CARTITUDE-6: A Study of 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

Sponsor

European Myeloma Network (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05257083

Collaborator

Janssen Research & Development, LLC (Industry)

750

Enrollment

Locations

Arms

233

Anticipated Duration (Months)

14.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the efficacy of 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 newly diagnosed multiple myeloma patients.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Daratumumab Drug: Bortezomib Drug: Lenalidomide Drug: Dexamethasone Drug: Cilta-cel Drug: Cyclophosphamide Drug: Fludarabine	Phase 3

Detailed Description

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) that is being evaluated to treat participants with multiple myeloma. The primary hypothesis is that in transplant-eligible participants with newly diagnosed multiple myeloma (NDMM), cilta-cel will significantly improve progression-free survival (PFS) and Sustained MRD-negative CR rate compared with Autologous Stem Cell Transplant (ASCT).

Approximately 750 participants (375 per arm) will be randomly assigned in a 1:1 ratio into 2 arms.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

750 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Jun 1, 2022

Anticipated Primary Completion Date :

Jun 1, 2026

Anticipated Study Completion Date :

Nov 1, 2041

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A: DVRd + ASCT+DVRd (Standard Therapy) Participants will receive daratumumab, bortezomib, lenalidomide and dexamethasone (DVRd) for 4 induction cycles. Followed by ASCT and 2 cycles of DVRd consolidation, and lenalidomide maintenance therapy for 2 years Daratumumab subcutaneously (SC), 1800 mg on days 1, 8, 15 and 22 of cycle 1 and 2, on days 1 and 15 of cycle 3-6. Bortezomib SC 1.3 mg/m^2 on days 1, 4, 8, and 11 of each cycle 1-6. Lenalidomide orally, 25 mg on days 1 to 21 of each cycle 1-6. Dexamethasone orally, 40 mg once a week on days 1, 8, 15 and 22 of each cycle 1-6. Each cycle will consist 28 days. Lenalidomide maintenance orally 10 to 15 mg on days 1 to 28 (continuously) until confirmed progressive disease or unacceptable toxicity or for a maximum of 2 years	Drug: Daratumumab Daratumumab will be administered SC. Drug: Bortezomib Bortezomib will be administered SC. Drug: Lenalidomide Lenalidomide will be administered orally. Drug: Dexamethasone Dexamethasone will be administered orally.
Experimental: Arm B: DVRd followed by Ciltacabtagene Autoleucel Participants will receive daratumumab, bortezomib, lenalidomide and dexamethasone (DVRd) for 6 induction cycles. 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), followed by lenalidomide post CAR-T cell therapy for 2 years Daratumumab subcutaneously (SC), 1800 mg on days 1, 8, 15 and 22 of cycle 1 and 2, on days 1 and 15 of cycle 3-6. Bortezomib SC 1.3 mg/m^2 on days 1, 4, 8, and 11 of each cycle 1-6. Lenalidomide orally, 25 mg on days 1 to 21 of each cycle 1-6. Dexamethasone orally, 40 mg once a week on days 1, 8, 15 and 22 of each cycle 1-6. Each cycle will consist of 28 days. Lenalidomide maintenance orally 10 to 15 mg on days 1 to 28 (continuously) until confirmed progressive disease or unacceptable toxicity or for a maximum of 2 years	Drug: Daratumumab Daratumumab will be administered SC. Drug: Bortezomib Bortezomib will be administered SC. Drug: Lenalidomide Lenalidomide will be administered orally. Drug: Dexamethasone Dexamethasone will be administered orally. Drug: Cilta-cel Cilta-cel will be administered intravenously Other Names: JNJ-68284528 Drug: Cyclophosphamide Cyclophosphamide will be administered intravenously. Drug: Fludarabine Fludarabine will be administered intravenously.

Arm

Intervention/Treatment

Active Comparator: Arm A: DVRd + ASCT+DVRd (Standard Therapy)

Participants will receive daratumumab, bortezomib, lenalidomide and dexamethasone (DVRd) for 4 induction cycles. Followed by ASCT and 2 cycles of DVRd consolidation, and lenalidomide maintenance therapy for 2 years Daratumumab subcutaneously (SC), 1800 mg on days 1, 8, 15 and 22 of cycle 1 and 2, on days 1 and 15 of cycle 3-6. Bortezomib SC 1.3 mg/m^2 on days 1, 4, 8, and 11 of each cycle 1-6. Lenalidomide orally, 25 mg on days 1 to 21 of each cycle 1-6. Dexamethasone orally, 40 mg once a week on days 1, 8, 15 and 22 of each cycle 1-6. Each cycle will consist 28 days. Lenalidomide maintenance orally 10 to 15 mg on days 1 to 28 (continuously) until confirmed progressive disease or unacceptable toxicity or for a maximum of 2 years

Drug: Daratumumab

Daratumumab will be administered SC.

Drug: Bortezomib

Bortezomib will be administered SC.

Drug: Lenalidomide

Lenalidomide will be administered orally.

