To minimize the risk of cytokine release syndrome (CRS) events in patients with relapsed or refractory (R/R) multiple myeloma (MM) after a dose interruption of elranatamab (ELRA), researchers recommend a modified step-up dosing based on ELRA exposure thresholds associated with CRS events, according to a study presented at the 65th ASH Annual Meeting and Exposition.
This dosing recommendation “should be used as routine,” said Ruben Niesvizky, MD, of Weill Cornell Medicine and New York Presbyterian Hospital in New York, who led the study and presented the findings.
Researchers used a multivariable analysis to measure clinical factors associated with CRS and a population pharmacokinetic model to determine a safe dosing recommendation by simulating different interruption scenarios using data from the open label ELRA trials MagnetisMM-1, -2, -3, and -9.
In the MagnetisMM-3 study, patients were treated with priming doses of 12 mg on day one, 32 mg on day four, and 76 mg once weekly thereafter.
After the initial dose, 43% (79/183) of patients developed CRS, and 19% (35/180) of patients who received a second ELRA dose developed CRS.
Researchers found that after the initial ELRA dose, patients who had extramedullary disease (EMD) had fewer overall incidences (47% vs. 65%) and grade 2 incidences (1% vs. 17%) of CRS than patients without EMD.
Dr. Niesvizky hypothesized that “the inability of T cells to reach the extramedullary sites might lead to a lesser benefit, or perhaps the sequestering of the molecule or activated T cells, and thus less CRS.” However, researchers recognize the need to seek further confirmation and evaluation in a prospective study that focuses on EMD to determine why it was predictive of reduced risk of CRS after the initial ELRA dose.
Prior tocilizumab use was also predictive of reduced risk of CRS after the second dose of ELRA, which is “intuitive, as tocilizumab is used as part of the strategy to ameliorate the side effects of CRS,” Dr. Niesvizky said.
Additionally, after receiving 76 mg of ELRA, no patient developed CRS with any duration of dose interruption and subsequent continuation. Thirty-one percent (5/16) of patients who had dose delays between six and 12 weeks and 50% (2/4) of patients who had dose delays greater than 12 weeks after receiving 76 mg of ELRA repeated the 32 mg step-up dose. The remaining patients who received 76 mg of ELRA continued with doses greater than 32 mg post-interruption.
Still, to reduce the risk of CRS, researchers determined the level at which ELRA exposure drops below the threshold associated with CRS events.
With dose delays between six and 12 weeks, ELRA exposure decreased below the maximum concentration (Cmax) after a 32 mg dose, but it remained no lower than that observed for the 12 mg dose. Therefore, researchers recommend that patients who experience dose delays of six to 12 weeks should resume treatment at a dose of 32 mg.
Furthermore, with dose delays of greater than 12 weeks, ELRA exposure decreased below the Cmax after a 12 mg dose. Accordingly, researchers recommend these patients resume treatment at 12 mg to decrease the risk of CRS.
Researchers cite the small number of patients as a limitation to their study and anticipate further analysis in a larger patient population.
“If, indeed, you had to interrupt the dosing [of ELRA], you should feel comfortable resuming the dose at a less aggressive step-up,” Dr. Niesvizky said.
Any conflicts of interest declared by the authors can be found in the original abstract.
Reference
Niesvizky R, Arnulf B, Mohty M, et al. Clinical factors associated with cytokine release syndrome and dosing recommendations for restarting elranatamab following an interruption. Abstract 3384. Presented at the 65th American Society of Hematology Annual Meeting and Exposition; December 10, 2023; San Diego, California.