A Phase 3 Randomized Study Comparing Daratumumab, Bortezomib, Lenalidomide and Dexamethasone (DVRd) followed by Ciltacabtagene Autoleucel versus Daratumumab, Bortezomib, Lenalidomide and Dexamethasone (DVRd) followed by Autologous Stem Cell Transplant (ASCT) in Participants with Newly Diagnosed Multiple Myeloma who are Transplant Eligible

JNJ-68284528 (ciltacabtagene autoleucel [cilta-cel]) is an autologous chimeric
antigen receptor T-cell (CAR-T) therapy that targets B-cell maturation antigen
(BCMA), a molecule expressed on the surface of mature B-lymphocytes and
malignant plasma cells. Results from the Phase 1b and Phase 2 portions of Study
68284528MMY2001 (CARTITUDE-1) indicate that cilta-cel has significant
antimyeloma activity and a safety profile consistent with the known mechanism
of action of CAR-T therapies.

This study has been transitioned to CTIS with ID 2023-507632-20-00 check the CTIS register for the current data.

The primary objective is to compare the efficacy of DVRd followed by cilta-cel
and lenalidomide therapy versus DVRd followed by ASCT, DVRd consolidation, and
lenalidomide therapy, in terms of progression-free survival (PFS) and sustained
minimal residual disease (MRD)-negative complete response (CR). Key secondary
objectives are to further compare the efficacy and safety of the treatment
regimens.

This is a randomized, open-label, global, multicenter, Phase 3 study in adult
participants with NDMM according to the International Myeloma Working Group
(IMWG) diagnostic criteria for whom high-dose therapy and ASCT are part of the
intended treatment plan.
At randomization, eligible participants will be stratified by age (<60 or >=60
years), International Staging System (ISS) (I, II, or III; based on β-2
microglobulin and albumin), and cytogenetic risk (as defined by presence of
deletion 17p [del(17p)] translocation t[4;14], t[14;16], or amplification 1q
[amp(1q)]).
Participants randomized to Arm A will receive DVRd induction, followed by ASCT,
DVRd consolidation, and lenalidomide maintenance therapy. Participants who
discontinue study treatment for reasons other than documented disease
progression (PD), death, or withdrawal of consent will enter the Post-treatment
Follow-up Phase during which they will continue to be monitored for efficacy,
safety, and health-related quality of life (HRQoL) until confirmed PD, death,
withdrawal of consent, lost-to-follow-up, or end of study, whichever occurs
first. After confirmed PD, participants will be followed for related adverse
events (AEs)/serious adverse events (SAEs), subsequent antimyeloma therapies,
response to subsequent antimyeloma therapies including the date of subsequent
progression (PFS2), second primary malignancies (SPMs), and survival status
until death or end of study.
Participants randomized to Arm B will receive DVRd induction, followed by
cilta-cel infusion and lenalidomide post-CAR-T therapy. Participants will have
intensive monitoring for efficacy, safety, pharmacokinetics (PK), biomarkers,
and HRQoL during the first 112 days after cilta-cel infusion in the
Post-infusion Follow-up Phase. Thereafter, participants will continue to be
monitored until confirmed PD, death, withdrawal of consent, lost to-follow-up,
or end of study, whichever occurs first in the Post-treatment Follow-up Phase.
After confirmed PD, participants will be followed for subsequent antimyeloma
therapies, response to subsequent antimyeloma therapies including the date of
subsequent progression (PFS2), and

survival status until death or end of study. In addition, all participants who
received cilta-cel will continue to be monitored for long-term safety
(including all SAEs, nonserious related AEs, delayed AEs [including SPMs], and
assessments for replication-competent lentivirus [RCL]) up to 15 years after
cilta-cel infusion in the present study (until end of study) or in a separate
long-term follow-up study (68284528MMY4002). Events of hepatitis B virus (HBV)
reactivation will be reported during the first year after cilta-cel infusion.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this
study. Safety and efficacy data will be periodically reviewed by the IDMC.
The end of study is when approximately 350 overall survival (OS) events have
been accumulated, or approximately 15 years after the last participant is
randomized, whichever occurs first.

