TRIlogy-5

Adults ≥18 with measurable R/R multiple myeloma, 1–3 prior lines including an anti-CD38 antibody and lenalidomide, ECOG 0–2, adequate organ/marrow function, no prior BCMA/GPRC5D T-cell redirection.

Age 1. At the time of informed consent, be ≥18 years of age or at least the legal age of majority in the jurisdiction in which the study is taking place. Type of Participant and Disease Characteristics 2. Documented diagnosis of MM as defined by the criteria below: a. MM diagnosis according to the IMWG diagnostic criteria (Rajkumar 2014) b. Measurable disease at screening as assessed by central laboratory, defined by any of the following: i. Serum M-protein level ≥0.5 g/dL; or ii. Serum Ig FLC ≥10 mg/dL and abnormal serum Ig kappa lambda FLC ratio; or iii. Urine M-protein level ≥200 mg/24 hours NOTE: In exceptional circumstances and after discussion with, and written approval by, the sponsor, local laboratory results may be used to determine initial eligibility, but only if the local results are clearly (≥25%) above the thresholds for measurability. In such cases, central laboratory results should still be obtained from samples collected prior to the start of study treatment to establish baseline values and confirm the results from the local laboratory. 3. Received 1 to 3 prior lines of antimyeloma therapy, including an anti-CD38 antibody and lenalidomide. The participant must have undergone at least 2 consecutive cycles of an anti-CD38 antibody at the approved dosing schedule (or a minimum of 6 doses if the anti-CD38 antibody was only part of a maintenance regimen) in any prior line and 2 consecutive cycles of lenalidomide in any prior line, unless PD was the best response to the line of therapy. Refer to Section 10.7 for the definition of a line of therapy. 4. Relapsed or refractory disease as defined below: i. Relapsed disease is defined as an initial response to prior treatment, followed by confirmed PD by IMWG response criteria >60 days after cessation of treatment. ii. Refractory disease is defined as failure to achieve a response or confirmed PD by IMWG response criteria during previous treatment or ≤60 days after cessation of treatment. 5. Have an ECOG performance status of 0 to 2 at screening and immediately before the first dose of study medication (Oken 1982). 6. Criterion modified per Amendment 1. 6.1. Have clinical laboratory values meeting the following criteria during the screening and within 1 day of the start of administration of study treatment. Hematology Hemoglobin: ≥7.5 g/dL, without use of transfusion or growth factors within 7 days prior to laboratory testing ANC: ≥0.75×10³/µL (prior growth factor support is permitted but must be without support for 7 days for G-CSF or GM-CSF and for 14 days for pegylated G-CSF prior to the laboratory testing) Platelets: ≥50×10³/µL, without use of transfusion or growth factors within 7 days prior to laboratory testing Chemistry AST and ALT: <2.5×ULN Total bilirubin: <1.5×ULN Bilirubin in case of known congenital nonhemolytic hyperbilirubinemias such as Gilbert's Syndrome: Isolated total bilirubin ≥1.5×ULN with direct bilirubin <1.5×ULN eGFR, calculated with the CKD-epi creatinine formula using adjusted BSA (Section 10.12): >30 mL/min Sex and Contraceptive/Barrier Requirements 7. Participants must agree, while on study treatment and for 6 months after the last dose of study treatment, to: - Not breastfeed or be pregnant. - Not donate gametes (ie, eggs or sperm) or freeze for future use for the purposes of assisted reproduction. - Wear an external condom. - If of childbearing potential: - Have a negative highly sensitive (eg, β-hCG) pregnancy test at screening and within 24 hours before the first dose of study treatment and agree to further pregnancy tests. - Practice at least 1 highly effective method of contraception; if oral contraceptives are used, a barrier method of contraception must also be used. - If a participant's partner is of childbearing potential: - The partner must practice a highly effective method of contraception unless the participant is vasectomized. See Section 10.3 for details. Informed Consent 8. Must provide informed consent as described in Section 10.2.3. 9. Must be willing and able to adhere to the lifestyle restrictions specified in this protocol (see Section 5.3).

Prior BCMA/GPRC5D-directed T-cell redirecting therapy; CNS myeloma; PC leukemia, WM, POEMS or AL amyloidosis; active infection; recent major cardiac/thromboembolic events; high-dose steroids ≤14 days.

