JNJ-79635322

As of Jan 15, 2025, 126 pts received JNJ-5322 (36 at 100 mg Q4W); median follow-up (mFU) 8.2 mo. Median age 64 yrs; median 4 prior lines of therapy; 100% triple-class exposed (56% refractory); 31% high-risk cytogenetics; 23% had prior anti-BCMA/-GPRC5D therapy (77% naïve). The putative RP2D was identified as 100 mg Q4W. Overall, 99% of pts had ≥1 AE, most commonly CRS (59%; all grade [gr] 1 [45%]/2 [14%]; no gr ≥3), nail AEs (gr 1/2 56%), taste AEs (gr 1/2 56%), neutropenia (48%; gr 3/4 41%), and non-rash skin AEs (47%; gr 3/4 1%). Overall, 16% had weight decreases (no gr ≥3), 16% had rashes (no gr ≥3), 2% had ICANS (all gr 1), and 75% had infections (gr 3/4 28%). 5 pts had dose-limiting toxicities. 4 pts died due to AEs. In response-evaluable pts, ORR was 86% (75% ≥VGPR) at the RP2D (n=36), and 73% (66% ≥VGPR) overall (n=124). ORR was 100% (89% ≥VGPR) at the RP2D among pts naïve to anti-BCMA/-GPRC5D therapies (n=27), and all patients remain in response (mFU 8.5 mo). Median time to first response was 1.2 mo.

Results: As of July 9, 2025, 36 patients received JNJ-5322 at the RP2D with a median follow-up of 14.4 months. At baseline, 26.5% (9/34) had high-risk cytogenetics, 13.9% had ISS stage III disease, and 8.3% had extramedullary disease. Patients received a median of 4 (range 2–11) prior lines of therapy; 75.0% were BCMA/GPRC5D naive and 52.8% were triple-class refractory. The most common nonhematologic TEAEs were infections (80.6% [gr 3, 33.3%]) and skin-related (66.7%, all gr 1/2) and nail-related (61.1%, majority [58.3%] gr 1) TEAEs. The most common hematologic TEAEs were lymphopenia (47.2% [gr 3/4, 44.4%]) and neutropenia (44.4% [gr 3/4, 33.3%]). The cumulative incidence of gr ≥3 infections plateaued within the first year of therapy. Intravenous immunoglobulin (IVIg) use was recommended to maintain Ig levels ≥400 mg/dL; 91.7% of patients received IVIg. Hypogammaglobulinemia was reported in 52.8% of patients; among these, 94.7% received IVIg. CRS occurred in 52.8% (gr 1, 41.7%; gr 2, 11.1%). In cohorts without (received 100 mg Q4W) and with (received 100 mg Q4W/Q8W) prophylactic tocilizumab, CRS occurred in 69.2% (gr 2, 15.4%) and 20.0% (gr 2, 0%), respectively. No ICANS events were reported. Taste changes occurred in 58.3% (gr 1, 41.7%; gr 2, 16.7%); median duration was 57 days. Of 36 patients who received the RP2D, 27 were BCMA/GPRC5D naive with a median follow-up of 15.0 months; these patients showed a high ORR of 100.0% with deepening of response (complete response or better [≥CR], 77.8%) and a 12-month progression-free survival rate of 96.3%. Apart from 1 patient who died while in very good partial response (due to pneumonia in the setting of hypogammaglobulinemia <200 mg/dL), all 26 patients remain in response at 15.0 months of median follow-up, demonstrating durable responses. MRD negativity at 10 –5 was achieved in 100.0% (10/10) of evaluable patients. Updated analyses with 6 additional months of follow-up will be presented at the conference.

Conclusions: With longer follow-up in part 1 of the phase 1 trial, JNJ-5322 continues to demonstrate responses comparable to CAR-T therapy (ORR 100.0%) that are durable and continue to deepen (≥CR 77.8%), with a safety profile similar or improved compared with BsAbs targeting BCMA or GPRC5D. JNJ5322 offers off-the-shelf, Q4W dosing and 1 SUD with low rates of gr 2 CRS that may enable an efficient approach to dual antigen targeting via convenient administration and outpatient treatment. These findings support further evaluation of JNJ-5322 in patients with RRMM.