PF636 NATURAL KILLER CELL ALLOREACTIVE HAPLOIDENTICAL STEM CELL TRANSPLANTATION FOR MULTIPLE MYELOMA PATIENTS
Authors: Van Elssen C. , Wieten L. , Von dem Borne P. , Nijhof I. , Meyer E. 
Published: June 2019

Background:

Notwithstanding the progress made over the past years in survival of Multiple Myeloma (MM) patients, MM remains incurable. Haploidentical bone marrow transplantation (Haplo‐BMT) is a treatment option with curative potential. Haplo‐BMT already has shown clinical results however, only in a minority of MM patients. We hypothesize that this observation might be due to differences in natural killer (NK) cell alloreactivity and in this study we set out to prospectively investigate if NK cell mismatch is relevant for the outcome of haplo‐BMT.

Aims:

The aim of this prospective phase 2 study is to evaluate if KIR‐ligand mismatched haplo‐BMT with post‐transplant cyclophosphamide will improve progression free survival in poor risk MM patients.

Methods:

Poor risk MM patients, aged < 66 years were enrolled if they were responsive to their last line of therapy. Poor risk was defined as high‐risk cytogenetics, relapse within a year after autologous SCT, or treatment with threeor more previous lines of therapy. A prerequisite of enrolment was the possibility of an NK cell mismatch and availability of a mismatched family donor. Patients were excluded if donor‐specific HLA‐antibodies were present. Patients receive a haplo‐BMT with a non‐myeloablative conditioning regimen and post‐transplant cyclophosphamide. Primary endpoint is PFS at 1,5 years. Secondary endpoints are engraftment, bone marrow reconstitution, NK cell reconstitution, graft versus host disease (GvHD), infections and non‐relapse mortality (NRM).

Results:

In total 12 poor risk patients were included in the study of which 10 could be evaluated for the primary end point. Graft failure (1/12) and disease progression before transplant (1/12) rendered the remaining two patients not evaluable. At this interim analysis, 5 patients have reached 1,5 years follow up. Off all included patients mortality was 4/12 (33%), only 2 patients were in remission at death (NRM 17%). Of the 8 ‐ for the primary endpoint evaluable‐ patients 7 patients relapsed within 1,5 years. The last included patient is still in a stringent very good partial response at day 120. Average time of relapse is 141 days (30–360 days). Though relapsed, only 4/7 patients had to start anti‐myeloma treatment (time to next treatment 188 days). Of the 11 engrafted patients, average time to neutrophil recovery was 18 days (12–30 days) and average time to platelet recovery was 31 days (23–49 days). At day 30, all of the 9 analyses patients showed NK cell recovery, though with an immature phenotype (NKG2A+, KIR−). At day 60 in both the peripheral blood as well as bone marrow, mature NK cells (KIR+) could be identified. Of the engrafted patients 7 developed aGvHD, 55% grade I‐II and 9% grade II‐IV. Four patients developed cGvHD, all 36% grade I‐II. Treatment related mortality was 25%, which was in all cases due to infections. Infections were common post‐transplant and 45% of patients suffered from severe infections.

Summary/Conclusion:

The majority of patients showed early disease progression after mismatched haplo‐BMT. We predefined that with a PFS of 25% at 1,5 years we would qualify this treatment option successful. With only one patient still in remission this goal will not be achieved and we hypothesize that the late reconstitution of functional mature NK cells is responsible for the lack of response. Though, not yet successful, we show that mismatched haplo‐BMT in MM patients is feasible, in terms of engraftment and late NK cell reconstitution, save and forms a possible platform for future immunotherapeutic strategies.