Comparing Combinations of Drugs to Treat Newly Diagnosed Multiple Myeloma (NDMM) When a Stem Cell Transplant is Not a Medically Suitable Treatment

Inclusion Criteria:

• Participants must have documented multiple myeloma satisfying standard InternationalMyeloma Working Group (IMWG) diagnostic criteria within 28 days prior to registration
• Participants must have measurable disease within 28 days prior to registration asdefined by any of the following:
• Immunoglobulin (Ig) G myeloma (serum monoclonal paraprotein [M-protein] level >= 0.5 gram/deciliter [g/dL] or urine M-protein level >= 200 milligram[mg]/24hours[hrs]); OR
• IgA, IgM, IgD, or IgE multiple myeloma (serum M-protein level >= 0.2 g/dL orurine M-protein level >= 200 mg/24 hrs); OR
• Light chain multiple myeloma (serum immunoglobulin free light chain >= 10 mg/dLand abnormal serum immunoglobulin kappa lambda free light chain ratio)
• All disease must be assessed and documented on the baseline/pre-registration tumorassessment form
• Participants must have a calculated myeloma frailty index (Myeloma Frailty ScoreCalculator; http://www.myelomafrailtyscorecalculator.net/) categorized as frail orintermediate fit (regardless of age) within 28 days prior to registration
• For Participants Meeting "Frail" Status:
• Participants with any degree of kidney dysfunction are allowed; however,participants on dialysis are not eligible
• For Participants Meeting "Frail" Status:
• Hemoglobin >= 7 g/dL (must be performed within 28 days prior to registration)
• Note: growth factor and transfusion utilization are allowed if cytopeniasare considered secondary to bone marrow involvement from MM)
• For Participants Meeting "Frail" Status:
• Platelets >= 50 x 10^9/L (must be performed within 28 days prior to registration)
• Note: growth factor and transfusion utilization are allowed if cytopeniasare considered secondary to bone marrow involvement from MM)
• For Participants Meeting "Frail" Status:
• Absolute neutrophil count (ANC) >= 0.75 x10^9/L (must be performed within 28 daysprior to registration)
• Note: growth factor and transfusion utilization are allowed if cytopeniasare considered secondary to bone marrow involvement from MM)
• For Participants Meeting "Intermediate Fit" Status, one or more of the followingcriteria must be present:
• Kidney dysfunction showing calculated creatinine clearance (CrCl) <30 ml/min.
• Actual lab serum creatinine value with a minimum of 0.7 mg/dL.
• Participants must have bone marrow function assessed and meet the below criteriaranges:
• Hemoglobin between 7-8 g/dL, OR
• Platelets between 50-75 x10^9/L, OR
• ANC between 0.75-1 x10^9/L
• Note: growth factor and transfusion utilization are allowed as long ascytopenias are considered secondary to bone marrow involvement from MM)
• Revised International Staging System (R-ISS) stage III disease
• Note: All labs must be performed within 28 days prior to registration
• Participants must have a complete medical history and physical exam within 28 daysprior to registration
• Participants must have whole body imaging within 60 days prior to registration. Therecommended method of imaging is a positron emission tomography/computed tomography (PET/CT); a low-dose whole body CT scan or whole-body magnetic resonance imaging (MRI)or skeletal survey should be done only if a PET/CT scan cannot be done or isnon-feasible. This must be documented in the comments section of the Onstudy form.
• Total bilirubin =< 2 times institutional upper limit of normal (ULN) unless history ofGilbert's disease. Participants with history of Gilbert's disease must have totalbilirubin =< 5 x institutional ULN (within 28 days prior to registration)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 × institutionalULN (within 28 days prior to registration)
• Participants must have adequate cardiac function, as assessed by the treatingphysician within 14 days prior to registration. Participants with known history orcurrent symptoms of cardiac disease, or history of treatment with cardiotoxic agents,must have a clinical risk assessment of cardiac function using the New York HeartAssociation Functional Classification and must not be assessed as class 3 or 4
• Participants with known diabetes must show evidence of controlled disease within 14days prior to registration. Uncontrolled diabetes is defined as: A glycosylatedhemoglobin (Hg)A1C > 7
• Participants with known human immunodeficiency virus (HIV)-infection must be receivinganti-retroviral therapy and have an undetectable viral load test on the most recenttest result obtained, within 6 months prior to registration
• All participants with evidence of chronic hepatitis B virus (HBV) infection must haveundetectable HBV viral load on suppressive therapy within 28 days prior toregistration
• Participants with a history of hepatitis C virus (HCV) infection must have beentreated and cured. For participants with HCV infection who are currently on treatment,participant must have an undetectable HCV viral load within 28 days prior toregistration
• Participants must have an Eastern Cooperative Oncology Group (ECOG)/Zubrod performancestatus score of 0-2 (Note: Participants with ECOG/Zubrod performance score [PS] 3,especially where the deterioration of PS is considered secondary to the MM diagnosis,will be allowed)
• Participants must be offered the opportunity to participate in specimen banking. Withparticipant consent, specimens must be collected and submitted via the SouthwestOncology Group (SWOG) specimen tracking system
• Participants who are able to complete the patient-reported outcomes measures inEnglish or Spanish must agree to participate in the PRO portion of the study
• Participants must be informed of the investigational nature of this study and mustsign and give informed consent in accordance with institutional and federalguidelines. For participants with impaired decision-making capabilities, legallyauthorized representatives may sign and give informed consent on behalf of studyparticipants in accordance with applicable federal, local, and Central InstitutionalReview Board (CIRB) regulations

Exclusion Criteria:

• Participants must not have received any prior systemic therapy for multiple myelomawith the exception of any one or more of the following:
• An emergency use of a short course of corticosteroids (equivalent ofdexamethasone 160 mg) any time before registration, or
• Up to one complete cycle of a non-daratumumab and hyaluronidase-fihj containinganti-myeloma regimen (1 cycle = 21 or 28 days depending on the regimen beingused), or
• Localized palliative radiation therapy for multiple myeloma, as long as theradiation therapy is completed at least 3 days prior to starting the systemictreatment as per the study protocol.
• Participants must not have evidence of grade 4 peripheral neuropathy prior to studyregistration
• Participants must not have uncontrolled blood pressure within 14 days prior toregistration. Uncontrolled blood pressure: systolic blood pressure (SBP) > 140 mmHg ordiastolic blood pressure (DBP) > 90 mmHg. Participants are permitted to be receivingmultiple anti-hypertensive medications (unless otherwise indicated in the study). Allblood pressure measurements within the 14 days prior to registration must be SBP =< 140 and DBP =< 90. A participant with a single blood pressure elevation who uponrechecking has a normal blood pressure will remain eligible at the discretion of theregistering investigator.
• Participants must not have a prior or concurrent malignancy whose natural history ortreatment (in the opinion of the treating physician) has the potential to interferewith the safety or efficacy assessment of the investigational regimen.
• Participants must not be pregnant or nursing. Individuals who are of reproductivepotential must have agreed to use an effective contraceptive method with detailsprovided as a part of the consent process. A person who has had menses at any time inthe preceding 24 consecutive months or who has semen likely to contain sperm isconsidered to be of "reproductive potential." In addition to routine contraceptivemethods, "effective contraception" also includes refraining from sexual activity thatmight result in pregnancy and surgery intended to prevent pregnancy (or with aside-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy,bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in thesemen.