For patients with multiple myeloma (MM) who become refractory to therapy, subsequent treatment often consists of regimens containing the anti-CD38 antibodies daratumumab or isatuximab. Pharmacists play a crucial role in managing patients with relapsed/refractory MM (RRMM) and are heavily involved in driving formulary decisions based on efficacy, safety, and cost. Shah and colleagues recently published a review article aimed at assessing current evidence on daratumumab and isatuximab, including mechanism of action (MOA), efficacy, safety, and pharmacoeconomic perspectives, and evaluating the implications of pharmacists as part of the integrated team.
Both daratumumab and isatuximab are immunoglobulin G1 monoclonal antibodies that bind CD38 on the surface on MM cells, killing tumor cells in a variety of ways. Differences in their MOA have been elucidated, however. First, they bind to different epitopes on CD38. In addition, isatuximab’s inhibition of CD38 enzymatic activity is dose-dependent, whereas daratumumab’s is 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 compared with daratumumab and relies on antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis in MM cell lines.
Based on various clinical trials, the 2 therapies have several FDA-approved indications. Daratumumab in combination with pomalidomide/dexamethasone (Pd) is approved for RRMM in patients who have received ≥2 lines of therapy; it is used in combination with carfilzomib/dexamethasone (Kd) in patients refractory to 1 to 3 lines of therapy. Intravenous isatuximab is indicated in combination with Pd for patients previously treated with 2 lines of therapy, and it is used with Kd in patients who are refractory to 1 to 3 lines of therapy. (Subcutaneous isatuximab is currently being investigated.) Both therapies improve progression-free survival and have manageable safety profiles, but it is difficult to 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 such 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 adverse events or other variables that affect a patient’s experience from the illness or treatment. Once the QALYs for a treatment are determined, a cost can be assessed. Costs include drug cost, administration time, adverse-event management, and monitoring. Two pharmacoeconomic studies have compared isatuximab-based regimens with daratumumab-based regimens in patients with RRMM. One study assessed isatuximab versus daratumumab plus Pd from a US payer perspective. The second study assessed isatuximab versus daratumumab plus Kd in patients with RRMM with short-term outcomes. Both studies showed that isatuximab-based regimens were more cost-effective than daratumumab-based regimens for up to a 3-year time frame; in addition, treatment with isatuximab-based regimens yielded substantial savings between 6 months and 3 years of treatment.
These considerations are important for pharmacists—they are heavily involved in formulary decisions and in investigating cost-effective use that does not compromise patient 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, monitoring pre- and post-medication use, managing adverse events, and guiding time and sequencing of anti-CD38 therapy among other tasks. Incorporating a pharmacist into the care team can have substantial clinical and financial benefits, which is important in the RRMM space, where treatment selection can be complicated.
Source
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. June 20, 2022. Epub ahead of print.