RIC alloSCT in MM: a long way to go

The prognosis of multiple myeloma (MM) has improved markedly over the past decade and the majority of younger patients are likely to benefit from high-quality remissions for a median of 3 to 4 years, largely because of the introduction of novel agents within the context of high-dose therapy and autologous stem cell transplantation (ASCT).¹ 

Although the introduction of reduced-intensity conditioning (RIC) has decreased treatment-related mortality associated with myeloablative conditioning, it is currently being actively debated whether patients should be treated with RIC allogeneic stem cell transplantation (RIC alloSCT) with its substantial morbidity and risk of mortality as part of first-line therapy, even if a late survival benefit can be demonstrated. A recent consensus report on alloSCT in MM concluded that new strategies are needed to improve the safety and efficacy of the procedure, and until this has been achieved RIC alloSCT in myeloma should only be recommended within the setting of clinical trials.² 

In the Haemato Oncology Foundation for Adults in the Netherlands (HOVON) 76 study, Kneppers et al found that maintenance treatment consisting of low-dose lenalidomide after RIC alloSCT in MM patients was not feasible, mainly because of the rapid induction of acute GVHD.³  The objective of the study was to demonstrate a progression-free survival (PFS) rate of at least 75% at 1 year through the use of maintenance treatment started soon after RIC alloSCT. The study failed to reach this end point and was prematurely closed when an interim analysis revealed that 87% of the patients had to discontinue treatment early, mainly because of the rapid induction of acute GVHD at a median of 18 days after the start of lenalidomide. Of note, immunosuppression, which consisted of the combination of cyclosporine A and mycophenolate mofetil, was not tapered during maintenance, and lenalidomide therapy was found to be associated with an early activation of T cells.

This negative trial illustrates the difficulties of attempting to improve the results of RIC alloSCT. The study was based on the rationale that the incorporation of novel agents, in this case lenalidomide, may enhance the graft-versus-myeloma effect of alloSCT. Lealidomide was chosen because favorable results had been obtained with lenalidomide used as salvage therapy in patients with progressive disease after RIC alloSCT.⁴  Disappointingly, the considerable challenge of GVHD remains, and the results of the HOVON 76 study clearly show that maintenance with immunomodulatory drugs as part of the RIC alloSCT procedure should be abandoned. These negative findings will certainly fuel the hot debate surrounding RIC alloSCT.

Of note, lenalidomide maintenance after ASCT is also a matter of debate, because the highly significant improvement in PFS in this setting does not seem to be associated with an improvement in overall survival,⁵  and may additionally carry the risk of specific toxicity, such as second primary malignancies, which were also reported in 2 of 30 patients in the HOVON 76 study receiving lenalidomide maintenance after RIC alloSCT.³  Despite these concerns, we should not eliminate RIC alloSCT completely from our therapeutic armamentarium. Further clinical trials are warranted, and some are already planned. The addition of bortezomib to this procedure could be of interest, because it has shown remarkable efficacy in patients with relapsed disease after RIC alloSCT, without the apparent stimulation of excessive GVHD.⁶ 

In addition, in a study involving mismatched unrelated donors, the combination of bortezomib, tacrolimus, and methotrexate proved to be very effective at preventing GVHD after RIC alloSCT.⁷  RIC alloSCT should also be evaluated as part of frontline treatment in patients with ultra high-risk disease, such as those carrying the 17p deletion, in whom prognosis and outcome remain dismal despite the application of ASCT.⁸  Many challenges remain and need to be resolved before the role of RIC alloSCT in MM is clear.