Drug: Dexamethasone

Dexamethasone will be administered orally.

Experimental: Arm B: DVRd followed by Ciltacabtagene Autoleucel

Participants will receive daratumumab, bortezomib, lenalidomide and dexamethasone (DVRd) for 6 induction cycles. 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), followed by lenalidomide post CAR-T cell therapy for 2 years Daratumumab subcutaneously (SC), 1800 mg on days 1, 8, 15 and 22 of cycle 1 and 2, on days 1 and 15 of cycle 3-6. Bortezomib SC 1.3 mg/m^2 on days 1, 4, 8, and 11 of each cycle 1-6. Lenalidomide orally, 25 mg on days 1 to 21 of each cycle 1-6. Dexamethasone orally, 40 mg once a week on days 1, 8, 15 and 22 of each cycle 1-6. Each cycle will consist of 28 days. Lenalidomide maintenance orally 10 to 15 mg on days 1 to 28 (continuously) until confirmed progressive disease or unacceptable toxicity or for a maximum of 2 years

Drug: Daratumumab

Daratumumab will be administered SC.

Drug: Bortezomib

Bortezomib will be administered SC.

Drug: Lenalidomide

Lenalidomide will be administered orally.

Drug: Dexamethasone

Dexamethasone will be administered orally.

Drug: Cilta-cel

Cilta-cel will be administered intravenously

Other Names:

JNJ-68284528

Drug: Cyclophosphamide

Cyclophosphamide will be administered intravenously.

Drug: Fludarabine

Fludarabine will be administered intravenously.

Outcome Measures

Primary Outcome Measures

Progression free survival (PFS) [up to 10 years ( or 300 PFS events)]
Progression free survival is defined as the time from the date of randomization to the date of first documented PD, as defined in the IMWG criteria, or death due to any cause, whichever occurs first
Sustained MRD-negative CR [up to 24 months]
Sustained MRD-negative CR is defined as being MRD negative by bone marrow aspirate, as determined by NGS with a sensitivity of at least 10-5, and meeting the IMWG criteria for CR, and with MRD-negativity status confirmed at a minimum 12 months apart and without any examination showing MRD-positive status or PD in between.

Secondary Outcome Measures

Overall Response (OR) [up to 17 years]
OR is defined as participants who achieve a partial response (PR) or better according to the IMWG criteria.
Complete Response (CR) or better status [up to 17 years]
CR or better is defined as percentage of participants who achieve a CR response or Stringent Complete Response (sCR) response according to the IMWG criteria.
Overall Minimal Residual Disease (MRD) -negative CR [up to 17 years]
achieving MRD-negative CR, as determined by NGS at any time after the date of randomization before initiation of subsequent antimyeloma therapy.
Time to subsequent antimyeloma therapy [up to 17 years]
Time to subsequent anti-myeloma therapy is defined as the time from randomization to the start of subsequent anti-myeloma therapy.
Progression Free Survival on Next-line Therapy (PFS2) [up to 17 years]
the time from the date of randomization to the date of event, defined as PD as assessed by investigator that starts after the next line of subsequent therapy, or death due to any cause, whichever occurs first.
Overall Survival (OS) [up to 17 years]
Overall survival is measured from the date of randomization to the date of the participant's death.
Change from Baseline in Health-Related Quality of Life (HRQoL) as Assessed by European Organization for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC-QLQ-C30) Scale Score [up to 17 years]
The EORTC QLQ-C30 includes 30 items in 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (pain, fatigue, nausea/vomiting), and 6 single symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The responses are reported using a verbal rating scale. The item and scale scores are transformed to a 0 to 100 scale. A higher score represents greater HRQoL, better functioning, and more (worse) symptoms.
Change from Baseline in Health-Related Quality of Life as Assessed by MySIm-Q Scale Score [up to 17 years]
The MySIm-Q is a disease-specific PRO assessment complementary to the EORTC-QLQ-C30. It includes 17 items with recall period of "7 days" and responses are reported on a 5-point verbal rating scale. Item responses are scored from 0 to 4. Higher scores indicate greater severity/impact.
Change from Baseline in Health-Related Quality of Life as Assessed by European Quality of Life - 5 Dimensions-5 Levels (EQ-5D-5L) Scale Scor [up to 17 years]
The EQ-5D-5L is a generic measure of health status. The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems, where Level 1: no problem, Level 2: slight problems, Level 3: moderate problems, Level 4: severe problems and Level 5: extreme problems, plus a visual analog scale rating "health today" with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).
Change from Baseline in Health-Related Quality of Life as Assessed by Patient Global Impression of Symptom Severity (PGIS) Scale Score [up to 17 years]
The PGIS uses 2 items to assess the participant's perception of the severity of their disease symptoms and impact using a 5-point verbal rating scale. Score ranges from 1 (None) to 5 (Very Severe).
Patient-reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) [up to 280 days]
The National Cancer Institute's PRO-CTCAE is an item library of common adverse events experienced by people with cancer that are appropriate for self-reporting. Each symptom selected for inclusion can be rated by up to 3 attributes characterizing the presence/frequency, severity, and/or interference that ranges from 0 to 4 with higher scores indicating higher frequency or greater severity/impact.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Participants with documented NDMM according to IMWG diagnostic criteria, for whom high-dose therapy and ASCT are part of the intended initial treatment plan.
Measurable disease, as assessed by central laboratory, at screening as defined by any of the following:

Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or
Light chain MM without measurable disease in serum or urine: serum Ig free-light chain (FLC) ≥10 mg/dL and abnormal serum Ig kappa lambda FLC ratio.

