Phase 3 Randomized Trial of Bortezomib, Lenalidomide, Dexamethasone, and Ciltacabtagene Autoleucel in Newly Diagnosed Multiple Myeloma Without Planned Stem Cell Transplant
- Trial ID
- 2023-505850-16-00
- Protocol
- 68284528MMY3004
- Sponsor
- Janssen Cilag International
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3 randomized study is to compare the **efficacy** of bortezomib, lenalidomide, and dexamethasone (VRd) induction followed by a single administration of ciltacabtagene autoleucel versus VRd induction followed by lenalidomide and dexamethasone (Rd) maintenance in terms of progression-free survival (PFS) in participants with newly diagnosed **Multiple Myeloma** for whom hematopoietic stem cell transplant is not planned as initial therapy. This comparison is clinically relevant as it aims to determine the most effective treatment regimen for prolonging PFS, which is a critical endpoint in the management of Multiple Myeloma, potentially impacting patient outcomes and quality of life.
Participants
The clinical trial involves a total of **250 participants** diagnosed with **Multiple Myeloma**. The study population includes both male and female subjects, aged **18 years and older**, who are not considered for high-dose chemotherapy with autologous stem cell transplant. Participants were selected based on specific inclusion criteria, including a documented diagnosis of Multiple Myeloma according to the International Myeloma Working Group diagnostic criteria and a measurable disease at screening. The trial population is characterized by an Eastern Cooperative Oncology Group Performance Status grade of 0 or 1, indicating a generally good health status. Lifestyle considerations include adherence to contraceptive and barrier requirements for both men and women of childbearing potential, as well as restrictions on egg and sperm donation during and after the study. The trial does not specifically exclude vulnerable populations, allowing for a diverse representation of individuals affected by the condition.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of a treatment regimen for patients with newly diagnosed **multiple myeloma** who are not candidates for hematopoietic stem cell transplant as initial therapy. The trial compares the efficacy of bortezomib, lenalidomide, and dexamethasone (VRd) induction followed by a single administration of ciltacabtagene autoleucel versus VRd induction followed by lenalidomide and dexamethasone (Rd) maintenance. The primary endpoint is progression-free survival (PFS), with progression defined by the International Myeloma Working Group (IMWG) criteria or death, whichever occurs first. The trial is expected to run from August 19, 2021, to June 13, 2034, with an estimated duration of 13 years.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented diagnosis of multiple myeloma, and measurable disease. Follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse events. The end-of-study visit will conclude the trial for each participant, assessing the final outcomes and any long-term effects of the treatment. The expected length of participant involvement is contingent upon the treatment regimen and response, with a maximum treatment period of 4865 days for some components. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study protocols.
Treatment
The clinical trial involves the administration of **CARVYKTI**, a dispersion for infusion containing **ciltacabtagene autoleucel**, a chimeric antigen receptor T cell (CAR-T) therapy. This experimental medication is administered via **intravenous use**. The dosage range is from 3.2 × 10^6 to 1.0 × 10^8 cells, and the treatment is conducted with clinical material using the same CAR-T drug product manufacturing process as the authorized product. The maximum treatment period for this medication is 1 day. The final cell dispersion for infusion is stored in OriGen Biomedical CryoStore freezing bags.
**Lenalidomide** is used in various formulations as a comparator treatment in the study. It is available in hard capsules with dosages of 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg. The capsules are administered orally, with a maximum treatment period of 4865 days. The lenalidomide products are provided by Mylan Ireland Limited and Accord Healthcare S.L.U., and they undergo re-labeling and packaging for the trial.
**Dexamethasone** is another comparator treatment used in the trial. It is available in tablet form with dosages of 2 mg and 4 mg. The tablets are administered orally, with a maximum treatment period of 4865 days. The dexamethasone products are provided by Merck Healthcare Germany GmbH, MIBE GmbH Arzneimittel, and Aspen Pharma Trading Limited, and they are re-labeled and packaged for the trial.
