Clinical pharmacology strategies to support dose optimization of the recommended Phase 2 dose regimen of JNJ-5322, a BCMA×GPRC5D×CD3 trispecific antibody, in Relapsed/Refractory multiple myeloma

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Abstract Introduction JNJ-5322 is a next-generation trispecific antibody that contains novel B-cell maturation antigen (BCMA), G protein–coupled receptor class C group 5 member D (GPRC5D), and CD3 binding domains, and has shown potent and selective T-cell mediated antitumor activity against BCMA and GPRC5D. In a first-in-human study in patients with relapsed/refractory multiple myeloma, JNJ-5322 demonstrated promising efficacy with an overall response rate (ORR) of 100% and 12-month progression-free survival rate of 95% in patients naive to BCMA/GPRC5D therapies, with a manageable safety profile. We present pharmacology data supporting the recommended phase 2 dose (RP2D) of 100 mg every 4 weeks (Q4W) with 1 step-up dose (SUD) of 5 mg. Methods The phase 1 dose escalation and expansion study (NCT05652335) evaluated subcutaneous doses of JNJ-5322 (0.4–300 mg) every other week, Q4W, or every 8 weeks (Q8W). Serum samples were collected for pharmacokinetic (PK) and antidrug antibody analyses. Population PK analyses were conducted to characterize PK of JNJ-5322 and assess the impact of clinically relevant covariates on drug exposure. Efficacy and safety exposure–response (E–R) relationships were evaluated using predicted PK metrics, ORR, and key treatment-emergent adverse events (TEAEs), including weight loss, infections, GPRC5D-related TEAEs (oral-, skin-, and nail-related TEAEs), and cytokine release syndrome (CRS). Analyses were based on data collected through February 2025. Results PK exposure increased in an approximately dose-proportional manner across all doses. Steady state was reached after 12 weeks with an estimated steady state half-life of 17 days. At the RP2D (100 mg Q4W), the mean serum concentration was maintained at or above the mean concentration associated with the 90% maximal drug effect identified in an ex vivo cytotoxicity assay. Population PK and covariate analyses revealed that no dose adjustments were required based on the clinically relevant covariates tested (eg, body weight, tumor burden). E–R analyses for efficacy showed that a maximal ORR was observed at or above 100 mg Q4W, which was determined to be the RP2D. Exposures with lower doses did not provide sufficient efficacy, while exposures above the RP2D provided comparable ORR and very good partial response or better. E–R analyses for safety showed no relationships across key TEAEs, including weight loss and grade ≥3 infections; lower drug exposures were not associated with additional safety benefit across the majority of clinically significant TEAEs. Although there was an E–R relationship observed for GPRC5D-related TEAEs, the increased TEAE rates from 50- to 100-mg exposure were minimal, and 100 mg Q4W was well tolerated and AEs were manageable. Taken together, E–R analyses for efficacy and safety supported the RP2D as the lowest maximally efficacious dose. A maximum tolerated dose was not reached. E–R analyses for efficacy demonstrated that exposures and ORR were lower with Q8W vs Q4W dosing, supporting Q4W as the optimal starting schedule. E–R analyses also substantiated the use of 5 mg as the SUD, providing optimal exposure to induce tolerance for the 100-mg treatment dose while minimizing the risk of CRS. Modeling showed that higher SUDs (eg, ≥7.5 mg) increased the overall risk of CRS, while a lower SUD (2.5 mg) reduced the risk of CRS after the SUD but increased the overall risk of CRS during the subsequent 100-mg treatment dose. Following a 5-mg SUD, the model estimated that the overall rate of grade ≥2 CRS after the 100-mg treatment dose was 6% without any tocilizumab use. With the administration of prophylactic tocilizumab before the 100-mg treatment dose (either before the SUD or after the SUD to treat CRS), modeling showed that the rate of grade 2 CRS was further reduced to 2%. These analyses confirmed that a 5-mg SUD before the 100-mg RP2D dose was optimal, effectively minimizing the occurrence of CRS following both SUD and treatment doses. Conclusions Clinical pharmacology strategies utilizing populationPK and E–R analyses supported extensive dose optimization of the JNJ-5322 RP2D, supporting the most optimal regimen of 1 SUD (5 mg) followed by the treatment dose (100 mg Q4W).

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