Clinical Overview: Anti-CD38 Monoclonal Antibodies for Relapsed/Refractory Multiple Myeloma

In a recent review, researchers compared the anti-CD38 monoclonal antibodies (mAbs) daratumumab (Darzalex) and isatuximab (Sarclisa) for the treatment of relapsed and/or refractory multiple myeloma (RRMM). Pharmacists must evaluate multiple clinical and pharmacoeconomic factors when selecting the appropriate treatment.

Isatuximab and daratumumab are IgG1 mAbs that bind to different epitopes on CD38, which causes their mechanisms of action (MoA) to be triggered in different ways. Both agents kill MM cells through various MoA, including apoptosis, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). Isatuximab causes direct apoptosis unlike daratumumab.

Daratumumab has several indications, whereas isatuximab is only indicated for MM. The FDA approved daratumumab in combination with pomalidomide/dexamethasone (Pd) for patients with MM previously treated with at least 2 therapies, including lenalidomide and a proteasome inhibitor (PI), based on findings from the APOLLO study.

The ICARIA-MM study led to the approval of isatuximab in combination with Pd for the same indication and usage. Daratumumab or isatuximab in combination with carfilzomib/dexamethasone (Kd) is approved for patients with RRMM who were previously treated with 1-3 prior lines of therapy based on data from the CANDOR and IKEMA studies.

Findings from these clinical studies show that isatuximab and daratumumab improve profession-free survival and have manageable safety profiles in patients with RRMM. However, caution should be taken when making cross-trial comparisons of APOLLO with ICARIA-MM or CANDOR with IKEMA.

Besides the inherent differences between the study populations, follow-up duration, and outcomes, the key difference was the exclusion of patients with chronic obstructive pulmonary disease (COPD) and forced expiratory volume in 1 second less than 50% for the daratumumab studies. Experts do not recommend daratumumab in certain populations with COPD or asthma.

The prescribing information for daratumumab and isatuximab recommend pre-infusion medications to reduce the occurrence of infusion-related reactions (IRRs). Post-infusion medications, mainly oral methylprednisolone, are recommended for daratumumab during the initial infusions, but are not necessary for isatuximab.

Intravenous (Dara-IV) or subcutaneous (Dara-SC) formulations of daratumumab may be used for all regimens. Dara-SC decreases treatment burden, reduces the number of IRRs, and improves patient satisfaction while maintaining similar efficacy and pharmacokinetics compared to Dara-IV.

According to pharmacoeconomic analyses, isatuximab-based regimens for up to a 3-year time horizon yield substantial savings to US payers compared with daratumumab-based regimens. Overall, shorter treatment durations between 6 months and 3 years also indicated cost-effectiveness for isatuximab-based regimens.

Pharmacists play an integral role in managing patients with MM by evaluating cost-effective treatment options, monitoring pre- and post-medications, and managing administration-related adverse events. Because many patients with MM have preexisting comorbidities, pharmacists should assist in evaluating concomitant medications that may affect treatment decisions. Pharmacists should monitor clinical and lab parameters, and advise providers on supportive care agents, dose modifications, or drug interruptions.

Several other anti-CD38 agents are in development for the treatment of patients with MM. Drugs in the pipeline include other mAbs, antibody-drug conjugates, chimeric antigen receptor T-cell therapies, bispecific T-cell engager therapies, and immunocytokines.

About the Author

Wendy La, PharmD, is a clinical pharmacist at a pharmacy benefits manager.

Reference

Shah B, Gray J, Abraham I, Chang M. Pharmacy considerations: Use of anti-CD38 monoclonal antibodies in relapsed and/or refractory multiple myeloma. J Oncol Pharm Pract. 2023;29(1):170-182. doi:10.1177/10781552221107850