Summary

The purpose of this study is to evaluate the overall minimal residual disease (MRD)
negative rate of participants who receive JNJ-68284528.

Objectives

Multiple myeloma is characterized by the production of monoclonal immunoglobulin (Ig)
proteins or protein fragments (M proteins) that have lost their function. The main aim of the
study is to determine the safety and efficacy of JNJ-68284528 in various clinical settings.
JNJ-68284528 is an autologous chimeric antigen receptor T-cell (CAR-T) therapy that targets
B-cell maturation antigen (BCMA). The study comprises of a Screening Phase (less than or
equal to [<=] 28 days prior to apheresis) followed by Apheresis (will occur upon enrollment);
a Treatment Phase including a conditioning regimen followed by infusion of JNJ-68284528 and
post-infusion assessments from Day 1 to Day 100 (participants who receive an infusion of
JNJ-68284528 should continue all subsequent assessments); and a Post-treatment Phase (Day 101
and up to the end of each study cohort). Safety evaluations will include a review of adverse
events, laboratory test results, vital sign measurements, physical examination findings
(including neurologic examination), assessment of cardiac function, immune effector
cell-associated encephalopathy (ICE) score, handwriting assessment, and assessment of Eastern
Cooperative Oncology Group (ECOG) performance status grade. Efficacy evaluations will include
measurements of tumor burden/residual disease, myeloma proteins, bone marrow examinations,
skeletal surveys, extramedullary plasmacytomas, and serum calcium corrected for albumin. For
certain participants (those without measurable disease in serum or urine) efficacy will be
assessed via imaging: positron emission tomography/ computed tomography (PET/CT) or whole
body magnetic resonance imaging (MRI). The overall duration of the study is up to 2.5 years.

Eligibility

1. Cohort A: Received a minimum of 1 to a maximum of 3 prior lines of therapy including a proteasome inhibitor (PI) and immunomodulatory therapy (IMiD), and lenalidomide refractory per International Myeloma Working Group (IMWG) guidelines
2. Cohort B: Received one line of prior therapy including a PI and an IMiD, and disease progression per IMWG criteria less than or equal to (<=) 12 months after treatment with autologous stem cell transplantation (ASCT) or <=12 months from the start of anti-myeloma therapy for participants who have not had an ASCT
3. Cohort C: Previously treated with a PI, an IMiD, an anti-CD38 monoclonal antibody and B-cell maturation antigen (BCMA)-directed therapy
4. Cohort D: Newly diagnosed multiple myeloma per IMWG with a history of 4 to 8 total cycles of initial therapy, including induction, high-dose therapy, and ASCT with or without consolidation
5. Cohort E: Have newly diagnosed multiple myeloma without prior therapy (one cycle of prior therapy before enrollment is acceptable) and classified as high risk defined as either: 1) International Staging System (ISS) stage III criteria, Beta 2 microglobulin greater than or equal to (>=) 5.5 milligrams per liter (mg/L) (via local or central laboratory assessment) or 2) high risk cytogenetic features del(17/17p), t (14;16), t(14;20), 1q amplification (at least 4 total copies) in at least 20 percent (%) of the total plasma cell population
6. Cohort F:
7. Participant must have a documented efficacy response of very good partial response (VGPR) or better, without progressive disease prior to enrollment, as assessed per IMWG 2016 criteria
8. Received initial therapy as specified below. The dose/schedule of cycles administered will be as per standard of care. It is acceptable for up to 1 cycle of the protocol-specified regimens to be missing one of the listed agents (example, held due to toxicity). Acceptable combinations include: At least 5 to 8 cycles of initial therapy with daratumumab, bortezomib, lenalidomide and dexamethasone (D-VRd). The dose/schedule of cycles administered will be as per standard of care or; at least 4 to 8 cycles of initial therapy with daratumumab, lenalidomide and dexamethasone (D-Rd) or; at least 4 to 8 cycles of initial therapy with a carfilzomib-based triplet or quadruplet regimen
9. Cohort G: Not considered for high-dose chemotherapy with autologous stem cell transplantation (ASCT) due to: a) Ineligibility due to advanced age; or b) Ineligibility due to presence of comorbid condition(s) likely to have a negative impact on tolerability of high-dose chemotherapy with ASCT; or c) Subject refusal of high-dose chemotherapy with ASCT as initial treatment
10. Cohort H: Considered a candidate for high-dose chemotherapy with ASCT as initial treatment
11. Cohorts A, B, C, E, G, H:
12. Serum monoclonal paraprotein (M-protein) level greater than or equal to (>=) 1.0 gram per deciliter (g/dL) or urine M-protein level >=200 milligrams (mg)/24 hours
13. Light chain multiple myeloma in whom only measurable disease is by serum free light chain (FLC) levels in the serum: Serum immunoglobulin FLC >=10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio
14. Cohort A: For participants with neither serum nor urine measurable disease, baseline positron emission tomography/ computed tomography (PET/CT) or whole -body magnetic resonance imaging (MRI) may be used to satisfy the measurable disease criteria. A minimum of one lesion with a bi-dimensional measurement of at least 1 centimeter (cm)*1 cm is required
15. Cohorts B, C: For participants with neither serum nor urine measurable disease, baseline positron emission tomography/ computed tomography (PET/CT) or whole body magnetic resonance imaging (MRI) may be used to satisfy the measurable disease criteria
16. Cohorts A, B, C, D, E, F, G, H: Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1