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E. Maffini et al.
100 days and 14% at 5 years) and, with a median follow up of 8.3 years, median OS was 6.4 years. By risk stratifi- cation, median OS was not reached in standard-risk patients, while high-risk and ultra-high-risk patients had worse outcomes with median OS of 8.4 and 2.3 years, respectively. Of note, only a minority of our patients achieved a complete remission after induction treatments, and a subset of them received tandem autologous-allo- geneic HCT beyond first line. Moreover, none of our patients received recently Food and Drug Administration- approved monoclonal antibodies, such as daratumumab and elotuzumab, which have been associated with remarkable response rates.
Although restricted to a small group of patients, we demonstrated that the achievement of MRDNEG predicted long-term CR among patients with IFIX-negative CR after autologous HCT. Whether long-term persistence of MRDNEG indicates disease eradication is unclear. Multi- parameter flow cytometry and PCR-based methods are two sensitive techniques currently used to evaluate MRD in MM. Evaluation of MRD through immuno-phenotyp- ing is more broadly available than PCR-based methods. In the present series, patients who achieved MRDNEG by flow cytometry experienced a significantly lower relapse rate as compared with MRDPOS patients (P=0.03). These findings confirm previous observations by Giaccone et al. who reported on the clinical impact of immuno-phenotypic remission after allografting in 66 MM patients.47 Conditioning was 2 Gy TBI-based in 55 of the 66 patients. After a median follow up of 7.1 years, patients who achieved conventional CR and MRDNEG disease status had better clinical outcomes in terms of OS (median not reached) and PFS (median 59 months). Moreover, Ladetto et al. reported a PCR-based molecular analysis of MRD after minimal-intensity TBI-based conditioning in newly diagnosed patients who had not been exposed to new drugs.48 After a median follow up of 12.1 years, the medi- an OS and PFS were not reached in patients who achieved PCR MRD negativity. Overall, MRD studies support the hypothesis that potentially curative graft-versus-myeloma effects after minimal intensity conditionings allowed long- term disease control and persistent yet non-progressive MRD in a subset of MM patients.
Whether graft-versus-myeloma effects are associated with chronic GvHD is still a subject of debate. Ringdén et al. evaluated the impact of acute and chronic GvHD on relapse and survival in 177 patients transplanted from HLA-identical siblings after non-myeloablative or reduced-intensity conditioning.49 Acute GvHD was associ- ated with a significantly higher risk of TRM, while limited chronic GvHD significantly reduced the risk of relapse. However, the reduced relapse risk did not translate into better OS. Crawley et al. reported that chronic GvHD was associated with better PFS and OS after reduced-intensity conditioning.3 In the present study, we report an incidence of chronic GvHD of 55%, which, as in other comparative prospective trials,7,9 was not associated with better disease control. A trend towards higher chronic GvHD rates after the introduction of minimal/reduced-intensity condition- ing was shown in a Center for International Blood and Marrow Transplant Research (CIBMTR) analysis on 1207 MM recipients between 1989 and 2005. Overall, 50% of the patients who survived at least five years in the 2001- 2005 cohort developed chronic GvHD, 65% of whom had extensive involvement.4 Discontinuation of all immuno-
suppressive agents is a surrogate for achieving immunotol- erance, and is associated with improved quality of life. Importantly, only a minority of current survivors remained on immunosuppressive drugs long-term: 24%, 12%, and 4% at five, ten, and 15 years, respectively.
Indications for allografting in MM have greatly changed over the years due to remarkable advances in the under- standing of disease biology and new treatment modalities that increased median survival rates up to 8-10 years in standard-risk patients. However, relapse has remained a major issue, and poor outcomes have been observed in patients with high-risk/ultra-high-risk disease.50 Interestingly, Sobh et al. described trends and clinical out- comes of allogeneic HCT for MM in Europe between 1990 and 2012.51 The study included 7333 patients who were divided into 3 groups: 1) allogeneic HCT upfront (n=1924); 2) tandem autologous-allogeneic HCT (n=2004); and 3) allogeneic HCT as a second-line treatment or beyond (n=3405). A steady increase in numbers of allo- geneic HCT over the years was observed. The use of upfront allogeneic HCT increased up to the year 2000, fol- lowed by a decline thereafter, representing 12% of allo- geneic HCT performed in 2012. Tandem autologous-allo- geneic HCT peaked around the year 2004 and represented 19% of allogeneic HCTs in 2012. Allogeneic HCT as sal- vage after at least one autograft has steadily increased over recent years and represented 69% of allogeneic HCTs in 2012. Unfortunately, only a minority of these patients were enrolled in controlled trials and remarkable hetero- geneity in using allogeneic HCT was observed among dif- ferent European countries.
The potential role combining “new drugs” with graft-versus-myeloma effects has not yet fully been explored. In a Phase II study, the feasibility of using borte- zomib within a reduced-intensity conditioning regimen and as maintenance therapy post allograft was evaluated.52 Conditioning consisted of fludarabine, melphalan, and bortezomib, while maintenance treatment consisted of 7 cycles of bortezomib. Sixteen high-risk patients who had relapsed after an autograft were prospectively enrolled. Nine of 16 patients (56%) achieved CR and 5 of 16 (31%) achieved PR after allogeneic HCT. In this heavily pre- treated high-risk population, 3-year cumulative incidences of NRM, relapse, and OS were 25%, 54% and 41%, respectively. For the first time, this trial showed safety and efficacy of an intensified conditioning with a “new drug” in poor prognosis patients. Moreover, the concept of maintenance treatment after an allograft was also intro- duced. Our group recently published the results of a prospective Phase II single-center trial evaluating borte- zomib as maintenance treatment after tandem autolo- gous/allogeneic HCT for high-risk MM. At a median fol- low up of 51 months, a net benefit in terms of OS and PFS was shown among newly diagnosed patients over those with relapsed/persistent disease, suggesting that borte- zomib maintenance may add a survival benefit among untreated patients. Treatment-related toxicity was limit- ed, without any GvHD exacerbations.53 Different observa- tions were reported with immunomodulatory drugs. Somewhat compromised by an unacceptably high drop- out rate, the Phase III BMT CTN 0102 trial did not show a benefit of thalidomide maintenance after tandem autol- ogous/allogeneic HCT.13 Lenalidomide maintenance was evaluated in a study by the HOVON Group54 where the unexpectedly high toxicity profile, mainly exacerbation of
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haematologica | 2019; 104(2)