Daratumumab combinations: what can we learn?

In this issue of Blood, Chari et al¹  show that the combination of pomalidomide and dexamethasone with daratumumab induces high rates of deep and durable responses in heavily pretreated myeloma patients.

After years of research, a monoclonal antibody (MoAb) targeting CD38 has been approved (daratumumab) and 2 other anti-CD38 MoAbs are in clinical development. These MoAbs showed significant single-agent activity in heavily pretreated myeloma patients and can be combined with other antimyeloma therapies without a significant increase in toxicity. The mechanisms of anti-CD38 MoAb activities implicate direct killing by binding to CD38,²  but mostly involve immune-mediated mechanisms such as activation of antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Indirect antimyeloma effects also include the downregulation of CD38⁺ regulatory T cells, of CD38⁺ regulatory B cells, and of myeloid-derived suppressor cells,³  all of which may play a role in the “immune tolerance” provided to myeloma cells in their microenvironment. Drugs that enhance the antimyeloma activity of the immune system may be preferred partners to combine with daratumumab and other anti-CD38 MoAbs. Immunomodulatory drugs (IMiDs), lenalidomide and pomalidomide, have immunostimulatory effects at various levels of the immune system and at least part of their antimyeloma activity is due to their immune-modulating properties. Indeed, the immunomodulatory effects of IMiDs and daratumumab may act synergistically by activation of T cells and increase of T-cell clonality and T-cell receptor repertoire.⁴ 

The combination of daratumumab with lenalidomide was recently approved by the Food and Drug Administration and European Medicines Agency for the treatment of patients with relapsed or refractory multiple myeloma after at least 1 line of therapy. Pomalidomide is a more potent immunomodulator than lenalidomide and may be a preferred companion for daratumumab. In the study by Chari et al, the daratumumab/pomalidomide combination was very effective in heavily pretreated patients. Beyond high response rates, the depth of response in some patients reached minimal residual disease negativity and some achieved long remissions, despite multiple relapses after prior therapies.

However, not all patients achieve deep and durable responses and eventually most will relapse during therapy with this combination. What drives this failure to anti-CD38 therapy? Mechanisms involving downregulation of CD38 expression, exhaustion of the immune system, development of complement resistance, or target saturation failure have been postulated to lead to anti-CD38 failure.⁵  The investigation of these escape mechanisms is crucial for the identification of optimal combinations and new targets that could be useful for the development of adjunct therapies. Pomalidomide may increase CD38 levels in myeloma cell lines and may lead to increased activity of anti-CD38 therapies⁶ ; however, what if the increase of CD38 is a mechanism of resistance to IMiDs, acting as an additional checkpoint, as was recently found in lung tumors treated with checkpoint inhibitors?⁷  In this case, do anti-CD38 MoAbs act by blocking a mechanism of resistance? What are the implications of CD38 upregulation in other immune system cells by IMiDs? What is the role of steroids when immunotherapy, such anti-CD38, is given? What could be the role of an adjunct drug that could enhance the antimyeloma activity of the immune system? Some of these questions are under investigation in clinical trials exploring addition of all-trans retinoic acid to daratumumab to enhance CD38 expression or checkpoint inhibitors to daratumumab, with or without an IMiD (NCT02431208, NCT01592370).

Another aspect of immunotherapy-based treatments is the timing of introduction of such therapies. The response rates and median progression-free survival (PFS) of the daratumumab/pomalidomide combination is about double that of pomalidomide/dexamethasone⁸  in a similar patient population, but, given that patients in the Chari et al study had not been previously exposed to daratumumab or to pomalidomide and that the drugs were given in combination, one may feel slightly disappointed with a PFS of 9 months and an overall survival of 18 months. The patients in this study had a long history of myeloma (median of 5 years) and a median of 4 prior lines of therapy; thus, many of them received the combination at very advanced stages of their disease, at which point, disease biology, but most important the immune system, may be quite different than in earlier stages. Data from the POLLUX study (Phase 3 Study Comparing Daratumumab, Lenalidomide, and Dexamethasone vs Lenalidomide and Dexamethasone in Subjects with Relapsed or Refractory Multiple Myeloma) show that, in patients who received lenalidomide/daratumumab early in the disease course, PFS and response rates are unprecedented, indicating that early anti-CD38 therapy, when the immune system may be more competent, may be crucial.⁹  In the era of immunotherapies, we cannot rely only on “medians”: some patients had substantial benefit in terms of quality but also of duration of response with daratumumab/pomalidomide. Unfortunately, we do not have reliable biomarkers to identify those with higher chances to benefit from such therapies, both for anti-CD38 and for IMiDs: the expression of CD38 is not consistently associated with response to daratumumab,⁵  cereblon expression has not been standardized as a reliable biomarker for response to IMiDs, and relevant immune function tests have not been evaluated.

Another question concerns the potential use of the 2 therapies (pomalidomide and daratumumab) sequentially rather than concomitantly: both therapies (pomalidomide with dexamethasone⁸  and single-agent daratumumab¹⁰ ) are associated with a PFS of about 4 months, whereas, given in combination, there is a PFS of about 9 months. Thus, for some patients, the sequential use of the 2 regimens could be associated with a similar outcome. In the SIRIUS (Daratumumab Monotherapy in Patients with Treatment-Refractory Multiple Myeloma) and GEN501 (Daratumumab [HuMax-CD38] Safety Study in Multiple Myeloma) studies, a significant proportion of patients (55%) had received prior pomalidomide and the efficacy of daratumumab monotherapy was not adversely affected, whereas after daratumumab, the response to subsequent therapies was favorable.¹⁰  The randomized study comparing daratumumab with pomalidomide and dexamethasone to pomalidomide with dexamethasone (APOLLO study, NCT03180736) will address some of these questions.

Other concerns include the treatment options for patients failing the combination of pomalidomide and daratumumab: should anti-CD38 therapy stop? Should other drugs substitute for pomalidomide whereas daratumumab remains as a backbone? Should other immunotherapies (such as checkpoint inhibitors) be added to daratumumab? Combining pomalidomide with daratumumab is a very effective therapy; however, we need better understanding of the mechanisms of resistance, the optimal timing for such a therapy, and reliable biomarkers to identify those with a higher probability of benefit, especially given the financial toxicity of these combinations.