Page 19 - 2019_02-Haematologica-web

Editorials
Figure 1. Proposed indication for allogeneic (allo)-hematopoietic cell transplantation (HCT) based on studies by Greil et al.,1 Maffini et al.,2 and other authors. 4,7,17 ASCT: autologous stem cell transplantation; DLI: donor lymphocyte infusion, CNI: calcineurin inhibitors; GVHD: graft-versus-host disease; VGPR: very good partial remission; CAVE: possible adverse effect.
ly evaluated by PCR. At a remarkable median follow up of 12.1 years, median OS and EFS were not reached in patients who achieved nested-PCR negativity while they were 3.3 and 1.5 years, respectively, in the remaining patients.
Besides the intuitive recognition that “responders do bet- ter than non-responders”, the biological relevance of achieving a deep response prior to allogeneic HCT, and maintaining this response for a certain time post HCT, is that the establishment of graft-versus-myeloma activity requires time. In both studies published in this edition of Haematologica, relapses mostly occurred early, during the first 1-2 years post allogeneic HCT, reflecting the ongoing balance between disease biology (aggressiveness) and effec- tiveness of graft-versus-myeloma activity. The implementa- tion of novel agents not only prior to HCT, but also post HCT, likely results in deeper responses prior to HCT and can help to maintain these responses post allogeneic HCT. Such strategies may translate into lower relapse rates during the first year, and thereby provide time for graft-versus- myeloma effects to establish, particularly once patients are off immunosuppression.
2) Both trials clearly indicate that there is anti-myeloma activity in some patients, as more than 20% were long-term survivors beyond ten years post HCT. Patients who relapsed post HCT appeared to have a relatively long sur- vival, which is consistent with two recently published reports on long-term follow up post autologous versus autol- ogous-allogeneic tandem HCT, in which patients post allo- grafting had a significantly longer OS compared with those with relapse post autologous HCT.4,5 The question not answered by the studies published here is whether and how anti-myeloma activity of donor T cells could be enhanced in vivo, e.g. by donor lymphocyte infusions (DLI),
immunomodulatory drugs (IMIDs), proteasome inhibitors, monoclonal antibodies, etc. In both studies, not all patients had been treated with novel myeloma drugs as induction or post HCT, in the latter context, mostly for treatment of active disease. Moreover, at relapse, many patients received drugs outside the context of clinical trials depending on which one was readily available at that time. Defined sub- groups in available studies were thus too small to provide statistically significant results regarding the impact of novel therapeutics in general or the influence of a specific drug. Newer data show that the application of post-HCT borte- zomib is feasible, safe, and effective even in heavily pre- treated, poor-risk patients.6,7 IMIDs, in contrast, resulted in higher toxicity, acute GvHD, and early discontinuation in one trial,8 whereas in other trials, lenalidomide was given at lower doses and tolerability was good.9,10
3) The current major cause of treatment failure after allo- grafting is disease relapse, not treatment-related mortality. In contrast to early trials, today, under appropriate standard care, transplant procedures are associated with low toxicity and GvHD rates are acceptable. In the early 2000s, a num- ber of trials introduced the tandem approach with an auto- graft for tumor debulking followed by reduced-intensity or non-myeloablative allogeneic HCT, a strategy that was able to lower the toxicity of the regimens. Yet, even today, allo- geneic HCTs still bear the negative connotation of high tox- icity, morbidity, treatment-related mortality, and a substan- tial negative impact on the quality of life. Interestingly, using the revised Myeloma Comorbidity Index (R-MCI), an established tool and prognostic instrument for risk predic- tion in myeloma patients that evaluates renal and lung func- tion, Karnofksy Performance Status impairment, frailty, and age,11 Greil et al. showed, that over time, the R-MCI
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