**Bortezomib**, marketed as VELCADE, is used as a comparator treatment in the form of a 3.5 mg powder for solution for injection. It is administered via **subcutaneous use** with a maximum treatment period of 168 days. The product is provided by Janssen-Cilag International NV and is re-packaged with a clinical label attached to each vial.
**Cyclophosphamide** and **fludarabine** are used as auxiliary treatments in the trial. Cyclophosphamide is administered intravenously with a pharmaceutical form of PHF00231MIG, while fludarabine is also administered intravenously with a pharmaceutical form of PHF675. Both medications have a maximum treatment period of 3 days and are of chemical origin.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)**. PFS is defined as the time from randomization to disease progression, as per the International Myeloma Working Group (IMWG) criteria, or death from any cause, whichever occurs first. This endpoint is chosen to evaluate the effectiveness of the treatment regimens in delaying disease progression in participants with newly diagnosed multiple myeloma who are not planned for hematopoietic stem cell transplant as initial therapy.
The trial involves a comparison between two treatment regimens: bortezomib, lenalidomide, and dexamethasone (VRd) induction followed by a single administration of ciltacabtagene autoleucel, a chimeric antigen receptor T cell (CAR-T) therapy, versus VRd induction followed by lenalidomide and dexamethasone (Rd) maintenance. The efficacy assessments will be conducted at specified intervals throughout the study duration, with the final analysis occurring at the end of the treatment period. The trial is designed to provide robust data on the comparative efficacy of these treatment strategies in improving PFS in the target patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- ≥18 years of age
- Documented diagnosis of MM according to IMWG diagnostic criteria
- Measurable disease at Screening
- Not considered for high-dose chemotherapy with autologous stem cell transplant (ASCT)
- Eastern Cooperative Oncology Group Performance Status grade of 0 or 1 Contraceptive/Barrier Requirements
- A woman of childbearing potential (WOCBP) must have 2 negative highly sensitive serum or urine pregnancy test (beta-human chorionic gonadotropin) tests prior to starting VRd and must agree to further testing during the study.
- When a woman is of childbearing potential, the participant must commit either to abstaining continuously from heterosexual intercourse or agree to practice 2 methods of reliable birth control simultaneously, ie, one highly effective method of contraception (failure rate of <1% per year when used consistently and correctly; see examples below) and one other effective method (ie, male latex or synthetic condom, diaphragm, or cervical cap).
- A man must commit either to abstaining continuously from heterosexual intercourse or a man • Who is sexually active with a WOCBP or a pregnant woman must agree to use a barrier method of contraception (eg, latex or synthetic condom with spermicidal foam/gel/film/cream/suppository), without interruption, from the time of signing the informed consent form (ICF) until at least 4 weeks after the last dose of lenalidomide, 3 months after the last dose of bortezomib, 1 year after receiving the conditioning regimen (cyclophosphamide and fludarabine) or 1 year after receiving cilta-cel infusion (whichever is later), even if they have undergone a successful vasectomy. • Should agree to practice contraception according to and for the time frame specified in the global REVLIMID® ( or generic lenalidomide) pregnancy prevention program or equivalent local REVLIMID® (or generic lenalidomide) pregnancy prevention program, whichever is more stringent.
- Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively, during the study and until at least 4 weeks after the last dose of lenalidomide, 3 months after the last dose of bortezomib, 1 year after receiving the conditioning regimen (cyclophosphamide and fludarabine), or 1 year after receiving cilta-cel infusion (whichever is later).
Exclusion Criteria
- Frailty index of ≥ 2 according to Myeloma Geriatric Assessment score
- Active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study.
- 3.Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.
- The following cardiac conditions: • New York Heart Association Stage III or IV congestive heart failure • Myocardial infarction or coronary artery bypass graft ≤6 months prior to enrollment • History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration • History of severe non-ischemic cardiomyopathy • Screening 12-lead ECG showing a baseline corrected Prolonged corrected QT interval (QTc) >470 msec (for women) and >450 msec (for men), as assessed by 12-lead ECG, except in participants with a pacemaker. • Impaired cardiac function (left ventricular ejection fraction <45%) as assessed by echocardiogram or multiple-gated acquisition (MUGA) scan.