Medical Conditions 1. Serious underlying medical conditions, such as: i. Evidence of active systemic viral, fungal or bacterial infection requiring systemic antiviral, antifungal, or antimicrobial therapy. ii. Active autoimmune disease requiring systemic immunosuppressive therapy within 6 months before start of treatment. EXCEPTION: Participants with vitiligo, Type 1 diabetes, or prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing are eligible regardless of when these conditions were diagnosed. iii. Overt clinical evidence of dementia or altered mental status. 2. Major surgery, (eg, requiring general anesthesia) or significant traumatic injury within 2 weeks prior to first dose, or not fully recovered from prior surgery, or has major surgery planned during the time the participant is expected to participate in the study. Note: Participants with planned surgical procedures to be conducted under local anesthesia may participate. 3. Suspected or known allergies, hypersensitivity, intolerance, or other contraindications to the use of JNJ-79635322 or teclistamab, or their excipients (refer to the IBs). 4. Any of the following within 6 months prior to first dose of study treatment: Seizure, severe or unstable angina, myocardial infarction, major thromboembolic events (eg, pulmonary embolism, cerebrovascular accident [including transient ischemic attack and stroke]), clinically significant ventricular arrhythmias or heart failure New York Heart Association functional classification Class III to IV (see Section 10.13). Uncomplicated deep vein thrombosis is not considered exclusionary. Prior Malignancies 5. Presence of any of the following: i. Any ongoing myelodysplastic syndrome or B-cell malignancy (other than MM). ii. Any history of malignancy, other than MM, that is considered at high risk of recurrence requiring systemic therapy. iii. Any active malignancy (ie, progressing or requiring treatment change in the last 24 months) other than MM. The only allowed exceptions are malignancies treated within the last 24 months that are considered cured: i. Non-muscle invasive bladder cancer (solitary Ta-papillary urothelial neoplasm of low malignant potential or low-grade, <3 cm, no carcinoma in situ). ii. Non-melanoma skin cancers treated with curative therapy or localized melanoma treated with curative surgical resection alone. iii. Non-invasive cervical cancer. iv. Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer (anti-hormonal therapy is permitted). v. Localized prostate cancer (M0, N0) with a Gleason Score ≤7, treated locally only (radical prostatectomy/radiotherapy/focal treatment). vi. Other malignancy that is considered cured with minimal risk of recurrence in consultation with the sponsor. 6. PC leukemia at the time of screening (≥5% circulating PCs in peripheral blood smear), Waldenstrom's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or systemic amyloid light chain amyloidosis (Rajkumar 2014; participants with myeloma who have incidental amyloid deposits on biopsy of an impacted organ, without clinical manifestations of amyloidosis, are not excluded and may participate in the study). Brain and Central Nervous System Metastases 7. Known active or prior CNS involvement or exhibits clinical signs of meningeal involvement of MM. If either is suspected, negative whole brain MRI and lumbar cytology are required. HIV Status 8. Participants who are HIV-positive and meet any of the following: i. Detectable viral load (ie, >50 copies/mL) at screening. ii. CD4+ count <300 cells/mm³ at screening. iii. AIDS-defining opportunistic infection within 6 months of screening. iv. Receive treatment other than continued HAART. A change in HAART due to resistance/progression must occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed up to 4 weeks prior to screening. Note: HAART that could interfere with study treatment is excluded (consult the sponsor for a review of medications prior to enrollment). Viral Hepatitis Assessments 9. Active hepatitis of infectious origin. i. Seropositive for hepatitis B: defined by a positive test for HBsAg. Participants with resolved infection (ie, participants who are HBsAg negative with positive antibodies to total HBc antigen [anti-HBc]) must be screened using RT-PCR measurement of HBV DNA levels. Those who are RT-PCR positive will be excluded. Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by RT-PCR (see Section 10.6). ii. Known hepatitis C infection or positive serologic testing for HCV (anti-HCV) antibody. Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative hepatitis C RNA test is obtained at screening or within 3 months prior to first dose of study treatment. iii. Other clinically active liver disease of infectious origin. Prior/Concomitant Therapy or Clinical Study Experience 10. Concurrent use of any other anticancer treatment (including non-palliative radiotherapy) or investigational agent. For participants who received an allogeneic stem cell transplant, the transplant must be dated at least 6 months before first dose of study drug. Participants who received an allogeneic transplant must be off all immunosuppressive medications for 6 weeks before the start of study treatment administration without signs of graft-versus-host disease. Toxicity related to prior anticancer treatment must have resolved to Grade 1 or better (except alopecia, skin fibrosis or discoloration, dry mouth, hearing loss, endocrinopathy managed with replacement therapy, peripheral neuropathy, which must be Grade 2 or better). 11. Received prior or concurrent exposure to T-cell redirecting therapy (eg, CAR-T, bispecific antibodies), directed at BCMA or GPRC5D. 12. Received a cumulative dose of corticosteroids equivalent to ≥160 mg of dexamethasone within 14 days prior to first dose of study drug. 13. Received or plans to receive any live, attenuated vaccine within 4 weeks before the first dose of study drug or within 90 days after the last dose of study drug. Non-live and non-replication-competent vaccines approved or authorized for emergency use by local HAs are allowed. Other Exclusions 14. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments.