This study is being done to find out whether carfilzomib, lenalidomide, and dexamethasone (KRD) or KRD and Daratumumab (KRD+DARA) might be safer and more effective ways of controlling multiple myeloma than the standard of care treatment, which is lenalidomide, bortezomib, and dexamethasone (VRD).

Per protocol amendment version 4.0 (May 23, 2022), Arm A will be closed and no additional participants will be enrolled in this arm.

Inclusion Criteria:

1. Newly diagnosed patients with histologically confirmed Multiple Myeloma (MM) based on the IMWG diagnostic criteria and measurable disease within the past 4 weeks (or past 8 weeks if patient received pre-study MM therapy) based on one of the following:

   • Serum monoclonal protein ≥ 1.0 g/dL
   • Urine monoclonal protein ≥ 200 mg/24 hour
   • Involved serum immunoglobulin free light chain ≥ 10 mg/dL and abnormal kappa/lambda ratio.

2. Evidence of underlying end organ damage and/or myeloma defining event attributed to underlying plasma cell proliferative disorder meeting at least one of the following (Note: Myeloma defining event does not need to be based on repeat testing done at screening, if previous pathology, radiology, etc., confirm diagnosis of myeloma per IMWG)

   • Hypercalcemia: serum calcium >0.25 mmol/L (> 1 mg/dL) above upper limit of normal or ≥ 2.75 mmol/L (11 mg/dL)

   • Anemia: hemoglobin value <10 g/dL or > 2 g/dL below lower limit of normal

   • Bone disease: ≥ 1 lytic lesions on skeletal X-ray, CT, or Positron Emission Tomography (PET)-C. For patients with 1 lytic lesion, bone marrow should demonstrate ≥10% clonal plasma cells

   • Clonal bone marrow plasma cell percentage ≥60%

   • Involved/un-involved serum free light chain ratio ≥100 and involved free light chain

     ≥100 mg/L.

   • > 1 focal lesion on magnetic resonance imaging study (lesion must be >5 mm) in size

   • For patients with 1 lytic lesion, bone marrow should demonstrate ≥10% clonal plasma cells

3. Creatinine Clearance (CrCl) ≥ 60 ml/min. CrCl can be measured or estimated using Cockcroft-Gault method, Modification of Diet in Renal Disease (MDRD), or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulae

4. Age ≥ 18 years at the time of signing the informed consent documentation. Age limit of ≤ 75 years.

5. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

6. Absolute neutrophil count (ANC) ≥ 1.0 K/microliter (uL), hemoglobin ≥ 8 g/dL, and platelet count ≥ 75 K/uL, unless if cytopenias are deemed to be due disease at discretion of clinical investigator. Transfusions and growth factors are permissible.

7. Adequate hepatic function, with bilirubin < 1.5 x the pper Limit of Normal (ULN), and Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) < 3.0 x ULN.

8. All study participants must be able to tolerate one of the following thromboprophylactic strategies: aspirin, oral facto Xa inhibitors, low molecular weight heparin, warfarin (coumadin), or alternative anti-coagulant.

9. All study participants must be registered into the mandatory electronic REMS (eREMS) program and be willing and able to comply with the requirements of Risk Evaluation Management and Safety (REMS).

10. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) 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. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy.

A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Exclusion Criteria:

1. Patients receiving >1 cycle of prior treatment or concurrent systemic treatment for multiple myeloma:

   • Treatment of hypercalcemia or spinal cord compression or aggressively progressing myeloma with current or prior corticosteroids is permitted
   • Bone targeting agents are permitted
   • Concurrent or prior treatment with corticosteroids for indications other than multiple myeloma is permitted
   • Prior treatment with radiotherapy is permitted
   • Prior MM treatments, such as Immunomodulating Drugs (IMIDs) or non-MM drugs in clinical trials for smoldering myeloma is permitted with a washout period of 2 weeks from last dose. Smoldering patients previously treated with carfilzomib are excluded.
   • Patients with measurable disease who received up to one cycle of any therapy within 60 days with a washout period of 2 weeks from last dose (on a trial or outside a trial) are eligible (Note: Measurable disease is defined as one or more of the following: Serum monoclonal protein ≥ 1.0 g/dL, Urine monoclonal protein ≥ 200 mg/24 hour and/ or Involved serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal kappa/lambda ratio)

2. Prior or current exposure to any of the following:

   • To daratumumab or other anti- Cluster of Differentiation (CD) -38 therapies (unless a re-treatment study)
   • Exposure to an investigational drug (including investigational vaccine) or invasive investigational medical device for any indication within 4 weeks or 5 pharmacokinetic half-lives, whichever is longer.
   • Focal radiation therapy within 14 days prior to randomization with the exception of palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma.

3. Patients with plasma cell leukemia

4. Patients with Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes syndrome (POEMS syndrome)

5. Patients with amyloidosis

6. Patients with known Chronic Obstructive Pulmonary Disorder (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD, and subjects must be excluded if FEV1 <50% of predicted normal.

7. Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.

8. Pregnant or lactating females. Because there is a potential risk for AEs in nursing infants secondary to treatment of the mother with carfilzomib in combination with lenalidomide, pregnant or lactating females are excluded from study participation. These potential risks may also apply to other agents used in this study.

9. Uncontrolled hypertension (i.e., systolic blood pressure (BP) >160 mmHg, diastolic BP > 100 mmHg)

10. Uncontrolled diabetes (i.e., two independent glucose readings >200 mg/dL)

11. Active hepatitis B or C infection

12. Subject is:

    • Seropositive for human immunodeficiency virus (HIV)
    • Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core (HBc) antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (RT-PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR.
    • 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).
    • Patients with active Coronavirus Disease of 2019 (COVID-19) infection are not to be enrolled until 10 days have passed from the initial positive test, and the patient is symptom-free. COVID-19 vaccinations following national guidelines (i.e., CDC) are encouraged; however, the series should be completed prior to the first day of study treatment. If this is not possible, every effort should be made to administer vaccines at a time when patient is not scheduled to receive study treatment (e.g., "off-weeks").

13. Clinically significant cardiac disease, including:

    • Myocardial infarction within 6 months before randomization, or unstable or uncontrolled disease/condition related to or affection cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association (NYHA) Class III-IV) or a left ventricular ejection fraction of <40%.
    • Uncontrolled cardiac arrhythmia
    • Intolerance to hydration due to pre-existing pulmonary or cardiac impairment.

14. Pulmonary hypertension

15. Has refractory gastrointestinal (GI) disease with refractory nausea/vomiting, inflammatory bowel disease, or bowel resection that would prevent absorption of oral agents

16. Uncontrolled intercurrent illness including but not limited to active infection or psychiatric illness/social situations that would compromise compliance with study requirements

17. Significant neuropathy ≥ Grade 3 or Grade 2 neuropathy with pain at baseline

18. Contraindication to any concomitant medication, including antivirals or anticoagulation

19. Major surgery within 3 weeks prior to first dose