- Known active, or prior history of central nervous system (CNS) involvement or exhibits clinical signs of meningeal involvement of MM.
- 6.Stroke or seizure within 6 months of signing ICF.
- 7.Plasma cell leukemia at the time of screening (>2.0 x 10^9/L plasma cells by standard differential), Waldenström's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or primary amyloid light-chain amyloidosis.
- Seropositive for human immunodeficiency virus (HIV).
- Vaccinated with live, attenuated vaccine within 4 weeks prior to first dose of VRd.
- Hepatitis B infection. In the event the infection status is unclear, quantitative levels are necessary to determine the infection status.
- Hepatitis C infection (defined as anti-hepatitis C virus [HCV] antibody positive or detectable HCV-RNA) or known to have a history of hepatitis C.
- Participant must not require continuous supplemental oxygen.
- Contraindications, known life-threatening allergies, hypersensitivity, or intolerance to any of the study treatments, including cyclophosphamide or fludarabine (if known) or any of their excipients, including boron, mannitol, dimethyl sulfoxide.
- Serious underlying medical condition, such as: • Evidence of active viral or bacterial infection requiring systemic antimicrobial therapy, or uncontrolled systemic fungal infection • Active autoimmune disease • Overt clinical evidence of dementia or altered mental status • Any history of Parkinson's disease or other neurodegenerative disorder Prior/Concomitant Medications.
- Prior treatment with CAR-T therapy directed at any target.
- Any therapy that is targeted to BCMA.
- Any prior therapy for MM or smoldering myeloma other than a short course of corticosteroids and/or maximum 1 cycle of VRd therapy prior to enrollment. •Radiation therapy for treatment of plasmacytoma within 14 days before enrollment (palliative radiation for pain control secondary to lytic lesion is allowed within 14 days of enrollment). However, if the radiation portal covered ≤5% of the bone marrow reserve, the subject is eligible irrespective of the end date of radiation therapy.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 19 Aug 2021 | 14 |
 Belgium | Not Recruiting | 19 Aug 2021 | 11 |
 Czechia | Not Recruiting | 19 Aug 2021 | 33 |
 Denmark | Not Recruiting | 19 Aug 2021 | 15 |
 Finland | Not Recruiting | 19 Aug 2021 | 9 |
 France | Not Recruiting | 19 Aug 2021 | 11 |
 Germany | Not Recruiting | 19 Aug 2021 | 54 |
 Greece | Not Recruiting | 19 Aug 2021 | 13 |
 Hungary | Not Recruiting | 19 Aug 2021 | 2 |
 Ireland | Not Recruiting | 19 Aug 2021 | 4 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Dexamethasone Tablets BP 2.0mg | Comparator | TABLETS | ORAL USE | 0 | 4865 | PRD3570594 |
Fortecortin® 2 mg Tabletten | Comparator | TABLETTEN | ORAL USE | 0 | 4865 | PRD10324898 |
Lenalidomide Accord 15 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 0 | 4865 | PRD6773399 |
CARVYKTI 3.2 × 10^6 – 1.0 × 10^8 cells dispersion for infusion | Test | DISPERSION FOR INFUSION | INTRAVENOUS USE | 0 | 1 | PRD9718535 |
Lenalidomide Mylan 5 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 0 | 4865 | PRD8601759 |
Lenalidomide Mylan 20 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 0 | 4865 | PRD8601769 |
VELCADE 3.5 mg powder for solution for injection | Comparator | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 0 | 168 | PRD703624 |
Lenalidomide Mylan 20 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 0 | 4865 | PRD9024381 |
Lenalidomide Accord 10 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 0 | 4865 | PRD6773396 |
Lenalidomide Accord 2.5 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 0 | 4865 | PRD6773392 |