This phase I trial will evaluate the safety, side effects, and best dose of talquetamab in combination with iberdomide and dexamethasone in treating patients with multiple myeloma that has come back after a period of improvement (relapsed) or has not responded to previous treatment (refractory). There is currently a significant unmet need for patients with relapsed or refractory multiple myeloma (RRMM) who are triple class refractory and have been exposed to B-cell maturation antibody (BCMA) targeted therapy. These patients currently have limited treatment options and poor survival. Talquetamab is an FDA approved drug that can bring T-cells to the myeloma cell, resulting in myeloma cell death. Iberdomide is an investigational drug and works by targeting and destroying proteins that help myeloma cancer cells to survive. Dexamethasone is a corticosteroid, is similar to a natural hormone produced by the adrenal glands to reduce inflammation (swelling, heat, redness, and pain) and is used to in helping to treat certain types of cancer including myeloma.

PRIMARY OBJECTIVES:

I. To assess safety of the combination of talquetamab (Tal), iberdomide (Iber) and dexamethasone (Dex) in patients with triple class exposed (TCE) RRMM. (Phase 1b-dose escalation (DE)).

II. To assess dose limiting toxicity (DLT) and determine the recommended phase 2 dose (RP2D) of the combination of Tal, Iber and Dex administered in 28-day cycles in patients with TCE RRMM. (Phase 1b-DE).

III. To further assess safety of RP2D of the combination of Tal, Iber and Dex administered in 28-day cycles in patients with TCE RRMM Len-refractory, and having received >= 2 prior lines of therapy. (Phase 1b-expansion (Exp)).

IV. To assess overall response rate (ORR) in patients with TCE RRMM, Len-refractory, and having received ≥ 2 prior lines of therapy. (Phase 1b-Exp).

SECONDARY OBJECTIVES:

I. To assess ORR, and to determine minimal residual disease (MRD) negative (-) rates in patients achieving ≥ very good partial remission (VGPR).

II. To assess toxicity (incidence of adverse events (AEs), serious AEs (SAEs), and treatment discontinuation due to toxicity) and safety (physical examination findings, vital signs, and clinical laboratory evaluations) in patients with RRMM.

III. Describe changes in health-related quality of life (HRQoL) using the European Organization for Research and Treatment of Cancer (C30) -Quality of Life questionnaire (QLQ) (EORTC-QLQ-C30), EORTC QLQ Oral Health 15 (OH-15) and EORTC QLQ-Multiple Myeloma Questionnaire (MY20)).

EXPLORATORY OBJECTIVES:

I. To assess serum cytokines levels with treatment of the combination of Tal, Iber and Dex and the predictive values of response, cytokine release syndrome (CRS) and other adverse events.

II. To assess changes in immune cells in blood and bone marrow with treatment of the combination of Tal, Iber and Dex.

III. To determine the efficacy of combination of Tal, Iber and Dex defined as Objective Response Rate (ORR) and achieving complete response (CR) and MRD (-) status and correlation between mass spectroscopy and bone marrow (BM) MRD assessments.

OUTLINE: This is a dose-escalation study of Iber followed by a dose-expansion study.

Participants receive Tal in cycle 1 then all 3 drugs will be given in combination in cycle 2 but may be continued at the discretion of the investigator. Cycles repeat every 28 days for as long as there is clinical benefit as determined by the Investigator. Study treatment will be discontinued if there is unacceptable toxicity, disease progression, withdrawal of consent by the participant, noncompliance with study requirements, intercurrent illness, or closure of the study by the Sponsor.

After completion of study treatment, patients are followed up at 30 days every 8 weeks for up to 3 years or until progression or initiation of subsequent therapy.

Inclusion Criteria:

1. Male or female ≥ 18 years of age.

2. Has a prior history of (h/o) MM (based on International Myeloma Working Group (IMWG) criteria) and now has evidence of relapsed or refractory MM. RRMM of progressive disease as defined by the IMWG 2006 and 2016 criteria (Kumar at al).

