Testing Teclistamab (TECVAYLI) in Combination With Iberdomide for Relapsed or Refractory Multiple Myeloma

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed multiple myeloma (MM),as defined in the International Myeloma Working Group (IMWG) criteria

• If patients have undergone autologous stem cell transplant (SCT), day 0 of SCT mustbe > 100 days to be eligible for the study

• Patients must have had disease progression after ≥ 4 prior lines of anti-myelomatreatments including one proteasome inhibitor (e.g., bortezomib, carfilzomib,ixazomib), one immunomodulatory imide drug (ImiD) (e.g., thalidomide, lenalidomide,pomalidomide [POM]), and one anti-CD38 monoclonal antibody (e.g., daratumumab,isatuximab)

• Patients must have measurable disease, defined as:

• Serum M-protein ≥ 0.5 g/dL (≥ 5 g/L)

• Urine M-protein ≥ 200 mg/24 h

• Serum free light chain (FLC) assay: "involved" FLC level ≥ 10 mg/dL (≥ 100mg/L) and an abnormal serum free light chain ratio (< 0.26 or > 1.65)

• Note: Patients with non-secretory disease will be allowed to participate

• Age ≥ 18 years

• Because no dosing or adverse event data are currently available on the use ofiberdomide in combination with teclistamab in patients < 18 years of age,children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60)

• Hemoglobin ≥ 7.0 g/dL (≤ 28 days prior to registration) (Without growth factorsupport, blood transfusion, or platelet stimulating agents for the past 7 days,excluding erythropoietin)

• Absolute neutrophil count ≥ 1,000/mcL (≤ 28 days prior to registration) (Withoutgrowth factor support, blood transfusion, or platelet stimulating agents for thepast 7 days, excluding erythropoietin)

• Platelets ≥ 50,000/mcL (≤ 28 days prior to registration) (Without growth factorsupport, blood transfusion, or platelet stimulating agents for the past 7 days,excluding erythropoietin)

• Total bilirubin ≤ 2 x institutional upper limit of normal (ULN) (≤ 28 days prior toregistration)

• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN (≤ 28 days prior to registration)

• Estimated glomerular filtration rate (eGFR) > 30 mL/min (≤ 28 days prior toregistration)

• Spot urine (albumin/creatine ratio) ≤ 500mg/g (56 mg/mmol) OR urine dipsticknegative/trace (if > 1+ only eligible if confirmed ≤ 500 mg/g (56 mg/mmol) byalbumin/creatinine ratio (spot urine from first void) (≤ 28 days prior toregistration)

• Note: Laboratory results obtained during screening should be used to determineeligibility criteria. In situations where laboratory results are outside thepermitted range, the investigator may re-test the subject and the subsequent withinrange screening result may be used to confirm eligibility

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging donea minimum of 28 days after completion of central nervous system (CNS)-directedtherapy shows no evidence of progression

• Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are eligible if the treating physician determines thatimmediate CNS specific treatment is not required and is unlikely to be requiredduring the first cycle of therapy

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class II or better

• Based on the mechanism of action, teclistamab may cause fetal harm when administeredto a pregnant woman. Females of child-bearing potential (FCBP): should use effectivecontraception during treatment with teclistamab and for 5 months after the lastdose. FCBP should not breast feed during treatment with teclistamab and for 5 monthsafter the last dose. Should a FCBP become pregnant or suspect she is pregnant whileshe or her partner is participating in this study, she should inform her treatingphysician immediately. The effects of iberdomide on the developing human fetus areunknown. However, IMiDs are known to be teratogenic. FCBP must have a negative serumor urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 daysprior to starting iberdomide, and again within 24 hours. FCBP must either commit tocontinued abstinence from heterosexual intercourse or begin two acceptable methodsof birth control-one highly effective method and one additional effective method-atthe same time, at least 28 days before starting iberdomide, while taking iberdomide,and for 28 days following discontinuation from the study. Examples of highlyeffective methods are intrauterine device, hormonal contraceptives, tubal ligation,or partner's vasectomy. Examples of barrier method are male condom, diaphragm, orcervical cap. FCBP must also agree to ongoing pregnancy testing. Men must practicecomplete abstinence or agree to use a condom during sexual contact with FCBP whileparticipating in the study, during dose interruptions, and for at least 28 daysfollowing discontinuation from the study, even if he has undergone a successfulvasectomy. All patients must be counseled at a minimum of every 28 days aboutpregnancy precautions and risk of fetal exposure

