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

* 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 \<60%
  * Absence of anemia: hemoglobin \>10 g/dl
  * Absence of renal failure: serum creatinine \<2.0 mg/dL
  * Absence of hypercalcemia: Ca \<10.5 mg/dl or 2.62 mmol/L
  * Absence of lytic bone lesion on X-ray, CT, or PET/CT and not more than 1 lesion on spinal MRI (NOTE: At the discretion of the investigator, PET/CT may replace MRI in patients who have a contraindication to MRI.)
  * Involved/un-involved light chain ratio must be \< 100 (unless involved light chain is \<=10 mg/dL)
* Measurable disease within the past 4 weeks defined by any one of the following:

  * Serum monoclonal protein \>= 0.5 g/dl
  * Urine monoclonal protein \>200 mg/24 hour
  * Serum immunoglobulin free light chain \>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 \<0.5 g/dL) may also be enrolled. This is in line with the most recent IMWG MM response criteria.
* Age \>=18 years.
* ECOG performance status \<=2
* Patients must have adequate organ and marrow function as defined below:

  * absolute neutrophil count (ANC) \>=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 = \<1.5 X institutional upper limit of normal
* AST(SGOT)/ALT(SGPT) =\<3.0 X institutional upper limit of normal
* creatinine within normal institutional limits, OR
* If creatinine is outside of the normal limits, then creatinine Clearance (CrCl) or Egfr (estimated glomerular filtration Rate) \>=40 ml/min calculated by Cockcroft-Gault method, modification of diet in renal disease (MDRD), or the chronic kidney disease (CKD)-epidemiology collaboration (EPI) (institutional standard) equations.

  -In addition to having SMM, patients must also be classified as high-risk SMM per at least one of three criteria below:
* Criteria 1: Mayo Clinic 2018, high-risk defined with two of the following:

  * Bone marrow plasmacytosis \>=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 \<100),
  * Progressive increase in M protein level (evolving type of SMM; increase in serum M protein by \>=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) \<50% of predicted normal.

  ---Known moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. NOTE: Subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.
* Seropositive for human immunodeficiency virus (HIV). HIV-infected patients on effective anti-retroviral therapy with undetectable viral load for at least the 3 months prior to enrollment are eligible for this trial.
* Active hepatitis B infection. NOTE: Patients who are hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive will need to have a negative HBV PCR result before enrollment. Those with a positive PCR for hepatitis B are excluded.
* Seropositive for hepatitis C (except in the setting of a sustained virologic response \[SVR\], defined as aviremia at least 12 weeks after completion of antiviral therapy).
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to carfilzomib or daratumumab or other agents used in study.
* Current uncontrolled hypertension (chronic systolic blood pressures \>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.