ECOG performance status of grade 0 or 1
Clinical laboratory values within prespecified range.

Exclusion Criteria:

Prior treatment with CAR-T therapy directed at any target.
Any prior BCMA target therapy.
Any prior therapy for MM or smoldering myeloma other than a short course of corticosteroids
Received a strong cytochrome P450 (CYP)3A4 inducer within 5 half-lives prior to randomization
Received or plans to receive any live, attenuated vaccine (except for COVID-19 vaccines) within 4 weeks prior to randomization.
Known active, or prior history of central nervous system (CNS) involvement or clinical signs of meningeal involvement of MM
Stroke or seizure within 6 months of signing Informed Consent Form (ICF)

Contacts and Locations

Locations

	Site	City	Country
1	Royal Adelaide Hospital	Adelaide	Australia
2	Princess Alexandra Hospital	Brisbane	Australia
3	Royal Prince Alfred Hospital	Camperdown	Australia
4	Royal Brisbane and Womens Hospital	Herston	Australia
5	Alfred Health	Melbourne	Australia
6	St. Vincent's Hospital	Melbourne	Australia
7	The Austin Hospital	Melbourne	Australia
8	Fiona Stanley Hospital	Murdoch	Australia
9	Calvary Mater Newcastle Hospital	Waratah	Australia
10	UZA	Antwerpen	Belgium
11	UZ Gent	Gent	Belgium
12	UZ Leuven	Leuven	Belgium
13	Centre Hospitalier Universitaire de Liege	Liège	Belgium
14	Fakultni nemocnice Brno	Brno	Czechia
15	Fakultni nemocnice Hradec Kralove	Králová	Czechia
16	Fakutni nemocnice Ostrava	Ostrava	Czechia
17	Vseobecna fakultni nemocnice v Prague	Prague	Czechia
18	University Hospital of Cologne	Cologne	Germany
19	Dresden	Dresden	Germany
20	Universitätsklinikum Hamburg - Eppendorf	Hamburg	Germany
21	University Hospital of Heidelberg	Heidelberg	Germany
22	Leipzig	Leipzig	Germany
23	Tübingen	Tübingen	Germany
24	University Hospital of Würzburg	Würzburg	Germany
25	Attikon University General Hospital of Attica	Athens	Greece
26	'G. Papanikolaou' Hospital of Thessaloniki	Thessaloníki	Greece
27	Hadassah University Hospita - Ein Kerem	Jerusalem	Israel
28	Sheba Medical Center	Ramat Gan	Israel
29	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano	Milan	Italy
30	A.O.U. Citta della Salute e della Scienza di Torino - Presidio Molinette, Turin	Turin	Italy
31	Chonnam National University Hwasun Hospital	Hwasun	Korea, Republic of
32	Asan Medical Center	Seoul	Korea, Republic of
33	Samsung Medical Center, Seoul	Seoul	Korea, Republic of
34	Seoul St. Mary's Hospital, The Catholic University of Korea	Seoul	Korea, Republic of
35	VU Medisch Centrum	Amsterdam	Netherlands
36	University Medical Center Groningen	Groningen	Netherlands
37	Radboud UMC	Nijmegen	Netherlands
38	Erasmus MC	Rotterdam	Netherlands
39	UMC Utrecht	Utrecht	Netherlands
40	HOSP. UNIV. GERMANS TRIAS I PUJOL, Badalona	Badalona	Spain
41	Hosp. Clinic I Provincial de Barcelona	Barcelona	Spain
42	Hosp. Gral. Univ. Gregorio Marañon	Madrid	Spain
43	HOSP. UNIV. 12 DE OCTUBRE, Madrid	Madrid	Spain
44	Ramon y Cajal, Madrid	Madrid	Spain
45	CLINICA UNIV. DE NAVARRA, Pamplona	Pamplona	Spain
46	Hosp. Clinico Univ. de Salamanca	Salamanca	Spain
47	Hospital de Santiago de Compostela	Santiago De Compostela	Spain
48	Hosp. Virgen Del Rocio	Sevilla	Spain
49	Hospital Universitario la Fe, Valencia	Valencia	Spain
50	Universitaetsspital Basel - Zentrum fur Hamato-Onkologie	Basel	Switzerland
51	Bern Inselspital	Bern	Switzerland
52	Lausanne CHUV	Lausanne	Switzerland