Arm A (DVRd Induction + ASCT + DVRd Consolidation + Lenalidomide Maintenance)

Participants randomized to Arm A will receive four 28-day cycles of DVRd
induction (Cycles 1-4), followed by stem cell harvest, high-dose melphalan,
ASCT, and two 28-day cycles of DVRd consolidation (Cycles 5-6).
Stem cell harvest for ASCT will be performed after Cycle 4 following
mobilization with either granulocyte colony-stimulating factor (G-CSF), or
plerixafor, or cyclophosphamide, or any combination of the 3 per institutional
standard.
After DVRd consolidation, participants will receive lenalidomide maintenance
therapy (in 28-day cycles) until PD or unacceptable toxicity, or for a maximum
of 2 years, whichever occurs first (Cycles 7-30).

Arm B (DVRd Induction + Cilta-cel + Lenalidomide Post-CAR-T Therapy)

Participants randomized to Arm B will undergo apheresis to acquire mononuclear
cells before start of DVRd induction therapy. Cilta-cel will be generated from
the participants* T-cells selected from the apheresis product. After apheresis,
participants will receive six 28-day cycles of DVRd induction (Cycles 1-6).
Of note, for participants with highly aggressive multiple myeloma (MM)
requiring immediate treatment, the investigator will need to discuss the timing
of apheresis with the medical monitor.
After completing 6 cycles of DVRd induction and cilta-cel production and
product release, participants will receive a conditioning regimen of
cyclophosphamide and fludarabine daily for 3 days. The conditioning regimen
will lead to lymphodepletion and help to promote CAR-T cell expansion in the
participants. Cilta-cel will be administered 5 to 7 days after the start of the
conditioning regimen.
After cilta-cel infusion, participants will receive lenalidomide post-CAR-T
therapy (in 28-day cycles) until PD or unacceptable toxicity, or for a maximum
of 2 years, whichever occurs first (Cycles 7-30).
For participants in Arm B who need ASCT at a later time (as part of subsequent
therapy after PD is confirmed), stem cell harvest following mobilization with
either G-CSF, or plerixafor, or cyclophosphamide, or any combination of the 3
per institutional standard is permitted after Cycle 4 while on study treatment.
Collection and storage of stem cells will be considered an allowed off-protocol
procedure.

Participants in both treatment arms who are benefiting from therapy have the
option to continue lenalidomide maintenance (Arm A) or post-CAR-T (Arm B)
therapy until PD per investigator's discretion after benefit-risk assessment
and review by the medical monitor. The reason for continuation of lenalidomide
beyond 2 years must be documented in the electronic case report form (eCRF) and
the sponsor should be notified.

In both treatment arms, disease status will be evaluated for response and PD
according to the IMWG 2016 response criteria for MM. Efficacy evaluations will
include measurements of myeloma protein, imaging of lytic lesions, assessment
of extramedullary and bone-based plasmacytomas, bone marrow examinations, and
MRD evaluations. MRD will be monitored using next-generation sequencing (NGS)
on bone marrow aspirate DNA and positron emission tomography/computed
tomography (PET/CT) if locally available.

Data regarding participants* HRQoL will be captured using patient-reported
outcome (PRO) measures in both treatment arms. Medical resource utilization
data associated with medical encounters will also be collected for both
treatment arms.

Safety evaluations will include a review of AEs, physical examination findings
(including neurologic examination), vital signs measurements, clinical safety
laboratory test results, assessment of cardiac function, and assessment of
Eastern Cooperative Oncology Group (ECOG) performance status. Participants in
Arm B who received cilta-cel will also undergo immune effector cell-associated
encephalopathy (ICE) and handwriting assessments.

In Arm B, samples, including but not limited to, blood and bone marrow will be
collected for assessment of cilta-cel PK, biomarkers, immunogenicity
parameters, and correlative studies. Blood and bone marrow samples for
exploratory biomarker assessments and correlative studies will also be
collected from participants in Arm A for comparison and to enrich the
understanding of MM disease and response to treatment.