Comparing Teclistamab to Lenalidomide with Dexamethasone for the Treatment of High-Risk Smoldering Multiple Myeloma, Immuno-PRISM Study

Inclusion Criteria

• Age >= 18 years
• High risk SMM defined as having 1 of the following 2 criteria: * High risk per "20-2-20" criteria defined as presence of any two of the following: ** Serum M-spike >= 2 gm/dL ** Involved to uninvolved free light chain (FLC) ratio >= 20 ** Bone marrow plasma cell (BMPC) % >= 20% OR total score of 9 using the following scoring system: ** Free light chain (FLC) ratio *** > 10-25 = 2 *** > 25-40 = 3 *** > 40 = 5 ** Serum M-protein (g/dL) *** > 1.5-3 = 3 *** > 3 = 4 ** Bone marrow plasma cells (BMPC) % *** > 15-20 = 2 *** > 20-30 = 3 *** > 30-40 = 5 *** > 40 = 6 ** Fluorescence in situ hybridization (FISH) abnormality (t[4,14], t[14,16], 1q gain, or del13q = 2) * Presence of >=10% BMPC and at least one of the following: ** Evolving pattern: *** Evolving m-protein (eMP) (>= 10% increase in serum M-protein) over a 6 month period OR; *** Evolving change in hemoglobin (eHb) >= 0.5 g/dl decrease over a 12 month period OR; *** Progressive involved light chain increase > 10% over a 6 month period along with a light chain ratio >= 8 ** Abnormal plasma cell (PC) immunophenotype (>= 95% of BMPCs are clonal) and reduction of >= 1 uninvolved immunoglobulin isotype. (Only immunoglobulin [Ig]G; IgA and IgM will be considered) ** High risk cytogenetics defined as presence of t(4;14), t(14;16), t(14;20), 17p deletion, TP53 mutation, 1q gain ** Monoclonal light chain excretion of >= 200mg/24 hours for those with monoclonal light chain smoldering multiple myeloma *** Of note- Patients with biclonal smoldering myeloma will be included and followed by their dominant clone for response
• No evidence of calcium elevation, renal dysfunction, anemia and bone disease (CRAB) criteria or new criteria of active MM (60% or more clonal plasma cells, light chains, and MRI [SLIM]-CRAB) which include the following: * Increased calcium levels: Corrected serum calcium > 0.25 mmol/L (> 1mg/dL) above the upper limit of normal or > 2.75 mmol/L (> 11mg/dL); * Renal insufficiency (attributable to myeloma); * Anemia (hemoglobin [Hgb] 2g/dL below the lower limit of normal or < 10g/dL); * Bone lesions (lytic lesions or generalized osteoporosis with compression fractures) * No evidence of the following new criteria for active MM including the following: ** Bone marrow plasma cells > 60% ** Serum involved/uninvolved FLC ratio >= 100 *** Serum involved/uninvolved FLC ratio >= 100 is not considered a myeloma defining events (MDE) if urinary monoclonal protein is < 200mg/24 hours ** MRI with more than one focal lesion * Participants with CRAB criteria that are attributable to conditions other than the disease under study may be eligible after discussion with the sponsor investigator
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
• Absolute neutrophil count (ANC) > 1000/mL (obtained < 28 days prior to registration)
• Platelets (PLT) > 75,000/mL (obtained < 28 days prior to registration)
• Total bilirubin =< 2.0 mg/dL (if total is elevated check direct and if normal patient is eligible) (obtained < 28 days prior to registration)
• Aspartate aminotransferase (AST) < 2.5 x institutional upper limit of normal (ULN) (obtained < 28 days prior to registration)
• Alanine aminotransferase (ALT) < 2.5 x institutional upper limit of normal (ULN) (obtained < 28 days prior to registration)
• Estimated creatinine clearance (CLcr) >= 60 mL/min (obtained < 28 days prior to registration)
• All female participants of child-bearing potential must have a negative pregnancy test before enrollment. Females of child-bearing potential randomized to lenalidomide must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days as required by Revlimid Risk Evaluation and Mitigation Strategy [REMS]®) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide * A female of child-bearing potential is a sexually mature female who: ** Has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries), or ** Has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months) * A woman must be: ** Not of childbearing potential, or ** Of childbearing potential and: *** Practicing true abstinence; or *** Have a sole partner who is vasectomized; or *** Practicing >= 1 highly‑effective, user‑independent method of contraception NOTE: Participant must agree to continue the above throughout the study and for 90 days after the last dose of study treatment NOTE: If a woman becomes of childbearing potential after start of the study the woman must comply as described above NOTE: An interaction between hormonal contraception and teclistamab has not been formally studied. Therefore, it is unknown whether teclistamab may reduce the efficacy of the contraception method * A woman must agree not to donate eggs (ova, oocytes) or freeze for future use, for the purposes of assisted reproduction during the study and for 90 days after receiving the last dose of study treatment * A man must wear a condom (with or without spermicidal foam/gel/film/cream/suppository) when engaging in any activity that allows for passage of ejaculate to another person during the study and for a minimum of 90 days after receiving the last dose of study treatment. If a female partner is of childbearing potential, she must also be practicing a highly effective method of contraception NOTE: If the male participant is vasectomized, he still must wear a condom (with spermicidal foam/gel/film/cream/suppository), but his female partner is not required to use contraception * A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 90 days after receiving the last dose of study treatment * Must be willing and able to adhere to the lifestyle restrictions specified in this protocol
• All study participants randomized to lenalidomide must be registered into the mandatory Revlimid REMS® program and be willing and able to comply with the requirements of the REMS® program
• Females of child-bearing potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program if randomized to lenalidomide
• Men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy
• Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria

