Haploidentical transplantation in patients with multiple myeloma making use of natural killer cell alloreactive donors

In recent years, the use of haploidentical donor cells for the treatment of hematological malignancies has been increasing and has proven effective and safe, especially with the use of PTCY [1, 2]. There is limited documentation about haploSCT in MM, but small retrospective studies show this is feasible with relatively low non-relapse mortality (NRM). Results in terms of PFS are however similar to HLA-identical SCT [3‐5]. HaploSCT offers an attractive opportunity to introduce natural killer (NK) cell alloreactivity based on a KIR-ligand mismatch. In myeloid malignancies, this NK alloreactivity, in the context of a T cell deplete haploSCT, leads to a decreased relapse rate and improved survival without causing GVHD [6‐8]. Unlike in T cell–depleted haploSCT, the benefit of NK cell alloreactivity in T cell replete haploidentical SCT is less clear and the limited number of small-sized studies concerning this effect is not conclusive [9‐12]. The differences concerning NK cell alloreactivity in these studies might be due to the disease heterogeneity of the included patients and differences in the conditioning regimen and stem cell source. Some studies point towards a better outcome when bone marrow stem cells were used compared to peripheral blood stem cells, which was shown to correlate with the T cell content of the graft that is higher in peripheral blood stem cell products [12]. This correlation is in line with reports on the inhibitory effect of T cells on the development of alloreactive NK cells [13].

There is much evidence to support the role of NK cells in fighting MM [14‐17]. It has been proven that therapeutic interventions like lenalidomide and elotuzumab result in increased NK cell–mediated anti-myeloma responses [18, 19]. In preclinical studies performed by our research group, we show that NK cells are able to kill MM cells, and this killing is improved in the presence of NK alloreactivity [20, 21]. This was shown in vitro as well as in a humanized mouse model. Two small clinical studies also implicated a beneficial role for KIR-ligand mismatch in MM. In one study, the role of administration of alloreactive NK cells before autologous SCT was examined. High remission rates were observed, although they were short-lived [22]. In another study, the impact of KIR-ligand mismatch in a HLA-identical and mismatched SCT setting was investigated and showed that KIR-ligand mismatch in the graft-versus-host direction was protective for relapse [23].

The aim of this phase 2 study was to prospectively evaluate if KIR-ligand mismatched haploidentical bone marrow transplantation (BMT) with PTCY improves PFS in poor-risk MM patients.

In total, 12 poor-risk patients were included from 3 hospitals in the Netherlands from April 2016 to May 2018 with a follow-up until April 2020 and the median time to follow-up is 30.2 months (range 11.8–44.9 months). Pre-transplantation patient characteristics are described in Table 1. They were all heavily pre-treated with both proteasome inhibition and immunomodulatory drugs; none of the patients received antibody treatment before inclusion. One patient had known high-risk cytogenetics and three patients showed progression within 12 months after autologous SCT. We excluded one patient for further analysis due to disease progression just before BMT, since this was a predefined exclusion criterion. This patient, however, was transplanted because pre-transplant M-protein levels became available during conditioning therapy. KIR/HLA incompatibility of the different donors is described in Table 2.

With this study, we tested the safety and the efficacy of a KIR-mismatched haploidentical BMT in high risk MM patients. We observed that the treatment is safe since there was a high engraftment rate, low NRM (18% at 1 year), and no unexpected adverse events. In the only two other retrospective studies concerning haploSCT with PTCY in MM where there was no selection on KIR-mismatch, comparable results were seen with respect to NRM (10–21% in 1.5 to 2 years); however, they had a slightly higher PFS (17–33% in 1.5 to 2 years). In our small study, unfortunately, there is a 1.5-year PFS of 0%. This 1.5-year PFS seems lower than in conventional alloSCT studies. However, the study is underpowered to draw these conclusions, since the study was prematurely terminated due to the defined stopping rules based on a 1.5-year PFS of 50%. Furthermore, this low PFS was also not unexpected since these were heavily pre-treated patients with very high-risk chemo-resistant myelomas. Though these patients showed a biochemical relapse, many of them did not require treatment for a long time after which is very unlikely for this fast progressive patient population. Even though it is difficult to draw conclusions in such a small, heterogenous group of patients, our results show that KIR-ligand mismatch in this patient category is not only harmful but also not more effective than non-matched haploSCT or conventional alloSCT in curing MM [3, 4].

We hypothesize that the late reconstitution of functional mature NK cells is responsible for the lack of response. This has already been described in other patient groups after PTCY: within days after SCT, mature graft-derived NK cells appear, but they are rapidly eliminated by PTCY. Full reconstitution of a mature and functional NK cell population took 6 to 12 months [12]. The median time point of relapse in our patients occurred shortly after transplantation (around 3 months). We detected that 30 days after haploBMSCT, most NK cells still had an immature phenotype without KIR expression and were not able to stop disease progression at this early stage after transplantation when myeloma cell load was still low. We hypothesize that the delayed NK cell reconstitution may be overruled by the infusion of mature, functional donor NK cells shortly after PTCY administration. In myeloid malignancies, this concept has already been used and seems successful in a small group of high-risk patients [27]. In this context, it may also be helpful to bridge the time to full NK cell restoration after the SCT with additional anti-MM therapy like elotuzumab or daratumumab, or to combine these two modalities. This concept is supported by the patient that showed a long-lasting complete response after temporary treatment with daratumumab. Another option would be to improve NK cell function and thereby increase the alloreactive effect by blocking antibodies, such as monalizumab, a novel checkpoint inhibitor against NKG2a [28].

In conclusion, in this study, we show that haploidentical BMT in MM patients is safe and feasible in terms of engraftment and late NK cell reconstitution. HaploBMT in MM forms a possible platform for future immunotherapeutic strategies in which the KIR-ligand mismatch might be beneficial. Though this study is limited in patient numbers, none of the patients showed a clinically relevant increase of PFS; therefore, we conclude that in the setting of haploBMT in combination with PTCY, however, a KIR mismatch probably is not clinically relevant.