplantation for mul- tiple myeloma. Haematologica. 2018;104(2):380-391.
3. Ladetto M, Ferrero S, Drandi D, et al. Prospective molecular monitoring of minimal residual disease after non-myeloablative allografting in newly diagnosed multiple myeloma. Leukemia. 2016;30(5):1211-1214.
4. Giaccone L, Evangelista A, Patriarca F, et al. Impact of New Drugs on the Long-Term Follow-Up of Upfront Tandem Autograft-Allograft in Multiple Myeloma. Biol Blood Marrow Transplant. 2018;24(1):189- 193.
5. Htut M, D'Souza A, Krishnan A, et al. Autologous/Allogeneic Hematopoietic Cell Transplantation versus Tandem Autologous Transplantation for Multiple Myeloma: Comparison of Long-Term Postrelapse Survival. Biol Blood Marrow Transplant. 2018;24(3):478- 485.
6. Caballero-VelazquezT,Lopez-CorralL,EncinasC,etal.PhaseIIclini- cal trial for the evaluation of bortezomib within the reduced intensity conditioning regimen (RIC) and post-allogeneic transplantation for high-risk myeloma patients. Br J Haematol. 2013;162(4):474-482.
7. GreenDJ,MaloneyDG,StorerBE,etal.Tandemautologous/allogeneic hematopoietic cell transplantation with bortezomib maintenance ther- apy for high-risk myeloma. Blood Adv. 2017;1(24):2247-2256.
haematologica | 2019; 104(2)