• Prior SMM directed therapy administered within 6 months of beginning treatment on study. To avoid including primary refractory cases to the lenalidomide arm, participants who received a prior lenalidomide-based therapy should have had at least an MR to be considered on this trial
• Symptomatic multiple myeloma or any evidence of CRAB criteria, including presence of myeloma defining events (MDE). Any prior therapy for active myeloma should also be excluded. Prior therapy for smoldering myeloma is not an exclusion criterion. Bisphosphonates are not excluded
• Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational. Prior therapy with bisphosphonate is allowed. Prior radiation therapy to a solitary plasmacytoma is allowed but had to be at least 6 months prior to enrollment on the trial. Prior clinical trials or therapy for smoldering MM or monoclonal gammopathy of undetermined significance (MGUS) are allowed per exclusion criteria described above
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study
• Diagnosed or treated for another malignancy within 2 years of enrollment
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Plans to father a child while enrolled in this study or within 90 days after receiving the last dose of study drug
• Pregnant or breast-feeding or planning to become pregnant while enrolled in this study or within 90 days after receiving the last dose of study drug
• Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV)
• Participants who are seropositive because of hepatitis B virus vaccine are eligible
• Participants who are positive for HIV1 and 2 antibody, hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded
• Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug or its excipients (refer to the teclistamab investigator’s brochure and appropriate package inserts)
• Prior or concurrent exposure to any of the following: * Investigational vaccine within 4 weeks * Live, attenuated vaccine within 4 weeks before randomization * Monoclonal antibody therapy within 21 days * Cytotoxic therapy within 14 days * Proteasome inhibitor (PI) therapy within 14 days * Immunomodulatory imide drug (IMiD) agent therapy within 14 days * Radiotherapy within 14 days or focal radiation within 7 days
• A maximum cumulative dose of corticosteroids of >= 140 mg of prednisone or equivalent within 14-day period before the first dose of study drug (does not include pretreatment medications)
• Known active central nervous system (CNS) involvement or exhibits clinical signs of meningeal involvement of multiple myeloma. If either is suspected, negative whole brain MRI and lumbar cytology are required
• Myelodysplastic syndrome or active malignancies (i.e., progressing or requiring treatment change in the last 24 months). The only allowed exceptions are: * Non-muscle invasive bladder cancer treated within the last 24 months that is considered completely cured * Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured * Noninvasive cervical cancer treated within the last 24 months that is considered completely cured * Localized prostate cancer (N0M0): ** With a Gleason score of =< 6, treated within the last 24 months, or untreated and under surveillance ** With a Gleason score of 3+4 that has been treated > 6 months prior to full study screening and considered to have a very low risk of recurrence, or * History of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence * Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence * Other malignancy that is considered cured with minimal risk of recurrence
• Stroke or seizure within 6 months prior to signing informed consent form (ICF)
• Presence of the following cardiac conditions: * New York Heart Association stage III or IV congestive heart failure * Myocardial infarction or coronary artery bypass graft =< 6 months prior to randomization * History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration * History of severe non-ischemic cardiomyopathy
• 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 * NOTE: Participants with planned surgical procedures to be conducted under local anesthesia may participate. Kyphoplasty or vertebroplasty are not considered major surgery. If there is a question whether a procedure is considered a major surgery, the investigator must consult with the appropriate sponsor representative and resolve any issues before enrolling a participant in the study
• 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: * Uncontrolled diabetes defined by hemoglobin A1C > 8.5 * Acute diffuse infiltrative pulmonary disease * Evidence of active systemic viral, fungal, or bacterial infection, requiring systemic antimicrobial therapy * 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 * Disabling psychiatric conditions (e.g., alcohol or drug abuse), severe dementia, or altered mental status * 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 (e.g., compromise the wellbeing) or that could prevent, limit, or confound the protocol-specified assessments * History of non-compliance with recommended medical treatments