The stepchild in myeloma treatments: is allogeneic transplantation not so bad after all?

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).21 Given the armamentarium of highly effective agents and a pipeline of novel therapeutic options, including chimeric antigen receptor 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 eventually 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 allogeneic 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-dexamethasone (VAD), whereas after 2006 mostly immunomodulatory / proteasome inhibitor triplet regimens were given. The majority of patients (86%) received tandem autologous-allogeneic treatment upfront, while 14% had failed previous autologous HCT. After high-dose melphalan and autologous 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 overall 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 mortality 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 biological 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 experienced 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 disease (MRD) had a significantly lower relapse rate as compared 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., survival 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/refractory 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.

Figure 1.Proposed indication for allogeneic (allo)-hematopoietic cell transplantation (HCT) based on studies by Greil et al.,¹ Maffini et al.,² and other authors.^4,7,17 ASCT: autologous stem cell transplantation; DLI: donor lymphocyte infusion, CNI: calcineurin inhibitors; GVHD: graft-versus-host disease; VGPR: very good partial remission; CAVE: possible adverse effect.

Six prospective trials examined the role of allografting compared with autologous HCT alone.2112 Substantial differences in inclusion criteria and treatment schemas partly contributed to conflicting outcomes. While most of these trials demonstrated an improved PFS in the allogeneic cohort, in only two studies did this response also translate into a longer OS. Similarly, a meta-analysis of published clinical trials containing 1192 newly diagnosed patients who received tandem auto-auto and 630 who underwent tandem auto-non-myeloablative allogeneic HCT showed that the CR rates were higher in the auto-allo group, but there was no survival advantage in the first three years.22 Of note, the survival advantage in the auto-allo group, reported in two of the published comparative studies, became statistically significant after a follow up of at least three years. All these studies were conducted prior to the routine implementation of novel drugs into induction therapy; treatment of relapsed disease following HCT varied and was not taken into consideration when analyzing survival rates.

Today, there is remarkable heterogeneity in the use of allogeneic HCTs for patients with myeloma among different countries, and even institutions, and few ongoing clinical trials are studying how to improve allogeneic HCT strategies in myeloma or clarify its role. Trends in the use of HCT in myeloma were published in a large evaluation of the European Group of Blood and Marrow Transplantation (EBMT) over a 25-year period that examined a total of 3405 myeloma patients given allogeneic HCT either as an upfront treatment, within an upfront autologous-allogeneic HCT concept or as salvage treatment after a failed autologous HCT.23 It was demonstrated that allogeneic HCT is currently mostly used as salvage therapy for myeloma patients after at least one autograft rather than within an intensified upfront induction-auto-allo approach. Similar to the studies by Maffini et al. and Greil et al., the EBMT analysis demonstrated that OS rates in the first few years following allogeneic HCT were comparable with novel induction strategies involving new drugs and high-dose chemotherapy with autologous HCT; however, also in the EBMT dataset, long-term survival was observed in more than 20% of patients given allogeneic HCT. Again, patients receiving allogeneic HCT within an upfront auto-allo tandem approach achieved better outcomes, but even later transplants, usually in progression or relapse following autologous HCT, resulted in encouraging long-term outcomes with 25% survivor rates at ten years.

In the light of the studies by Maffini et al. and Greil et al., and those by other groups, the abandonment of allografting, as some have suggested, appears rather premature even in newly diagnosed myeloma patients. The two reports draw particular attention to the long-term follow up with potential cure in subsets of patients. Reasons to re-examine the role of allogeneic HCT for patients with myeloma in controlled clinical trials are as follows.

In conclusion, despite the recent dramatic improvement in survival, the overwhelming majority of myeloma patients invariably relapse. Given the potentially curative effect of graft-versus-myeloma activity, the role of allografting should become a matter of sound scientific debate in the myeloma community. Combinations of allografts with potent anti-myeloma agents pre- and post-HCT should be examined in young high-risk and/or early relapsed patients for whom life expectancy is currently very poor. Modern MRD monitoring tools may guide individual treatment decisions and thereby further improve long-term outcomes.