Subcutaneous Daratumumab, Once Weekly Carfilzomib, and Dexamethasone (DKd) in Patients With High-Risk Smoldering Multiple Myeloma

Background: Multiple myeloma (MM) is a tumor in which malignant plasma cells accumulate in the bone marrow. It can cause organ damage and is not curable. Researchers want to see if a combination drug treatment can help. Objective: To try to prevent or slow down developing MM and its associated organ damage by treating it while still in the smoldering phase with a mix of drugs known as DKd. Eligibility: People ages 18 and older with smoldering MM that is at high risk of converting to symptomatic MM. Design: Participants will be screened with: Medical history Physical exam Blood and urine tests Bone survey (x-rays of their bones) Spinal magnetic resonance imaging Bone marrow biopsy (a needle is used to remove bone marrow from their hipbone) Electrocardiogram (to check heart function) Lung function tests Treatment will be given in 28-day cycles. Participants will get daratumumab by injection under the skin. They will get carfilzomib intravenously (IV) through a tube inserted in a vein. They will get dexamethasone as oral tablets or as an IV. They will get all 3 drugs for 8 or 12 cycles. Then they will get daratumumab alone for up to 24 cycles. They may have stem cells collected. Participants will have frequent study visits. At these visits, they will repeat some screening tests. They will complete questionnaires. They will have imaging scans. For these scans, they may receive an oral or IV contrast. Participants will have a follow-up visit 30 days after treatment ends. Then they will have visits every 3-12 months. They will be followed on this study for life.

* INCLUSION CRITERIA: * Patients must have histologically or cytologically confirmed smoldering multiple myeloma (SMM) based on the International Myeloma Working Group Criteria: * Serum M-protein \>=3 g/dl and/or bone marrow plasma cells \>=10 % and \10 g/dl * Absence of renal failure: serum creatinine \10 mg/dL AND abnormal kappa/lambda serum free light chain ratio (reference 0.26-1.65) * Because the primary endpoint is MRD (-) remission rate, per the discretion of the Principal Investigator, patients without measurable disease in the serum (e.g., Mspike \=18 years. * ECOG performance status \=1.0 K/uL NOTE: At the discretion of the investigator, patients with an ANC of 0.5 K/uL -1.0 K/uL may also be enrolled if clinically appropriate (e.g., patients with a baseline neutropenia that is chronic and that does not cause complications). * platelets \>=75 K/uL * hemoglobin \> =8 g/dL, for anemia not due to MM (transfusions are permissible) * total bilirubin = \=20%, * Serum monoclonal protein \>=2 g/dL * Serum free light chain ratio of \>=20 * Criteria 2: Spanish PETHEMA, high-risk defined as: * Immunoparesis (depression of one of the uninvolved immunoglobulin isotypes in the total serum immunoglobulin assay, AND --\>=95% aberrant plasma cells on bone marrow aspirate flow cytometry * Criteria 3: Rajkumar, Landgren, Mateos may also be used to define high risk disease, namely clonal bone marrow plasma cells \>=10% AND any one or more of the following: * Serum M protein \>=30g/L, * IgA SMM, * Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes, * Serum involved/uninvolved FLC ratio \>=8 (but \=25% on 2 successive evaluations within a 6-month period), * Clonal BMPCs 50%-60%, * Abnormal PC immunophenotype ( (Bullet)95% of BMPCs are clonal) and reduction of \>=1 uninvolved immunoglobulin isotypes, * t(4;14) or del(17p) or 1q gain, * Increased circulating PCs, * MRI with diffuse abnormalities or 1 focal lesion, AND/OR PET-CT with focal lesion with increased uptake without underlying osteolytic bone destruction * The effects of carfilzomib and daratumumab on the developing human fetus are unknown. For this reason, individuals of child-bearing potential (IOCBP) and individuals who can father children must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 3 months after daratumumab and/or 6 months after the last dose of carfilzomib, whichever is longer. Individuals who can father children must use adequate contraception during treatment and for 3 months after stopping daratumumab and/or carfilzomib. * Negative serum or urine pregnancy test at screening for IOCBP. * Ability of subject to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: * Patients who are receiving any other investigational agents. * Prior therapy for SMM. At the discretion of the investigator, exceptions might be made depending on prior treatments received and response to those treatments, provided that by the start of protocol therapy, there will be a 4-week washout period. Exceptions will not be made for patients who have received the current DKd with daratumumab maintenance regimen nor any other regimen consisting of daratumumab and a proteasome inhibitor (e.g., bortezomib, ixazomib). Treatment with corticosteroids for other indications is permitted. * Contraindication to any concomitant medication, including support/prophylaxis for infusion reaction, antiviral, antibacterial, anticoagulation or tumor lysis given prior to therapy. * Patient has either of the following: --Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) \160 mm Hg) or diabetes (chronic clinical signs/symptoms of hyperglycemia and/or an A1c value \>9%). * Significant cardiovascular disease with NYHA Class II, III or IV symptoms, or hypertrophic cardiomegaly, or restrictive cardiomegaly, or myocardial infarction within 3 months prior to enrollment, or unstable angina, or unstable arrhythmia. * No studies of carfilzomib or daratumumab have been conducted on nursing individuals and it is not known if it is excreted in milk. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, nursing should be discontinued if the mother is treated with carfilzomib/daratumumab. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, cardiac arrhythmia, venous thromboembolic disease, hemorrhage, pulmonary fibrosis, pneumonitis, or psychiatric illness/social situations that would limit compliance with study requirements.