Study of SubQ Dara With Dose-Attenuated Bortezomib, Lenalidomide, Dexamethasone in Elderly NDMM

Inclusion Criteria:

• Newly diagnosed, untreated, symptomatic MM as defined by standard criteria. Clonalbone marrow plasma cells >10% or biopsy-proven bony or extramedullary plasmacytoma*and any one or more of the following myeloma-defining events:

• Evidence of end-organ damage that can be attributed to the underlying plasmacell proliferative disorder, specifically:

• Hypercalcemia: serum calcium >0.25 mmol/L (> 1mg/dL) higher than the upperlimit of normal or > 2.75 mmol/L (>11 mg/dL) and/or,

• Renal insufficiency: creatinine clearance <40 mL per min or serumcreatinine >177 µmol/L (>2 mg/dL) and/or,

• Anemia: hemoglobin value of >20 g/L (>2g/100 mL)below the lower limit ofnormal, or a hemoglobin value <100 g/L (10g/100 mL) and/or,

• Bone lesions: one or more osteolytic lesions on skeletal radiography, CT,or PET-CT (if bone marrow has less than 10% clonal plasma cells, more thanone bone lesion is required to distinguish from solitary plasmacytoma withminimal marrow involvement)

• Any one or more of the following biomarkers of malignancy:

• Clonal bone marrow plasma cell percentage** (clonality should beestablished by showing kappa/lambda-light-chain restriction on flowcytometry, immunohistochemistry, or immunofluorescence. Bone marrowplasma cell percentage should preferably be estimated from a corebiopsy specimen; in case of a disparity between the aspirate and corebiopsy, the highest value should be used ≥60% or

• Serum free light chain (FLC) ratio greater than or equal to 100provided involved FLC level is 100 mg/L or higher, or

• More than one focal lesion on MRI*** (Each focal lesion must be 5 mmor more in size.

• Age ≥ 70 and ineligible for autologous hematopoietic stem cell transplantation (defined as age, ≥ 80 or age < 80 with cardiac/pulmonary/ or other comorbiditiesdeemed by investigator likely to have a negative impact on tolerability of high dosechemotherapy with stem cell transplantation).

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

• Patients must have measurable disease defined by at least 1 of the following 3measurements:

• Serum M-protein > 1 g/dL (10 g/L) or > 0.5 g/dL if IgA

• Urine M-protein > 200 mg/24 hours.

• Serum free light chain assay: involved free light chain level >10 mg/dL (> 100mg/L) provided the serum free light chain ratio is abnormal

• Due to the teratogenicity of lenalidomide and the lack of adequate reproductivetoxicity data for daratumumab, if a male subject is sexually active with a woman ofchild bearing potential, in addition to the user independent highly effective methodof contraception, a male or female condom with or without spermicide, diaphragm, orcervical cap is required. Male condom and female condom should not be used together (due to risk of failure with friction).

• During the study (including during dose interruptions), and for 4 weeks followingdiscontinuation of lenalidomide, and if receiving daratumumab, for 3 months afterthe last dose, in addition to the user independent highly effective method ofcontraception (even if he has undergone a successful vasectomy), a man:

1. Who is sexually active with a woman of childbearing potential must agree to usea barrier method of contraception (ie, latex or synthetic condom withspermicidal foam/gel/film/cream/suppository)

2. Who is sexually active with a woman who is pregnant must use a latex orsynthetic condom.

3. Must agree not to donate sperm

• Willing and able to adhere to the prohibitions and restrictions specified in thisprotocol and referenced in the informed consent form (ICF)

• Must sign an ICF (or their legally acceptable representative must sign) indicatingthat he or she understands the purpose of, and procedures required for, the studyand is willing to participate in the study.

Exclusion Criteria:

• Peripheral neuropathy > Grade 2 or >Grade 1 with pain on clinical examination duringthe Screening period.

