A Phase 3 Randomized Study Comparing Bortezomib, Lenalidomide and Dexamethasone (VRd) followed by Ciltacabtagene Autoleucel, a Chimeric Antigen Receptor T cell (CAR-T) Therapy Directed Against BCMA versus Bortezomib, Lenalidomide, and Dexamethasone (VRd) followed by Lenalidomide and Dexamethasone (Rd) Therapy in Participants with Newly Diagnosed Multiple Myeloma for Whom Hematopoietic Stem Cell Transplant is Not Planned as Initial Therapy

Multiple myeloma (MM) is a malignant plasma cell disorder characterized by the
production of monoclonal immunoglobulin (Ig) proteins or protein fragments (M
proteins) that have lost their function. 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.
The primary hypothesis of this study is that in participants with newly
diagnosed MM, treatment with VRd induction followed by a single administration
of cilta-cel will significantly improve progression free survival compared to
Bortezomib, Lenalidomide and Dexamethasone (VRd) induction followed by Rd
maintenance.

This study has been transitioned to CTIS with ID 2023-505850-16-00 check the CTIS register for the current data.

To compare the efficacy of VRd followed by cilta-cel therapy versus VRd
followed by Rd therapy in terms of progression free survival (PFS)

The study will screen participants with newly diagnosed MM who are not planned
to receive autologous stem cell transplant (ASCT) as initial therapy. This
study will be conducted in 4 phases: Screening (up to 28 days),
Pre-randomization Treatment, Treatment, and Follow-up. Assessments like
patient-reported outcome(s) (PROs), electrocardiogram (ECG), vital signs and
pharmacokinetics will be performed during the study. Safety evaluations will
include review of adverse events, laboratory test results, vital sign
measurements, physical examination findings, assessment of cardiac function,
Immune-Effector Cell-Associated Encephalopathy (ICE) and handwriting
assessments (only for Arm B) and Eastern Cooperative Oncology Group (ECOG)
performance status. Safety data will be periodically reviewed by an Independent
Data Monitoring Committee (IDMC). The duration of the study is approximately 12
years 5 months.

Arm A: VRd+Rd (Standard Therapy)
Participants will receive bortezomib, lenalidomide, and dexamethasone (VRd)
regimen for 6 cycles before randomization. Following randomization,
participants in Arm A will receive 2 more cycles of VRd. In VRd treatment,
participants will receive bortezomib 1.3 milligram per meter square (mg/m^2)
subcutaneously (SC) on Days 1, 4, 8 and 11 of each cycle (Cycles 1 to 8), oral
lenalidomide 25 mg on Days 1 to 14 of each cycle (Cycles 1 to 8) and oral
dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle (Cycles
1 to 8). Each cycle will consist of 21 days. After 8 cycles of VRd, treatment
will continue with lenalidomide and dexamethasone (Rd) maintenance therapy. In
Rd treatment, participants will receive oral lenalidomide 25 mg on Days 1 to 21
of each cycle and oral dexamethasone 40 mg on Days 1, 8, 15, and 22 of each
cycle. Each cycle will consist of 28 days. Participants will continue to
receive Rd until confirmed progressive disease or unacceptable toxicity.

Arm B: VRd+Ciltacabtagene Autoleucel (Cilta-cel)
Participants will receive VRd regimen for 6 cycles before randomization.
Following randomization, participants in Arm B will undergo apheresis and
receive two more cycles of VRd as bridging therapy. In VRd treatment,
participants will receive bortezomib 1.3 mg/m^2 SC on Days 1, 4, 8 and 11 of
each cycle for Cycles 1 to 8; oral lenalidomide 25 mg on days 1 to 14 of each
cycle for Cycles 1 to 8 and oral dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9,
11 and 12 of each cycle for Cycles 1 to 8. Each cycle will consist of 21 days.
After 8 cycles of VRd, participants will receive a conditioning regimen
(cyclophosphamide 300 mg/m^2 intravenous [IV] and fludarabine 30 mg/m^2 IV
daily for 3 days) and Cilta-cel infusion 0.75*10^6 chimeric antigen receptor
(CAR)-positive viable T cells/kilogram (kg).

Preliminary results of cilta-cel show good efficacy results in study MMY2001
and for the LEGEND 2 study. In this phase 3 study standard therapies are being
compared for efficacy to cilta-cel. The primary hypothesis is that cilta-cel
will significantly improve PFS compared with standard therapy (PVd or DPd). The
potential risks of cilta-cel are identified from the following:
1) results of nonclinical studies;
2) mechanism of action; and
3) previous clinical experience with cilta-cel and LCAR-B38M CAR-T cells.
Clinical experience with cilta-cel and LCAR-B38M CAR-T cells is limited.
Therefore, the treatment of additional subjects and prolonged follow-up may
reveal additional risks. By stimulating an inflammatory cascade, there is
potential for toxicity in other tissues or organs by nonspecific immune cell
activation. Therefore, special attention will be given to both immunological
and immunogenicityrelated toxicities. The patient information sheet of the
informed consent form describes in detail the potential risks for the patient.
This includes side effects such as cytokine release syndrome, tumor lysis
syndrome, neurologic adverse events, effects on blood cells, etc. Due to the
risks for side effects like CRS patient will be admitted in the hospital at the
day of the cilta-cel infusion until day 14, for the follow up of side effects
with potential discharge on day 10 (when the patients has no side effects).
Until day 21 the patient needs to staty in a short distance (1hour max) from
the hospital. When there are side effects, f.e. fever, the patient needs to
come directly to the hospital.