A Study of Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly-Diagnosed Multiple Myeloma

Inclusion Criteria:

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

• Serum monoclonal protein ≥ 1.0 g/dL

• Urine monoclonal protein ≥ 200 mg/24 hour

• Involved serum immunoglobulin free light chain ≥ 10 mg/dL and abnormalkappa/lambda ratio.

2. Evidence of underlying end organ damage and/or myeloma defining event attributed tounderlying 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 atscreening, if previous pathology, radiology, etc., confirm diagnosis of myeloma perIMWG)

• Hypercalcemia: serum calcium >0.25 mmol/L (> 1 mg/dL) above upper limit ofnormal 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 EmissionTomography (PET)-C. For patients with 1 lytic lesion, bone marrow shoulddemonstrate ≥10% clonal plasma cells

• Clonal bone marrow plasma cell percentage ≥60%

• Involved/un-involved serum free light chain ratio ≥100 and involved free lightchain ≥100 mg/L.

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

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

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

4. Age ≥ 18 years at the time of signing the informed consent documentation. Age limitof ≤ 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, andplatelet count ≥ 75 K/uL, unless if cytopenias are deemed to be due disease atdiscretion of clinical investigator. Transfusions and growth factors arepermissible.

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 followingthromboprophylactic strategies: aspirin, oral facto Xa inhibitors, low molecularweight 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 EvaluationManagement and Safety (REMS).

10. Females of childbearing potential (FCBP) must have a negative serum or urinepregnancy test within 10 - 14 days and again within 24 hours prior to prescribinglenalidomide for Cycle 1 (prescriptions must be filled within 7 days) and musteither commit to continued abstinence from heterosexual intercourse or begin twoacceptable methods of birth control, one highly effective method and one additionaleffective method at the same time, at least 28 days before she starts takinglenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree touse a latex condom during sexual contact with a FCBP even if they have had asuccessful 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 formultiple myeloma:

• Treatment of hypercalcemia or spinal cord compression or aggressivelyprogressing myeloma with current or prior corticosteroids is permitted

• Bone targeting agents are permitted

• Concurrent or prior treatment with corticosteroids for indications other thanmultiple myeloma is permitted

• Prior treatment with radiotherapy is permitted

• Prior MM treatments, such as Immunomodulating Drugs (IMIDs) or non-MM drugs inclinical trials for smoldering myeloma is permitted with a washout period of 2weeks from last dose. Smoldering patients previously treated with carfilzomibare excluded.

• Patients with measurable disease who received up to one cycle of any therapywithin 60 days with a washout period of 2 weeks from last dose (on a trial oroutside a trial) are eligible (Note: Measurable disease is defined as one ormore of the following: Serum monoclonal protein ≥ 1.0 g/dL, Urine monoclonalprotein ≥ 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) orinvasive investigational medical device for any indication within 4 weeks or 5pharmacokinetic half-lives, whichever is longer.

• Focal radiation therapy within 14 days prior to randomization with theexception of palliative radiotherapy for symptomatic management but not onmeasurable extramedullary plasmacytoma.

3. Patients with plasma cell leukemia

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

5. Patients with amyloidosis

6. Patients with known Chronic Obstructive Pulmonary Disorder (COPD) with a forcedexpiratory volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1testing is required for subjects suspected of having COPD, and subjects must beexcluded if FEV1 <50% of predicted normal.

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

8. Pregnant or lactating females. Because there is a potential risk for AEs in nursinginfants secondary to treatment of the mother with carfilzomib in combination withlenalidomide, 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, diastolicBP > 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 Bsurface antigen [HBsAg]). Subjects with resolved infection (i.e., subjects whoare 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) measurementof hepatitis B virus (HBV) DNA levels. Those who are PCR positive will beexcluded. EXCEPTION: Subjects with serologic findings suggestive of HBVvaccination (anti-HBs positivity as the only serologic marker) AND a knownhistory 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 virologicresponse (SVR), defined as aviremia at least 12 weeks after completion ofantiviral therapy).

• Patients with active Coronavirus Disease of 2019 (COVID-19) infection are notto be enrolled until 10 days have passed from the initial positive test, andthe patient is symptom-free. COVID-19 vaccinations following nationalguidelines (i.e., CDC) are encouraged; however, the series should be completedprior to the first day of study treatment. If this is not possible, everyeffort should be made to administer vaccines at a time when patient is notscheduled to receive study treatment (e.g., "off-weeks").

13. Clinically significant cardiac disease, including:

• Myocardial infarction within 6 months before randomization, or unstable oruncontrolled 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 oralagents

16. Uncontrolled intercurrent illness including but not limited to active infection orpsychiatric illness/social situations that would compromise compliance with studyrequirements

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

18. Contraindication to any concomitant medication, including antivirals oranticoagulation

19. Major surgery within 3 weeks prior to first dose