Managing Multiple Myeloma With Anti-CD38 Combination Therapy

Srinivas S. Devarakonda, MD, is assistant professor in the division of hematology at the James Cancer Hospital and Solove Research Institute of The Ohio State University Wexner Medical Center, Columbus, Ohio. He specializes in the treatment of plasma-cell dyscrasias, including multiple myeloma, amyloidosis, and Waldenstrom macroglobulinemia.

CD38 is a cell-surface protein that has receptor and enzyme functions and that is highly and uniformly expressed on multiple myeloma (MM) cells.¹ CD38 is also expressed, at a relatively low level, on normal lymphoid and myeloid cells, as well as on some tissues of nonhematopoietic origin, such as prostatic epithelial cells, pancreatic islet cells, and striated airway muscle. During the past 5 years, therapies targeting CD38 have been helping fuel rapid growth in treatment options for patients with MM.

What is the recommended first-line standard of care for patients with relapsed or refractory MM (RRMM)?

For patients with RRMM, 3-drug regimens that incorporate a CD38 antibody (daratumumab or isatuximab) or proteasome inhibitor (carfilzomib or ixazomib), or both, as backbones are recommended as initial treatment, depending on the treatment history and whether the patient is resistant to these agents. These drugs are usually combined with steroids and an immunomodulator, such as lenalidomide and pomalidomide. Several combination regimens have been approved, including:

●       Daratumumab plus pomalidomide plus dexamethasone;
●       Daratumumab plus lenalidomide plus dexamethasone;
●       Carfilzomib plus pomalidomide plus dexamethasone; and
●       Ixazomib plus carfilzomib plus dexamethasone.

Daratumumab was the first monoclonal antibody directed at CD38 to gain FDA approval for patients with MM. Now, daratumumab has been joined by isatuximab-irfc, an anti-CD38 monoclonal antibody with a novel mechanism of action.

Where do these 2 drugs fit in treatment regimens? When is one used ahead of the other? Are there patient characteristics that favor the use of one anti-CD38 agent over the other when used in combination regimens?

The 2 drugs are similar, but there are differences in their mechanisms of action and  approved indications. The FDA recently expanded the indication for daratumumab to include patients who are newly diagnosed with MM, in addition to those in the RRMM setting. Regulatory approval was granted for daratumumab to be used in combination with bortezomib, thalidomide, and dexamethasone for patients who are eligible for autologous stem-cell transplantation on the basis of results from the CASSIOPEIA trial (ClinicalTrials.gov Identifier: NCT02541383).^2,3 Patients for whom daratumumab was added to their regimen experienced a 53% reduction in the risk of progression or death, compared with the control group.

Approval was also granted to daratumumab, in combination with lenalidomide and dexamethasone, for patients with newly diagnosed MM who are ineligible for autologous stem-cell transplantation.⁴ The basis for that indication was findings from the MAIA trial (ClinicalTrials.gov Identifier: NCT02252172) that adding daratumumab in combination with lenalidomide and low-dose dexamethasone improved progression-free survival, compared with treatment with the standard regimen.⁵ The percentage of patients with a complete response or better was 47.6% in the daratumumab group compared with 24.9% in the control group (P <.001).

Isatuximab-irfc targets CD38 but binds to a different, and unique, epitope amino-acid sequence than daratumumab. It is the only CD38 antibody that can initiate apoptosis directly by targeting an enzyme uniformly expressed on myeloma cells through the CD38 mechanism of action. ⁶ Isatuximab-irfc has been approved for the treatment of RRMM only, to be used in combination with pomalidomide plus dexamethasone and carfilzomib plus dexamethasone. Because daratumumab is approved for subcutaneous use in some regimens, it might be preferred — by patients and providers — for its ease of administration and convenience.⁷ However, when given intravenously, the recommended duration of infusion for isatuximab-irfc is slightly shorter than that of daratumumab, and isatuximab-irfc does not require post-infusion prophylaxis with a corticosteroid or bronchodilator. A subcutaneous formulation of isatuximab-irfc is being tested and developed in a phase 1b study (ClinicalTrials.gov Identifier: NCT04045795).

Are there subgroups of patients who seem to derive the most benefit when these agents are added to their regimen? Does cytogenetic risk status have an impact on outcomes?

Both daratumumab and isatuximab-irfc demonstrated efficacy in clinical trials in all poor-prognosis patient subgroups. These include patients with advanced-stage disease (that is, International Staging System stage III), high-risk cytogenetics, renal impairment, and resistance to protease inhibitors and immunomodulators, as well as older patients. However, when used in combination, isatuximab-irfc appears to be synergistic with pomalidomide in terms of inducing antibody-dependent cellular toxicity; the same synergism is seen with bortezomib and lenalidomide for daratumumab. ⁸ The activity of isatuximab-irfc with other drugs is being investigated in clinical trials.

Both CD38 antibodies have efficacy in patients with high-risk cytogenetics, which is defined by the presence of a del(17p) or a t(4;14) or t(14;16) translocation by fluorescence in situ hybridization.

Will isatuximab-irfc offer better outcomes in patients previously exposed to daratumumab, instead of retreatment with daratumumab — a scenario that will become common, given the incorporation of daratumumab in the upfront setting?

We don’t have data yet to tell us if treatment with isatuximab-irfc offers better outcomes than daratumumab retreatment in patients with RRMM who had prior exposure to daratumumab. In the ICARIA-MM study (ClinicalTrials.gov Identifier: NCT02990338), adding isatuximab-irfc to pomalidomide plus dexamethasone almost doubled median progression-free survival: 11.5 months in the isatuximab-irfc plus pomalidomide plus dexamethasone group, compared with 6.5 months in the pomalidomide plus dexamethasone group.⁹ However, approximately half of patients in the pomalidomide plus dexamethasone group, compared with 10% in the isatuximab-irfc plus pomalidomide plus dexamethasone group, received daratumumab, and the overall survival analysis didn’t seem to be affected by prior exposure to daratumumab. The efficacy of an CD38 antibody after a previous one in a different line of treatment still should be investigated in randomized trials.

Several novel strategies directed at CD38 in MM are in earlier stages of development, including employing bispecific antibodies and chimeric antigen-receptor (CAR) T cells. Are any new agents nearing approval, or in phase 3 trials? Where might they fit into treatment regimens — that is, where is the greatest need?

Idecabtagene vicleucel, a B-cell maturation antigen (BCMA)–directed CAR T-cell therapy, was recently approved by the FDA for the treatment of patients with RRMM after 4 or more prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and a CD38 antibody. It is the first CAR T-cell product approved for this disease, and several other anti-B-cell maturation antigen–directed CAR T-cell products are being investigated in phase 3 trials. Various bispecific antibodies are also being investigated in early-phase trials — mostly, phase 1/2 — and early data are demonstrating efficacy.¹⁰

These newer agents are going to play a major role in the treatment of patients with RRMM whose disease has progressed on multiple prior therapies, including anti-CD38 agents. More so, with CD38 antibodies making a foray into the frontline treatment of newly diagnosed MM, agents with novel mechanisms of action, such as CAR T-cell therapy and bispecific antibodies, are crucial to overcoming drug resistance and improving survival in relapsed disease.