Patients With Newly Diagnosed Multiple Myeloma Comparing KTd vs. KRd Induction Therapy and Investigating a K-mono Maintenance Strategy

Inclusion Criteria:

* Able to provide written informed consent in accordance with federal, local, and institutional guidelines
* newly diagnosed, symptomatic multiple myeloma
* Transplant-ineligibility: age \> 65 years or patients not eligible due to comorbidities determined by investigator or patients not willing to undergo autologous stem-cell transplantation (ASCT) on personal preference
* Measurable disease, as defined by one or more of the following (assessed within 21 days prior to randomization):

  * Serum M-protein ≥ 0.5 g/dL, or
  * Urine M-protein ≥ 200 mg/24 hours, or
  * In subjects without detectable serum or urine M-protein, serum-free light chain (SFLC) \> 100 mg/L (involved light chain) and an abnormal κ/λ ratio
* No prior treatment for multiple myeloma
* Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1
* Patients at cardiac risk (NYHA \>II or pre-existing coronary heart disease or any other relevant cardiac complication) should be scheduled for a baseline echocardiography (ECHO) and can only be included if the left ventricular ejection fraction (LVEF) is ≥40%); independent of cardiac risk ECG has to be done for inclusion of Asian patients and patients \> 75 years of age
* Adequate organ and bone marrow function within the 21 days prior to randomization defined by:

  * Bilirubin \< 2 times the upper limit of normal (ULN), Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 times the ULN
  * growth factor support for max 3 days allowed to achieve an absolute neutrophil count (ANC) ≥ 1000/mm3 (screening ANC should be of required)
  * Hemoglobin ≥ 7.0 g/dL; use of erythropoietic stimulating factors and red blood cell (RBC) transfusion per institutional guidelines is allowed, however the most recent RBC transfusion may not have been done within 7 days prior to obtaining screening hemoglobin.
  * Platelet count ≥ 30,000/mm3
* Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min. Calculation should be based on the Cockcroft and Gault formula: \[(140 - Age) ∙ Mass (kg) / (72 ∙ Creatinine mg/dL)\]; multiply result by 0.85 if female
* Females of childbearing potential (FCBP) must have a confirmed negative serum pregnancy test within the 21 days prior to randomization (performed at a central laboratory).
* Females of childbearing potential and male subjects who are sexually active with FCBP must agree to use effective concomitant method(s) of contraception during the study and for 30 days (women) and 90 days (men) following the last study drug treatment administration.

Exclusion Criteria:

* ECOG ≥2
* Frail patients
* Waldenström macroglobulinemia
* POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
* Plasma cell leukemia (\> 2.0 × 109/L circulating plasma cells by standard differential)
* Myelodysplastic syndrome
* Smoldering myeloma and monoclonal gammopathy of undetermined significance (MGUS)
* Second malignancy within the past 5 years except:

  * Adequately treated basal cell or squamous cell skin cancer
  * Carcinoma in situ of the cervix
  * Prostate cancer ≤ Gleason score 6 with stable prostate-specific antigen (PSA over 12 months
  * Ductal breast carcinoma in situ with full surgical resection (i.e., negative margins)
  * Treated medullary or papillary thyroid cancer
  * Similar condition with an expectation of \> 95% five-year disease-free survival
* History of or current amyloidosis
* Immunotherapy within the 21 days prior to randomization
* Glucocorticoid therapy within the 14 days prior to randomization that exceeds accumulative dose of 160 mg dexamethasone or 1000 mg prednisone
* Extended field radio therapy (more than 3 fields) within the 21 days prior to randomization
* Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib) or any other component of formulation
* Contraindication to dexamethasone, thalidomide or lenalidomide or any of the required concomitant drugs, supportive treatments or antiviral drugs, also including contraindication or hypersensitivity to any other components of these drugs (eg. hereditary galactose intolerance, complete lactase deficiency or glucose-galactose malabsorbtion in case of excipient lactose)
* Active congestive heart failure (New York Heart Association \[NYHA\] Class III or IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, acute diffuse infiltrative pulmonary disease, pericardial disease, or myocardial infarction within 4 months prior to enrollment
* Active infection within the 14 days prior to randomization requiring systemic antibiotics and/or antiviral therapy
* Pleural effusions requiring thoracentesis within the 14 days prior to randomization
* Ascites requiring paracentesis within the 14 days prior to randomization
* Uncontrolled hypertension or uncontrolled diabetes despite medication
* Significant neuropathy (Grade 2 with pain or Grade 3 or higher) within the 14 days prior to randomization
* Known cirrhosis
* Known human immunodeficiency virus (HIV) seropositivity, hepatitis C infection, or hepatitis B infection: subjects with past hepatitis B virus (HBV) infection or resolved HBV infection defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen (HBc) antibody test are eligible; subjects positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
* Participation in another interventional study within the 28 days prior to randomization
* Major surgery (except kyphoplasty) within the 28 days prior to randomization
* Female subjects who are pregnant or lactating
* Any other clinically significant medical disease or social condition that, in the investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent, be compliant with study procedures, or provide accurate information.