Anti-CD38 Antibodies in the Treatment of RRMM: Considerations for Pharmacists

Implementation of a pharmacist on the healthcare team can have significant clinical and economic benefits.

Pharmacists play a significant role on the healthcare team in managing patients with relapsed/refractory multiple myeloma (RRMM) and are heavily involved in driving formulary decisions based on cost, efficacy, and safety. Anti-CD38 antibodies, daratumumab and isatuximab, are novel treatments utilized for MM patients progressing on current therapy. Current evidence on these agents, including mechanism of action (MOA), efficacy, safety, and pharmacoeconomic perspective, and the implications for pharmacists as part of the integrated team were discussed in a publication by Shah et al.

Both isatuximab and daratumumab are IgG1 monoclonal antibodies that bind CD38 on the surface on MM cells, killing tumor cells in a variety of ways; however, there are differences between their MOA. First, they both bind to different epitopes on CD38. Additionally, isatuximab has a dose-dependent inhibition of CD38 enzymatic activity, while daratumumab does not. CD38 receptor density is less affected by isatuximab, but both daratumumab and isatuximab directly activate natural killer cells. Overall, isatuximab’s MOA depends less on complement-dependent cytotoxicity, which daratumumab induces in Daudi cells, and relies on antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis in MM cell lines.

Both therapies have several FDA-approved indications, which are based on a variety of clinical trials. Intravenous (IV) daratumumab in combination with pomalidomide and dexamethasone (Pd) is approved for RRMM in patients who have received 2 or more lines of therapy but in combination with carfilzomib and dexamethasone (Kd) in patients who are refractory to 1 to 3 lines of therapy. Subcutaneous (SC) daratumumab with Pd is indicated in RRMM patients who are refractory to 1 prior line of therapy and is indicated with Kd in patients refractory to 1 to 3 prior lines. IV isatuximab is indicated with Pd for patients previously treated with 2 lines of therapy and with Kd in patients who are refractory to 1 to 3 lines of therapy. SC isatuximab is currently being investigated. Both therapies improve progression-free survival and have manageable safety profiles; however, it is difficult to cross compare results from clinical trials between the 2 therapies.

Pharmacoeconomic analyses are historically used to identify and select appropriate interventions based on costs and clinical outcomes, although the studies do come with limitations. Often life years or quality-adjusted life years (QALYs) have been used to describe the economics of treatments. QALYs are based on the quality of life impacted by side effects or other variables that affect a patient’s experience from the illness or treatment. Once the QALY for a treatment is determined, a cost can be assessed, which can include drug cost, administration time, adverse event management, monitoring, etc. There have been 2 pharmacoeconomic studies that compared isatuximab-based regimens with daratumumab-based regimens in RRMM. One study assessed isatuximab versus daratumumab plus Pd from a US payer perspective, while the other assessed isatuximab versus daratumumab plus Kd in RRMM with short-term outcomes. Both indicated that isatuximab-based regimens were more cost-effective for up to 3 years and yielded substantial savings between 6 months and 3 years of treatment.

These considerations are important for pharmacists as they are heavily involved in formulary decisions, as well as investigating cost-effective use that does not compromise safety and efficacy. It is important for them to understand both clinical and economic factors for currently approved therapies. As more anti-

CD38 products become available, pharmacists will be tasked with helping providers navigate treatment options in terms of cost, pre- and post-medication use, managing of side effects, guiding time and sequencing of anti-CD38 therapy, and more. Implementing a pharmacist into the care team can have substantial clinical and financial benefits, which is important in the RRMM space where treatment can be complicated.

Reference

1. 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;29:1-13.