Dexamethasone as a partner of isatuximab

In this issue of Blood, Dimopoulos et al report that dexamethasone improves the rates of response and progression-free survival with treatment using the anti-CD38 monoclonal antibody isatuximab. There were no significant deleterious effect on safety.¹  Dimopoulos, in the 1980s and 1990s as a young hematologist, worked with giants in myeloma, participating in several studies showing the benefit of dexamethasone as single agent in patients unresponsive to standard therapy. He also showed how dexamethasone was the key player when combined with vincristine and doxorubicine.²  He reported later on its benefit in newly diagnosed myeloma patients and showed a beneficial dexamethasone effect in patients with hypercalcemia, in patients with pancytopenia, or in those who required simultaneous radiotherapy for a pathological fracture.³  Despite the advances of the last 40 years, dexamethasone is still prescribed for patients with hypercalcemia, cord compression, and even acute renal failure.

High-dose dexamethasone was the control arm of phase 3 clinical trials conducted for relapse at the beginning of this century. Once the proteasome inhibitor bortezomib and immunomodulatory drugs thalidomide, lenalidomide, and pomalidomide entered the myeloma landscape, the experimental arm still often included dexamethasone.

As more agents have become available for the treatment of myeloma, the attributes of successful new therapies have evolved. New agents should have activity as a single agent, be well tolerated, and be at least additive when combined with other drugs. Successful agents will be used earlier during the course of therapy and eventually incorporated into treatment guidelines.

Isatuximab, as single agent, has shown activity in an open-label, multicenter dose-escalation study in patients with relapsed-refractory myeloma. The overall response rate was 23.8% with a reasonable safety profile, including 51% mostly mild, infusion-related reactions.⁴  These efficacy and safety results are similar to that reported in the isatuximab control arm of this published study by Dimopoulos et al.

Isatuximab is a monoclonal antibody, and it is therefore classified as immunotherapy. The addition of dexamethasone could potentially inhibit naive T-cell differentiation, causing a detrimental effect on CD8 T lymphocytes and impairing the immunomodulatory effect. Dimopoulos, likely influenced by his prior work with dexamethasone in myeloma, conducted this phase 2 randomized trial combining isatuximab with dexamethasone showing, once again, how the addition of corticosteroids improved the overall response rate up to 43.6% with a median progression-free survival of 10.2 months, more than double that of isatuximab as a single agent.

These data are similar to those reported by the Intergroupe Francophone du Myeloma. In their 2014-04 trial, daratumumab, another anti-CD38 monoclonal antibody, was combined with dexamethasone in heavily pretreated myeloma patients, but this is a single-arm study with no control arm.⁵ 

How relevant are these findings? From the scientific point of view, this study supports that anti-CD38 monoclonal antibodies can be combined with dexamethasone. The lack of deleterious effect on the T cells and NK cells was confirmed in ancillary studies. However, it is also important to note that (i) this was not a phase 3 randomized trial powered to detect a difference between the 2 arms; (ii) there was no difference in overall survival between the arms; (iii) although safety profile seems to be comparable, the addition of dexamethasone resulted in more psychiatric and gastrointestinal adverse events with no reduction in the incidence of infusion-related reactions; and (iv) the quality of life of the patients has not been evaluated, and it is well known how some patients do not tolerate dexamethasone.

Will we be able to offer corticosteroids-free regimens to our patients with myeloma? It will be difficult because dexamethasone continues to be the salt that flavors all combinations. Because of the synergistic effect reported here, all isatuximab-based combinations should include dexamethasone, as is the case already for pomalidomide or carfilzomib. Meanwhile, the best we can do is to inform the patient well about the potential side effects and treat them, since the benefit of dexamethasone in combination with other agents has again been demonstrated in the study by Dimopoulos et al in this issue of Blood.