EHA 2018: Preferred treatment combinations and sequencing in transplant eligible and elderly MM patients

The growing number of novel treatments for multiple myeloma (MM) means that more patients can achieve the therapeutic goal of a deep and prolonged first remission – in some cases even to the extent that it can be described as a cure. However, optimisation of second-line therapy and beyond continues to challenge clinicians in the novel therapy era. In his presentation at a Scientific Working Group session at EHA 2018, Professor Hartmut Goldschmidt from Heidelberg in Germany reviewed strategies for treating MM patients who are eligible and ineligible for stem cell transplantation, respectively.

Author: Maria Dalby. Interviewer: Esther Drain.

Professor Philippe Moreau (Nantes) and Dr Niels Van de Donk (Amsterdam) discuss updates on new combinations and therapies for maintenance following stem cell transplantation.

Incorporating novel agents into induction protocols has resulted in dramatic improvements in OS of more than 1.5 years among transplant-eligible MM patients.¹ In Professor Goldschmidt’s own centre at Heidelberg, the five-year OS has improved from around 50% prior to high-dose therapy to nearly 80% in the novel therapy era.² In the early days of high-dose therapy there were only a handful of options for induction and consolidation, and the only alternative as regards maintenance therapy was interferon alpha.³ Since then, the number of treatments has increased dramatically. The choice of initial therapy and the depth and duration of response achieved will influence the treatment choice at relapse, and it is therefore important to individualise therapy based on patient fitness and preferences and disease characteristics, and to include patients in clinical trials if possible to improve outcomes.

In patients who relapse following frontline autologous stem cell transplantation (auto-SCT), salvage options include a second auto-SCT, allogeneic stem cell transplantation (allo-SCT), or combination therapy within or outside a clinical trial for patients who are unable to undergo transplantation. A second auto-SCT has been shown in a retrospective analysis to result in significantly longer median survival compared with salvage therapy with novel agents or conventional chemotherapy.⁴ The randomised phase 3 Myeloma X trial showed that salvage auto-SCT was associated with superior PFS and OS compared with weekly oral cyclophosphamide for 12 weeks.^{5, 6} A study has recently been completed in the German myeloma network in which salvage auto-SCT at first to third relapse has been compared with continuous treatment with lenalidomide plus dexamethasone (Rd) until progressive disease, a comparator which better reflects current recommended treatment protocols.⁷ The primary endpoint in this trial (known as the GMMG ReLApsE trial) was PFS, and secondary endpoints included OS and outcomes following early versus late salvage transplantation. The results will be presented at ASH 2018.

Allo-SCT as salvage can prolong PFS in patients with early relapse and/or high-risk disease, but toxicity levels are high and the OS benefit is less clear.⁸ A trial is due to commence in Germany during 2019 which is part-funded by the German government and which will compare survival outcomes following salvage with allo-SCT versus auto-SCT at first to third relapse. For patients who are unable to undergo salvage transplantation, triplet regimens with and IMiD and proteasome inhibitor (PI) with dexamethasone have shown superiority over doublet regimens as salvage therapy at relapse following auto-SCT in terms of time to progression and OS, with acceptable tolerability.⁹

Professor Meletios Dimopoulos (Athens) reviews updates on continuous and maintenance therapy in MM.

Patients who are ineligible for transplantation in the frontline setting now have a range of available options under the latest evidence-based treatment guidelines, including VMP, Rd or VRd (first option), MPT or VCD (second option), or alternatives such as CTD, MP, bendamustine or prednisone.¹⁰ At first relapse, the choice of PI or IMiD-based therapy will depend on the frontline treatment – patients receiving bortezomib-based induction should receive Rd alone or as a triplet combination with daratumumab, carfilzomib, ixazomib or elotuzumab, whereas patients relapsing following IMiD-based induction should Kd or Vd doublet therapy, or triplet therapy with Vd and daratumumab, panobinostat, elotuzumab or cyclophosphamide.¹⁰ In addition to the initial therapy, treatment decisions in RRMM should take into account the depth and duration of response to the initial therapy, any previous toxicities such as myelosuppression or peripheral neuropathy,  whether the relapse is of an aggressive nature or more indolent, and the age and performance status of the patient.¹¹ Careful clinical evaluation of elderly patients is important since age alone is not sufficient for determining whether the patient is frail or fit, and frailty has been shown to be a significant predictor of treatment discontinuation and mortality in elderly MM patients.¹²

Professor Goldschmidt concluded his presentation by predicting that immuno-oncology will further expand treatment options and improve outcomes in MM. Monoclonal antibodies are already in clinical use, including elotuzumab which targets SLAMF7 and kills myeloma cells through direct cell activation and by tagging for antibody-dependent cellular cytotoxicity (ADCC) recognition;¹³ and daratumumab which induces tumour cell death by targeting CD38.^{14, 15} In addition, active immune therapy with CAR-T cells is a novel treatment option which Professor Goldschmidt expects will have a profound impact on the treatment of RRMM in the near future.^16-18

Professor Goldschmidt and his colleagues also presented a poster with results from a post hoc analysis of OS data from the ASPIRE and ENDEAVOR studies. The main results of these two studies demonstrated that PI carfilzomib at a dose of 27mg/m² plus lenalidomide and dexamethasone (ASPIRE) or 56mg/m² plus dexamethasone (ENDEAVOR) was significantly superior to Rd and bortezomib plus dexamethasone, respectively, for prolonging PFS and OS in RRMM.^{19, 20} The post hoc analysis of the two studies presented in the poster showed that the two carfilzomib-based regimens provided clinically meaningful improvements in OS in patients who had relapsed following auto-SCT. Patients in the ASPIRE study who received KRd after a prior auto-SCT had an 11.4 month improvement in median OS, and among patients who relapsed following frontline auto-SCT the improvement in median OS was 18.6 months. In contrast in ENDEAVOR, the OS benefit was more pronounced among patients with no prior transplantation. The carfilzomib-based regimens were well tolerated regardless of prior transplantation status (poster PS1309).

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