This is a multicenter, open-label phase II study with 2 parallel cohorts for frail patients with newly diagnosed multiple myeloma treated with daratumumab in combination with teclistamab and talquetamab.

The main purpose of this study is to determine the progression free survival at 18 months in patients treated with teclistamab and daratumumab (Cohort 1) or talquetamab and daratumumab (Cohort 2).

This study will consist of 4 phases:

• Initial treatment phase where patients will receive fixed duration of Tec-Dara or Tal-Dara.
• TFI.
• Re-treatment phase, where patients with confirmed PD will continue treatment with Tec-Dara or Tal-Dara per their assignment in the initial treatment phase.
• Post-treatment follow-up phase.

Inclusion Criteria:

1. Patient is ≥18 years of age and capable of giving informed consent and must sign an informed consent form (ICF), indicating that they understand the purpose of, and procedures required for, the study and is willing to participate in the study
2. Newly diagnosed and treatment-naïve patients with a confirmed diagnosis of MM with measurable disease according to IMWG criteria
3. Measurable disease defined as M-protein in the serum (≥1 g/dL) or serum free light chain assay ≥10 mg/dL [≥100 mg/L] and abnormal serum immunoglobulin kappa/lambda FLC ratio
4. Frail according to the Simplified IMWG frailty index
5. Have clinical laboratory values meeting defined range
6. Patients of childbearing potential must agree to use adequate/highly effective contraception from the time of signing the informed consent form through 3 months after the last dose of study drug

Exclusion Criteria:

1. Non-secretory MM or measurable disease by urine or plasmacytoma only

2. Central nervous system involvement of myeloma

3. Significant pulmonary dysfunction

4. Stroke, transient ischemic attack, or seizure within 6 months of eligibility

5. Evidence of active systemic viral, fungal, or bacterial infections, requiring systemic antimicrobial therapy

6. HIV and Hepatitis infections

7. Exclude for any of the following:

   1. Any history of malignancy other than MM which is considered at high risk of recurrence requiring treatment or a malignancy that has been treated with chemotherapy currently affecting bone marrow capacity.
   2. Any active malignancy (ie, progressing or requiring treatment change in the last 24 months) other than multiple myeloma.

8. Active autoimmune disease requiring systemic immunosuppressive therapy within 6 months before eligibility

9. Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study treatment or its excipients (refer to IB and most recently applicable RSI)

10. Extensive radiotherapy within 14 days or focal radiation only within 7 days of eligibility

11. Current or active therapy for multiple myeloma or received a cumulative dose corticosteroids equivalent to >40 mg dexamethasone within the 14 days prior to C1D1

12. Received a live attenuated vaccine ≤4 weeks before eligibility. Non-live vaccines or non-replicating authorized for emergency use (eg, COVID-19) are allowed

13. Received a strong CYP3A4 inducer or use of St. John's wort ≤5 half-lives prior to dosing

14. Patient had major surgery or significant traumatic injury within 2 weeks prior to eligibility. Kyphoplasty or Vertebroplasty is not considered major surgery

15. Have received an investigational drug (including investigation vaccines) or used an invasive investigational medical device <4 week or 5 PK half-lives, before eligibility or is currently enrolled in an interventional investigational study except if only long-term survival data are collected

16. Concurrent medical or psychiatric condition or disease (eg, uncontrolled diabetes, alcohol or drug abuse, severe dementia or altered mental status), that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participation in the study

17. Any other issue that would impair the ability of the patient 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 patient (eg,, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments