Focus on first-line therapy

The innovation of recent years has long since found its way into first-line therapy in multiple myeloma. Thus, the EHA-ESMO Guidelines were amended accordingly in January. Daratumumab, a monoclonal antibody directed against CD38, and new combinations of established agents such as bortezomib have become indispensable in the treatment of newly diagnosed multiple myeloma. And more changes are just around the corner.

Although life expectancy in multiple myeloma has doubled over the past 20 years, it remains modest at an average of eight to ten years [1]. A cure is usually not possible. This is partly due to the pronounced clonal diversity of the disease pattern, which often contributes to treatment failure. While treatment efficiently controls one clone, another – in the worst case, more aggressive – can spread unchecked. In addition to this clonal heterogeneity, which is present in all disease stages, other factors such as the microenvironment also influence the course. The introduction of proteasome inhibitors, immunomodulatory agents and, most recently, monoclonal antibodies has gradually improved first-line therapy over the last two decades (Fig. 1). This development is still ongoing – and was a major topic at this year’s European Hematology Association (EHA) congress.

The mixture makes the difference

In order to keep the disease in check, one thing seems to be particularly important: finding the right combination of active ingredients. Ideally, the combined use of different substances with different mechanisms of action can counteract therapy resistance and thus the progression of multiple myeloma. While only chemotherapeutic agents were available until 2004, proteasome inhibitors, immunomodulators, alkylates, and corticosteroids in particular played an important role in first-line therapy until recently.

These have recently been supplemented by the monoclonal antibody daratumumab, which was already included in the EHA-ESMO Guidelines in January of this year (Fig. 2) [2]. In Switzerland, the anti-CD38 antibody was approved for the first time in 2016 for the treatment of advanced cases. Today, daratumumab may also be used in combination with lenalidomide/dexamethasone or bortezomib/melphalan/prednisone (VMP) for the treatment of newly diagnosed multiple myeloma if autologous stem cell transplantation is not possible. Approval for first-line treatment of patients suitable for stem cell transplantation has been lacking, unlike in surrounding countries [3]. According to the EMA (European Medicines Agency) decision, daratumumab is already approved there together with bortezomib/thalidomide/daxamethasone (VTD) for the treatment of transplantable patients in the first line of treatment [4].

In the phase III Alcyone trial evaluating the addition of daratumumab to bortezomib/melphalan/prednisone (VMP) in non-transplant eligible patients, significant increases in overall and progression-free survival (PFS) were observed. With additional daratumumab administration, median PFS was 36.4 months, compared with 19.3 months without daratumumab [5]. Similar results were also seen in a phase III head-to-head comparison study of daratumumab/lenalidomide/dexamethasone and lenalidomide/dexamethasone alone in nontransplant-eligible patients. The PFS rate at 48 months was 60% with daratumumab treatment, whereas it was 38% without the additional administration of the anti-CD38 antibody [6]. Notably, this PFS benefit persisted even in high-risk patients with an unfavorable cytogenetic profile.

In addition to the introduction of daratumumab into first-line treatment, the EHA Congress also focused on new insights into the optimization of therapeutic combinations. Recent studies suggest that the combination of bortezomib, lenalidomide, and dexamethasone, also known as VRD, is likely to be not only more effective but also better tolerated than the bortezomib, thalidomide, and dexamethasone (VTD) therapy most commonly used in recent years. For example, lenalidomide does not induce peripheral neuropathy. According to an analysis presented at the EHA Congress, VRD has been proposed as a new therapeutic standard for induction and consolidation of transplant-eligible patients.

VRD is increasingly being used in patients for whom stem cell transplantation is not an option. Compared with current therapies with either lenalidomide/dexamethasone or bortezomib/melphalan/prednisone (VMP), VRD treatment shows significantly improved outcomes with a median progression-free survival of approximately 3 years and a median overall survival of approximately 74 months [7]. In comparison, with lenalidomide/dexamethasone therapy, median overall survival is approximately 59 months and progression-free survival is 26 months [8]. VMP treatment performed even slightly worse in the only relevant clinical trial, with a median overall survival of 56 months with a progression-free survival of 21 months [9].

Improvement possible?

Clear progress has already been made recently in the treatment of newly diagnosed multiple myeloma with the approval of daratumumab and the testing of new combination therapies. However, even with these improved therapeutic options, a cure for the disease is not yet in sight, so further innovation is needed. In the coming years, targeted therapies and immunotherapeutic approaches in particular could come into play here. According to the experts at the EHA Congress, these should be used as early as possible to take advantage of the maximum effect. Finally, 15-35% of patients are lost with each new line of therapy. Also, as the disease progresses, the immunological microenvironment of the tumor becomes increasingly dysfunctional, further complicating therapy [10]. For example, while there are still more CD4+ T cells in the first-line setting, these disappear with disease progression.

At present, science is focusing on various active substances. In addition to bispecific antibodies, antibody-drug conjugates and CAR-T cells, among others, are moving toward earlier lines of therapy. Currently, these are mainly used in refractory or relapsed tumors. Other monoclonal antibodies with different targets are also being investigated (Tab. 1) . For example, isatuximab – like daratumumab directed against CD38 – is already approved in Switzerland for third-line therapy of multiple myeloma. Elotuzumab targeting SLAMF-7 may also already be used in more advanced cases [3].

Apart from new active ingredients, the focus is also on further improving therapeutic combinations. In the transplant setting, the daratumumab-VRD and isatuximab/carfilzomib/lenalidomide/dexamethasone (Isa-KRD) combinations are currently being investigated for induction treatment [11]. In maintenance therapy, where lenalidomide is currently still the standard of care, daratumumab could also play an important role in the future, either as monotherapy or in combination with lenalidomide. For example, the Griffin study, which compared maintenance therapy using lenalidomide and daratumumab with lenalidomide treatment alone, showed promising results after one year.

The therapy of patients who are not suitable for transplantation could also be improved in the next few years by new combinations of active substances. As with induction therapy, daratumumab-VRD is an option in this setting. Similarly, the combination therapy VRD-isatuximab may soon be used. This is currently being investigated in the Phase III IMROZ trial.

Source: presentation “Immunotherapy in MM: Upfront Therapy: Novel antibody based combinations” at the EHA virtual congress, 11/06/2021, Maria-Victoria Mateos, Salamanca, Spain.

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