EMN28 - European Myeloma Network

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

Study map

Overview / Summary

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.

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.

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.

Study details

Patient eligibility criteria

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

Each potential subject must satisfy all of the following criteria to be enrolled in the study:

18 years of age or older.

Newly diagnosed participants for whom high-dose therapy and ASCT are part of the intended treatment plan with documented diagnosis of multiple myeloma according to IMWG diagnostic criteria (Rajkumar, 2014 Lancet Oncology).

Measurable disease at Screening as defined by any of the following:

· Serum monoclonal paraprotein (M-protein) level ³1.0 g/dL or urine M-protein level ³200 mg/24 hours; or

· Light chain multiple myeloma in whom the only measurable disease is by serum FLC levels in the serum: Serum immunoglobulin free light chain ³10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.

Note: Local laboratory assessments may be used to establish measurable disease at Screening, with local laboratory result ³125% of requirements (eg, M-protein ³1.25 g/dL if using local labs).

ECOG Performance Status grade of 0 or 1.

Clinical laboratory values meeting the following criteria during the Screening Phase:

Hematology
Hemoglobin	³7.5 g/dL (≥4.65 mmol/L; prior red blood cell [RBC] transfusions are not permitted within 7 days of randomization to achieve this minimum hemoglobin count*. But recombinant human erythropoietin use is permitted). Note: For participants who meet the inclusion criterion at screening, red blood cell transfusion is permitted after screening as needed to maintain a hemoglobin level ≥7.5 g/dL.
Platelets	≥50 x 10⁹/L (must be without transfusion support in the 7 days prior to the laboratory test)
Absolute Neutrophil Count (ANC)	³1 ×10⁹/L (prior growth factor support is permitted but must be without support in the 7 days prior to the laboratory test)
Chemistry
Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)	≤3 × upper limit of normal (ULN)
Estimated Glomerular Filtration Rate	³40 mL/min/1.73 m²based upon Modified Diet in Renal Disease formula calculation or a 24-hour urine collection.
Total bilirubin	≤2 × ULN; except in participants with congenital hyperbilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤1.5 × ULN is required)

A woman of childbearing potential must have a negative highly sensitive serum pregnancy test (b‑human chorionic gonadotropin [b‑hCG]) at screening.

When a female participant is of childbearing potential, she 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). The participant must agree to remain on both methods of birth control from

the time of signing the informed consent form (ICF) and for a minimum of 4 weeks prior

to initiating lenalidomide therapy and until at least 1 year after receiving cilta-cel or until

at least 1 year after receiving the conditioning regimen or until at least 4 weeks after

discontinuation of lenalidomide or until at least 3 months after discontinuation of

daratumumab and/or bortezomib, whichever occurs later. Reliable contraception is

indicated even when there is a history of infertility, unless it is due to hysterectomy.

Female participants of childbearing potential should be referred to a qualified provider of

contraceptive methods, if needed.

Examples of highly effective contraceptives include:

a. User-independent methods: 1) implantable progestogen-only hormone contraception

associated with inhibition of ovulation; 2) intrauterine device; 3) intrauterine

hormone-releasing system; 4) vasectomized partner; 5) bilateral tubal

ligation/occlusion.

b. User-dependent methods: 1) progestogen-only hormone contraception associated

with inhibition of ovulation (oral or injectable); 2) sexual abstinence.

Estrogen-containing hormonal contraception is contraindicated due to increased risk

of thromboembolic events with lenalidomide.Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively, during the study and for 1 year after receiving a cilta-cel infusion or for 4 weeks after discontinuing lenalidomide (whichever is later).

Note: Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy of the contraceptive method.

A male participant must commit either to abstaining continuously from heterosexual

intercourse or

a. a male participant who is sexually active with a woman of childbearing potential 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) from the time

of signing the ICF until at least 1 year after receiving cilta-cel or until at least 1 year

after receiving the conditioning regimen or until at least 4 weeks after

discontinuation of lenalidomide or until at least 3 months after discontinuation of

daratumumab and/or bortezomib, whichever occurs later, even if he has undergone

a successful vasectomy.

b. a male participant should agree to practice contraception according to and for the

time frame specified in the lenalidomide global PPP or local PPP/REMS

program/RMP applicable in their region, whichever is more stringent.

Participant must sign an ICF indicating that he or she understands the purpose of and procedures required for the study and is willing to participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard-of-care for the participant’s disease.

Willing and able to adhere to the prohibitions and restrictions specified in this protocol.

10.

Must be able to read, understand, and complete PRO instruments, and must intend to

comply with completion of PRO.

Publications

No publications connected to this trial at the moment