Bispecific T-cell Redirectors as Part of First Line Treatment in Transplant Eligible Multiple Myeloma Patients

This is Phase 2, open-label, multicentre, non-randomised study evaluating participants with newly diagnosed MM eligible for high-dose therapy. The goal of the study is to determine if consolidation with T-cell redirectors - Talquetamab and Teclistamab in sequence will improve the response depth: increase MRD negative CR rate.

A total of 50 transplant-eligible patients with newly diagnosed multiple myeloma in need of treatment will be enrolled.

The study consists of three phases: Induction, Consolidation, and Follow-up. Induction will consist of Dara-VRd and consolidation Part I will include talquetamab and Part II will include teclistamab.

Follow-up Phase After consolidation, treatment continues upon physician's choice: the options are ASCT with maintenance or only maintenance with lenalidomide.

Efficacy will be evaluated by serum/urine electrophoresis monthly; by serum/urine immunofixation, bone marrow morphology and flow cytometry when CR/sCR is suspected;

MRD will be evaluated by NGS ( at the level of 10-6) and FDG PET-CT ( by Deauville score) at various timepoints during induction, consolidation and follow-up.

Participants quality of life, symptoms, functional and general well-being will be captured using 3 PRO measures ( PRO-CTCAE, EORTC QLQ-C30, FACT-Cog).

The safety of study drugs will be assessed by physical examinations, vital signs, ECGs, clinical laboratory tests, neurologic examinations (including ICE scores), ECOG performance status, and AE monitoring according to NCI-CTCAE Version 5.0), grading of CRS and ICANS will be assessed based on ASTCT guidelines.

Eligibility Criteria:
Inclusion Criteria:

1. Participant must have documented MM satisfying the IMWG criteria.
2. Newly diagnosed patients eligible for high dose therapy and ASCT.
3. ECOG performance status score ≤2.
4. HIV-positive participants are eligible if they meet all of the following

   1. No detectable viral load (ie, \<50 copies/mL) at screening
   2. CD4+ count \>300 cells/mm3 at screening
   3. No AIDS-defining opportunistic infection within 6 months of screening
   4. Receiving HAART. Any changes in HAART due to resistance/progression should occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed up to 4 weeks prior to screening.
5. Must sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
6. Willing and able to adhere to the lifestyle restrictions specified in this protocol.
7. A female participant of childbearing potential must have a negative highly sensitive serum (β hCG) pregnancy test at screening
8. A female participant must be

   1. Not of childbearing potential or
   2. Of childbearing potential and practicing true abstinence; or have a sole partner who is vasectomized; or practicing 2 effective methods of contraception
9. A female participant must agree not to donate eggs or freeze for future use during the study and for 6 months after receiving the last dose of study treatment.
10. A male participant must wear a condom when engaging any sexual activity that allows for passage of ejaculate to another person during the study and for a minimum of 100 days after receiving the last dose of study treatment.
11. A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 100 days after receiving the last dose of study treatment.
12. Have clinical laboratory values meeting the following criteria

    1. Hemoglobin ≥8 g/dL
    2. Platelets ≥75×109/L
    3. ANC ≥1.0×109/L
    4. AST and ALT ≤2.5×ULN
    5. eGFR ≥30 mL/min
    6. Total bilirubin \<1.5×ULN

Exclusion Criteria:

1. Waldenström's macroglobulinemia, POEMS syndrome, or primary amyloid light chain amyloidosis.
2. Known active CNS involvement or exhibits clinical signs of meningeal involvement of MM. If either is suspected, negative whole brain MRI and lumbar cytology are required.
3. Peripheral neuropathy or neuropathic pain Grade 2 or higher
4. Excluded for any of the following:

   1. Any ongoing myelodysplastic syndrome or B cell malignancy (other than MM).
   2. Any history of malignancy, other than MM, which is considered at high risk of recurrence requiring systemic therapy.
   3. Any active malignancy (ie, progressing or requiring treatment change in the last 24 months) other than MM. The only allowed exceptions are malignancies treated within the last 24 months that are considered cured:

      1. Non-muscle invasive bladder cancer (solitary Ta-PUN-LMP or low grade, \<3 cm, no CIS).
      2. Non-melanoma skin cancers treated with curative therapy or localized melanoma treated with curative surgical resection alone.
      3. Non-invasive cervical cancer.
      4. Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ or history of localized breast cancer (anti-hormonal therapy is permitted).
      5. Localized prostate cancer (M0, N0) with a Gleason Score ≤7a, treated locally only (RP/RT/focal treatment).
      6. Other malignancy that is considered cured with minimal risk of recurrence in consultation with the sponsor's medical monitor.
5. Stroke within 6 months prior to signing ICF.
6. Presence of the following cardiac conditions:

   1. New York Heart Association stage III or IV congestive heart failure (see Appendix )
   2. Myocardial infarction or coronary artery bypass graft ≤6 months prior to enrollment, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina)
   3. Uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities
   4. History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration
   5. History of severe non-ischemic cardiomyopathy
7. Concurrent medical or psychiatric condition or disease that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study, such as:

   1. Uncontrolled diabetes
   2. Evidence of active systemic viral, fungal, or bacterial infection, requiring systemic antimicrobial therapy
   3. History of autoimmune disease with the exception of vitiligo, type I diabetes, and prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing
   4. Gastrointestinal disease that may significantly alter the absorption of oral drugs
   5. Disabling psychiatric conditions (eg, alcohol or drug abuse), severe dementia, or altered mental status
8. Any other issue that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
9. Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug or its excipients
10. Any of the following:

    1. Hepatitis B infection (ie, HBsAg or HBV-DNA positive).
    2. Active hepatitis C infection as measured by positive HCV-RNA testing.
11. Prior or current systemic therapy or stem cell transplantation for any plasma cell dyscrasia, with the exception of emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment.
12. Major surgery within 2 weeks prior to the start of administration of study treatment, or will not have fully recovered from surgery, or has major surgery planned during the time the participant is expected to be treated in the study or within 2 weeks after administration of the last dose of study treatment.
13. Contraindications to the use of Dara-VRd per SmPC.
14. Prior or concurrent exposure to any of the following, in the specified time frame prior to first dose of study treatment:

    1. Investigational vaccine other than SARS-CoV-2 vaccine approved/in use under emergency approval within 4 weeks. Non-live or non-replicating vaccines authorized for emergency use (eg, COVID-19) by local health authorities are allowed.
    2. Live, attenuated vaccine within 4 weeks
    3. Monoclonal antibody therapy within 21 days (not used for the treatment of MM)
    4. Received a strong CYP3A4 inducer within 5 half-lives prior to start of administration of study treatment
15. Participant is pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of study treatment.
16. Participant plans to father a child while enrolled in this study or within 100 days after the last dose of study treatment.