3. Specific criteria for dose escalation and dose expansion:

   1. Phase 1 dose escalation: patients will be required to have TCE RRMM (including a proteasome inhibitor (PI) (≥ 2 cycles or 2 months of treatment), an immunomodulatory drug (IMiD)) (≥ 2 cycles or 2 months of treatment) and a CD38 antibody (≥ 2 cycles or 2 months of treatment) after receiving ≥ 3 prior lines of therapy. Prior BCMA exposure is allowed. (Subjects with discontinued PI/IMiD/Cluster of differentiation 38 (CD38) therapy due to severe adverse event after < 2 months are allowed)
   2. Dose expansion cohort: RRMM patients will be lenalidomide refractory, TCE (exposed to IMiD, PI and CD38 antibody therapy (≥ 2 cycles or 2 months of treatment for each) and have received ≥ 2 prior lines of therapy. Prior BCMA targeted therapy is allowed, not required. (Subjects with discontinued PI/IMiD/CD38 therapy due to severe adverse event after < 2 months are allowed. Lenalidomide refractory is defined as having evidence of progressive disease on lenalidomide (≥ 10 mg or greater, ≥ 21 days/28) or within 60 days of stopping lenalidomide therapy.)

4. Has measurable disease defined as at least 1 of the following:

   1. Serum M-protein ≥ 0.5 g/dL (dose escalation) and 1.0 g/dL (dose expansion cohorts)
   2. Urine M-protein ≥ 200 mg/24 hours
   3. Serum free light chain (FLC) assay: involved FLC assay ≥ 10 mg/dL (≥ 100 mg/L) AND an abnormal serum FLC ratio (< 0.26 or > 1.65). (Can be used to fulfill the inclusion criteria of measurable disease in patients who do not have measurable disease by M-protein).

5. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6. Has adequate baseline organ function, as demonstrated by the following:

   1. Calculated creatinine clearance > 30 mL/min as assessed by the Cockcroft-Gault equation, Modification of Diet in Renal Disease (MDRD) equation (National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 2015) or as assessed by 24-hour urine collection.
   2. Serum bilirubin ≤ 1.5 mg/dL, excluding Gilbert's.
   3. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × institutional upper limit normal (ULN).
   4. Total serum calcium (corrected for serum albumin) or ionized calcium within normal limits (WNL) (treatment of hypercalcemia is allowed and patients may enroll if hypercalcemia returns to WNL with standard treatment).

7. Has adequate baseline hematologic function, as demonstrated by the following:

   1. Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L (myeloid growth factors must not have been administered within 7 days (14 days for extended 1/2-life products).
   2. Hemoglobin ≥ 8 g/dL (red blood cell transfusions permitted provided the anemia is disease-related).
   3. Platelet count ≥ 100 x 10^9/L and no platelet transfusions during the 7 days before first dose (without transfusions). (Dose expansion cohorts will be allowed to have platelets counts ≥ 75 x 10^9/L with no platelet transfusions during the prior 7 days).

8. Must have at least 2 negative serum beta-human chorionic gonadotropin (β-hCG) pregnancy test result obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second within 24 hours prior to initiating therapy if the patient is a female of childbearing potential (FCBP; defined as a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy or has not been naturally postmenopausal for at least 24 consecutive months).

9. Men and women of childbearing potential must agree to not donate sperm and eggs (ova and oocytes) throughout study therapy and for 3 months after the last treatment.

10. Men and women agree to use acceptable contraceptive methods for the duration of time on the study, and continue to use acceptable contraceptive methods for 3 months after the last treatment with study treatment.

    1. Women of childbearing potential must agree to 2 methods of reliable birth control simultaneously while receiving study treatment and until 100 days after last dose of study treatment: one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [oral, injectable, transdermal patches, vaginal rings or implants] or partner's vasectomy, and 1 additional effective contraceptive method (male latex or synthetic condom, diaphragm or cervical cap).
    2. Males must agree to always use a latex or synthetic condom during any sexual contact with females of reproductive potential.

11. All patients should be encouraged to be fully vaccinated prior to initiation of therapy including being up-to-date on vaccines against pneumococcus, yearly influenza, Coronavirus disease (COVID) booster(s), and any age appropriate vaccine. Live attenuated vaccines are not allowed while on study treatment or within 4 weeks of starting treatment.

