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Editorials
The stepchild in myeloma treatments: is allogeneic transplantation not so bad after all?
Antonia M.S. Müller,1 Shaji K. Kumar2 and Benedetto Bruno3
1Department of Medical Oncology and Hematology, University Hospital Zurich, Switzerland; 2Division of Hematology, Mayo Clinic, Rochester, MN, USA and 3Department of Oncology/Hematology, A.O.U. Città della Salute e della Scienza di Torino, Presidio Molinette, Torino, Italy
E-mail: benedetto.bruno@unito.it doi:10.3324/haematol.2018.206987
In this edition of Haematologica, two papers from the US and Germany report on the long-term follow up of patients with multiple myeloma (MM) treated with reduced intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (HCT).1,2 Given the armamentarium of highly effective agents and a pipeline of novel therapeutic options, including chimeric antigen recep- tor T (CAR-T) cells, many hemato-oncologists believe that there is no longer a role for allogeneic HCT in the treatment of MM. Despite remarkable improvements in outcomes with novel drugs, these advances have not yet translated into cure of the disease, even when combined with high- dose chemotherapy and autologous HCT. Patients eventu- ally relapse and die of their underlying disease. The two reports by Maffini et al. and Greil et al. both show that long- term survival, and potentially a cure, can actually be achieved in a proportion of myeloma patients by an allo- geneic HCT, a treatment outcome that so far has not been observed with any other therapeutic strategy.
Maffini et al. present the long-term clinical outcomes of 244 patients who underwent allogeneic HCT following non-myeloablative conditioning with fludarabine and total body irradiation (TBI) between 1998 and 2016. In this study, more than half the patients had a chemotherapy- based induction with vincristine-doxorubicin-dexametha- sone (VAD), whereas after 2006 mostly immunomodulato- ry / proteasome inhibitor triplet regimens were given. The majority of patients (86%) received tandem autologous- allogeneic treatment upfront, while 14% had failed previ- ous autologous HCT. After high-dose melphalan and autol- ogous HCT, 26% of patients were in a complete remission (CR), 19% in a very good partial remission (VGPR), 38% in a partial remission (PR), and 17% had progressive disease. Best responses following allogeneic HCT were: CR in 46%, VGPR in 17%, PR in 20% of patients [overall response rate (ORR) 83%], and 17% failed to achieve a response. With a median follow up of 8.3 years (range, 1.0-18.1), 5-year over- all survival (OS) and progression-free survival (PFS) rates were 54% and 31%, respectively, and 10-year OS and PFS rates were 41% and 19%, respectively. Non-relapse mortal- ity was low with 2% at day +100 and 14% at five years, The rate of acute graft-versus-host disease (GvHD) was acceptable (33% grade II, 11% grade III / IV), while the cumulative incidence of chronic GvHD was 46%. The key findings of this study were: i) that patients with disease that was refractory to induction and those with high-risk biolog- ical features experienced shorter OS and PFS, while among standard-risk patients the median OS was not reached, and the median PFS was 6.5 years. High-risk patients experi- enced a median OS of 8.4 years with a PFS of 2.5 years; ii) patients who proceeded to tandem HCT after a previously
failed autologous HCT had poor outcomes with a median OS of 1.2 years and a median PFS of 0.4 years; iii) those patients who achieved negativity for minimal residual dis- ease (MRD) had a significantly lower relapse rate as com- pared with MRD-positive (MRD+) patients, indicating that marrow sampling for MRD assessment post HCT is an important tool to guide treatment decisions.
Similar observations were made by Greil et al. who report on their single center experience of 109 consecutive patients who received fludarabine-based RIC preparation followed by allogeneic HCT between 2000 and 2017. With a median follow up of 71.5 months (6 years), the authors observed a high ORR of 70% (CR rate 42%), with a median PFS of 14.2 months (1.2 years) and a median OS of 39.2 months (3.3 years). Consistent with the findings of Maffini et al., sur- vival was better in patients with sufficient response to induction therapy with a median OS of 65 months (5.4 years vs. 11.5 months in non-responders) and best in those undergoing allogeneic-HCT within first-line treatment (median OS not reached vs. 21.6 months in relapsed/refrac- tory patients). Accordingly, the cumulative incidence of relapse was considerably lower in patients transplanted in first-line with 11% within the first year as compared to 50.3% after HCT for relapsed /refractory myeloma. Most relapses occurred within the first two years post HCT. Beyond five years, the survival curves appear to have reached a plateau with late relapses rarely occurring (10- year OS 28.4% and 10-year PFS 24%). Also in this cohort, the rate of high-grade GvHD was moderate and the non- relapse mortality low (8.4% within the first year, 12.4% at 10 years).
Both the studies by Maffini et al. and Greil et al. provide evidence that allogeneic HCT can induce graft-versus- myeloma activity that enables long-term disease control and survival (potentially even a cure) in selected myeloma patients. The following observations stand out and require further reflection and consideration.
1) Induction treatment in both trials was mostly chemotherapy-based. The majority of patients achieved “only” a partial response prior to autologous HCT. Both studies showed that the depth of response prior to HCT is critical, and that outcomes in patients who respond to induction are better when compared with non-responders, also after allogeneic HCT. Depth of response is a well- known parameter that predicts clinical outcomes in myelo- ma, and in recent years MRD testing by PCR or flow cytometry has become available at many centers. A hall- mark study underlining the importance of MRD monitor- ing was presented in a report on the long-term outcomes of molecular monitoring after a tandem “auto-non-myeloabla- tive allo” approach.3 Twenty-six patients were prospective-
haematologica | 2019; 104(2)