• Men must agree to abstain from donating and semen or sperm while taking iberdomide,during dose interruptions, and for at least 28 days after the last dose ofiberdomide. FCBP must agree not to donate eggs (ova, oocytes) for the purpose ofreproduction during this period

• All patients must agree to abstain from donating blood products while takingiberdomide and for at least 28 days after the last dose of iberdomide

• Ability to understand and the willingness to sign a written informed consentdocument. Legally authorized representatives may sign and give informed consent onbehalf of study subjects

• Willingness to adhere to the study visit schedule and other protocol requirementsand provide mandatory blood and bone marrow specimens for correlative research

• Willingness to return to the enrolling institution for follow-up

Exclusion Criteria:

• Patients who have active plasma cell leukemia, active amyloid light chain (AL) (primary) amyloidosis, active polyneurophathy, organomegaly, endocrinopathy,monoclonal gammopathy and skin changes (POEMS) syndrome (polyneuropathy,organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, myelomaprotein, and skin changes), and Waldenstrom macroglobulinemia are ineligible

• If a patient develops recurrent/refractory (R/R) disease while receiving the mostrecent line of therapy, there is no need for a washout period

• Patients who have had prior anti-BCMA directed bispecific antibody (BsAb) therapyexposure (prior treatment with anti-BCMA directed antibody drug conjugate,anti-BCMA-directed chimeric antigen receptor (CAR) T cell therapy, and priornon-BCMA-targeting BsAb are permitted)

• Patients who have had prior treatment with a cereblon E3 ligase modulator, includingmezigdomide, iberdomide, and CFT7455 (all currently in clinical development)

• Patients who received plasmapheresis ≤ 7 days prior to registration

• Patients who received a prior allogeneic stem cell transplant. Autologous SCT isallowed

• Patients who received a live or live-attenuated vaccine ≤ 30 days prior toregistration. Patients are allowed to receive a COVID-19 vaccine at any timepointduring protocol treatment

• Systemic active infection requiring treatment

• Any unresolved toxicity ≥ grade 2 from previous treatment except for alopecia orperipheral neuropathy up to grade 2

• Patients who have had any major surgery ≤ 4 weeks prior to registration

• Patients with uncontrolled intercurrent illness or any other significantcondition(s) that would make this protocol unreasonably hazardous

• Patients with evidence of active mucosal or internal bleeding

• Current unstable liver or biliary disease per investigator assessment defined by thepresence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal orgastric varices, persistent jaundice, or cirrhosis. Stable chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) or hepatobiliaryinvolvement of malignancy is acceptable if participant otherwise meets entrycriteria

• Patients with known immediate or delayed hypersensitivity reaction or idiosyncraticreaction to drugs chemically related to teclistamab or iberdomide, or any of thecomponents of the study treatment

• Patients who are taking any anticancer therapy other than hormonal therapy (forprostrate or breast cancer) and palliative radiotherapy (defined as radiation to ≤ 3sites of active multiple myeloma)

• Patients who require immunosuppressive medications including, but not limited to,systemic corticosteroids at doses exceeding 10 mg/day of prednisone or equivalent.Use of immunosuppressive medications for the management of iberdomide-relatedadverse events (AEs) or in subjects with contrast allergies is acceptable. Inaddition, use of inhaled, topical, intranasal corticosteroids or local steroidinjection (e.g., intra-articular injection) is permitted. Temporary use ofcorticosteroids for concurrent illnesses (e.g., food allergies, computed tomography [CT] scan contrast hypersensitivity, pneumonia, etc.) are acceptable

• Patients who require medications that are strong inhibitors or inducers of CYP3A4/5

• Patients who are receiving any other investigational agents

• Patients with uncontrolled intercurrent illness or any other significantcondition(s) that would make participation in this protocol unreasonably hazardous

• Pregnant women are excluded from this study because iberdomide is a thalidomideanalog and thalidomide is a known human teratogen. Because there is an unknown butpotential risk for adverse events in nursing infants secondary to treatment of themother with iberdomide, breastfeeding should be discontinued if the mother istreated with iberdomide. These potential risks may also apply to other agents usedin this study

• Patients who are unable or unwilling to undergo protocol required thromboembolismprophylaxis are excluded