12. Has provided signed informed consent before initiation of any study-specific procedures or treatment.

13. Must agree to, and be capable of, adhering to the study visit schedule and other protocol requirements, including follow-up for overall survival.

Exclusion Criteria:

1. Has persistent clinically significant toxicities (grade ≥ 2; per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0) from previous anticancer therapy (excluding alopecia which is permitted and excluding grades 2 and 3 laboratory abnormalities (including hematologic abnormalities) if participants are not associated with symptoms, are not considered clinically significant by the investigator, and can be managed with available medical therapies.

2. Has NCI CTCAE grade ≥ 3 peripheral neuropathy from any etiology or grade ≥ 2 peripheral neuropathy with pain.

3. Has received treatment with cytotoxic (alkylators) within 3 weeks, biologic (IMiDs/PIs) within 2 weeks, targeted therapies (monoclonal antibodies) within 4 weeks, chimeric antigen receptor (CAR) T-cell (CAR-T)or autologous stem cell transplant therapy within 3 months or any novel therapy within 5- 1/2 lives of therapy.

4. Has had radiation therapy within 14 days of first dose of study therapy, unless less than 5% marrow exposure, then no limit.

5. Has had any prior GPRC5D targeted bispecific antibody therapy or GPRC5D CAR-T therapy or has had previous treatment with Iber.

6. Has any active or uncontrolled infection including any viral, bacterial or fungal infection; and/or HIV, active hepatitis (Hep) C and active Hep B (hepatitis B (HB) surface antigen (HBsAg) (+), HB core antigen (HBcAb) (+) or (+) Hep B deoxyribonucleic acid (DNA) by polymerase chain reaction (pcr), Hep C ribonucleic acid (RNA) (+) by pcr. Patients who have received Intravenous immunoglobulin therapy (IVIG) replacement therapy may have (+) HBcAb results from the IVIG therapy. These patients can enroll if Hep B DNA by pcr test is negative. These patients need to be on antiviral therapy and be monitored for hepatitis B virus (HBV) DNA throughout study therapy per local guidelines and as clinically indicated.

7. Has an additional active malignancy that may confound the assessment of the study endpoints. If the patient has a past cancer history (active malignancy within 2 years before study entry) with substantial potential for recurrence, this must be discussed with the sponsor/investigator before study entry. Patients with the following concomitant neoplastic diagnoses are eligible: nonmelanoma skin cancer and carcinoma in situ (including transitional cell carcinoma, cervical cancer, anal carcinoma, ductal carcinoma in situ (DCIS) and melanoma in situ), any cancer resected with curative intent, low-grade cancer not requiring therapy.

8. Is pregnant or breast feeding.

9. Has clinically significant cardiovascular disease including, albeit not limited to:

   1. Uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure
   2. Uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months before study entry
   3. Uncontrolled hypertension or clinically significant arrhythmias not controlled by medication.

10. Has active POEMS (polyneuropathy, organomegaly, endocrinopathy/edema, monoclonal-protein, skin syndrome), amyloid light (AL) amyloidosis, primary plasma cell leukemia or active central nervous system (CNS) or parenchymal/leptomeningeal myeloma.

11. Has uncontrolled, clinically significant organ dysfunction that in the opinion of the investigator would put the patient at significant risk for toxicity from study therapy.

12. Has recent major surgery within 4 weeks or significant gastrointestinal (GI) disease that would interfere with GI absorption of oral medications.

13. Has a condition, including autoimmune disease, requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days before study therapy administration. Inhaled or topical steroids and adrenal replacement doses <10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.

14. Has received treatment with allogeneic stem cell transplant within 6 months before the first dose of study treatment and if > 6 months from allogeneic stem cell transplantation (alloSCT) must be off all immunosuppression and without evidence of active graft-versus-host disease (GVHD).

15. Uncontrolled epilepsy or new/recent seizure activity within 6 months of study entry.

16. Live vaccine administered within 4 weeks prior to study therapy.