Donor T-cell responses and disease progression patterns of multiple myeloma

Bone Marrow Transplantation (2017) 52, 1609–1615 © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0268-3369/17 www.nature.com/bmt ORIGINAL ARTICLE Donor T-cell responses and disease progression patterns of multiple myeloma M Eefting1,4, LC de Wreede2,4, PA Von dem Borne1, CJM Halkes1, S Kersting1, EWA Marijt1, H Putter2, H Veelken1, J Schetelig3 and JHF Falkenburg1 Donor T-cells transferred after allogeneic stem cell transplantation (alloSCT) can result in long-term disease control in myeloma by the graft-versus-myeloma (GvM) effect. However, T-cell therapy may show differential effectiveness against bone marrow (BM) infiltration and focal myeloma lesions resulting in different control and progression patterns. Outcomes of 43 myeloma patients who underwent T-cell-depleted alloSCT with scheduled donor lymphocyte infusion (DLI) were analyzed with respect to diffuse BM infiltration and focal progression. For comparison, 12 patients for whom a donor search was started but no alloSCT was performed, were analyzed. After DLI, complete disappearance of myeloma cells in BM occurred in 86% of evaluable patients. The probabilities of BM progression-free survival (PFS) at 2 years after start of donor search, alloSCT and DLI, were 17% (95% confidence interval 0– 38%), 51% (36–66%), and 62% (44–80%) respectively. In contrast, the probabilities of focal PFS at 2 years after start of donor search, alloSCT and DLI, were 17% (0–38%), 30% (17–44%) and 28% (11–44%), respectively. Donor-derived T-cell responses effectively reduce BM infiltration, but not focal progression in myeloma, illustrating potent immunological responses in BM with only limited effect of T-cells on focal lesions. Bone Marrow Transplantation (2017) 52, 1609–1615; doi:10.1038/bmt.2017.201; published online 2 October 2017 INTRODUCTION Multiple myeloma (MM) is a neoplasia of plasma cells characterized by diffuse bone marrow (BM) plasmacytosis and focal lesions like plasmacytomas and lytic bone lesions. Current treatment strategies for fit younger patients aim to obtain long-term remissions and consist of combinations of immunomodulation, chemotherapy and autologous stem cell transplantation.1 However, most patients eventually relapse, and these patients require other treatment strategies. The role of allogeneic stem cell transplantation (alloSCT) as treatment option for relapsed MM is currently under debate.2–8 However, important lessons can be learned from the effect of T-cell therapy in the context of alloSCT. This may help to further develop T-cell therapy exploiting chimeric antigen receptor (CAR) cells, which is increasingly being performed.9 AlloSCT can result in long-term control of the disease because immune-competent donor T-cells can exert efficient graft-versusmyeloma (GvM) effects.10–12 Conventional outcome parameters of interest after transplantation are overall survival (OS) and progression-free survival (PFS). However, these outcomes offer little insight into the kinetics of the disease and the impact of different components of the treatment. The complexity of the course of the disease with occurrence of GvM effects, graft-versushost disease (GvHD) or non-relapse mortality, requires a richer methodology capable of analysing multiple distinct event types. A multi-state model permits mapping of all relevant events,13 and from this several competing risks models can be derived to analyse the events of main interest.14–18 At present, little is known about the clinical kinetics of allo-reactive T-cells in controlling myeloma progression or inducing tumor regression. Efficient GvM responses require targeting of malignant cells by antigen-specific T-cells in all sites of myeloma infiltration. Homing of T-cells to BM has been found to occur constitutively, whereas homing to other tissues may need specific ligands on T-cells, or an inflammatory environment.19–21 Consequently, the strength of immune responses in BM and focal lesions may differ and result in differential progression patterns of myeloma after alloSCT and donor lymphocyte infusion (DLI) depending on the presence or absence of donor T-cell-mediated GvM reactivity.22–24 Precise analyses of T-cell-mediated GvM responses is impaired in T-cell replete alloSCT settings by simultaneous effects of pretransplant treatment, conditioning regimens, concurrent immune responses, and immune suppression. T-cell depletion (TCD) of the stem cell graft has been developed to prevent development of severe GvHD.25–27 In general, effective TCD obviates the need for prophylactic immunosuppression.25,27 However, TCD also adversely affects post-transplant anti-tumor immunity.28 To overcome this effect, our center has pioneered routine administration of DLI at pre-scheduled time points while maintaining a low risk of GvHD induced by the conditioning regimen.11,29–32 TCD-alloSCT with sequential DLI, i.e., systematic introduction of post-transplant immune therapy, has the benefit of offering a unique opportunity to assess the specific influence of donor lymphocytes on myeloma progression patterns since chemotherapy and the immune intervention are given at different points in time. 1 Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands; 2Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands and 3Medical Department I, University Hospital Carl Gustav Carus, Technische Universität Dresden & DKMS, German Bone Marrow Donor Center, Dresden, Germany. Correspondence: Dr LC de Wreede, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail: 4 These authors contributed equally to this work. Received 19 February 2017; revised 29 May 2017; accepted 10 July 2017; published online 2 October 2017 Donor T-cell responses M Eefting et al 1610 Definitions Focal progression was defined as an increase in size or new-onset of soft tissue plasmacytomas and/or bone lesions as described by the criteria of the international myeloma working group.33 New-onset BM infiltration (i.e., BM progression) was defined as ⩾ 10% diffuse myeloma infiltration after a previously negative BM sample (measured by morphology, immunophenotyping and/or trephine biopsy). In all other cases, BM progression was defined as ⩾ 5% increase of myeloma cells in the BM as compared with the previous BM sample. After alloSCT, BM progression was considered as primary failure. Therefore, a lower threshold was chosen to detect newonset BM involvement as early as possible: any percentage of myeloma cells in the BM with loss of donor chimerism (⩽90% donor chimerism). Progression mortality was defined as death after signs of progressive disease. Non-progression mortality after alloSCT (or DLI) was defined as death after alloSCT (or DLI) without signs of progressive disease between alloSCT (or DLI) and death, respectively. AlloSCT protocol Patients with r (...truncated)