• Kidney failure with CrCl ≤ 15 mL/min by Cockfraft Gault

• Significant cardiac disease as determined by the investigator including:

1. Known or suspected cardiac amyloidosis

2. Congestive heart failure of Class III or IV of the NYHA classification

3. Uncontrolled angina, hypertension or arrhythmia

4. Myocardial infarction in the past 6 months

5. Any uncontrolled or severe cardiovascular disease

6. QTc > 470 milliseconds (msec) on a 12-lead ECG obtained during the Screeningperiod. If a machine reading is above this value, the ECG should be reviewed bya qualified reader and confirmed on a subsequent ECG or by manual calculation.

• Prior cerebrovascular event with persistent neurologic deficit.

• Subject is:

1. Seropositive for hepatitis B (defined by a positive test for hepatitis Bsurface antigen [HBsAg]). Subjects with resolved infection (ie, subjects whoare HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must bescreened using realtime polymerase chain reaction (PCR) measurement ofhepatitis 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.

2. Seropositive for hepatitis C (except in the setting of a sustained virologicresponse [SVR], defined as aviremia at least 12 weeks after completion ofantiviral therapy).

• Human immunodeficiency virus infection

• Any medical conditions that, in the investigator's opinion, would impose excessiverisk to the subject.

• Prior or concurrent malignancy, except for the following:

1. Adequately treated basal cell or squamous cell skin cancer

2. Cervical carcinoma in situ

3. Adequately treated Stage I or II cancer from which the subject is currently incomplete remission.

4. Or any other cancer from which the subject has been disease-free for ≥ 3 years

• Known GI disease or GI procedure that could interfere with the oral absorption ortolerance of study drug, including difficulty swallowing.

• Males sexually active with females of childbearing potential who do not agree topractice 2 effective methods of contraception, at the same time, from the time ofsigning the informed consent form (ICF) through 90 days after the last dose of studydrug, or do not agree to practice true abstinence.

• Central nervous system involvement.

• Diagnosis of primary amyloidosis (with the exception of patients whose amyloidosishas been documented as a complication of MM, who will be evaluated on a case-by-casebasis for trial participation).

• Infection requiring systemic antibiotic therapy or other serious infection within 14days before study drug administration.

• Known chronic obstructive pulmonary disease with a forced expiratory volume in 1second (FEV1) <50% of predicted normal (for subjects > 65 years old FEV1 <50% orDLCO <50%). Note: FEV1 testing is required for subjects suspected of having chronicobstructive pulmonary disease and subjects must be excluded if FEV1 <50% ofpredicted normal.

• Known moderate or severe persistent asthma within the past 2 years or currently hasuncontrolled asthma of any classification. Note: Subjects who currently havecontrolled intermittent asthma or controlled mild persistent asthma are allowed inthe study.

• Persistent corrected serum calcium ≥ 14 mg/dL within 2 weeks of enrollment (despiteappropriate measure such a short course of steroids, bisphosphonates, hydration,calcitonin).

• Absolute neutrophil count < 1000 cells/mm3. No growth factors allowed within 1 weekof enrollment.

• Platelets < 75,000 cell/mm3 (75 x 109/L). Qualifying laboratory value must occur atmost recent measurement before enrollment and must be no more than 14 days beforeenrollment. No transfusions are allowed within 72 hours prior to study drugadministration.

• Hemoglobin < 8 g/dL. Qualifying laboratory value must occur at most recentmeasurement before enrollment and must be no more than 14 days before enrollment. Notransfusions are allowed within 72 hours before qualifying laboratory value.

• Total bilirubin > 1.5 x ULN, unless known have Gilbert's syndrome in which case 3 xULN).

• AST or ALT ≥ 3 x ULN.

• Major surgery or radiation therapy within 14 days before study drug administration.

• Kyphoplasty or vertebroplasty within 1 week of enrollment.

• Administration of Anti-myeloma chemotherapy, biological, immunotherapy, orinvestigational agent (therapeutic or diagnostic) within 3 weeks before enrollment;however, a cumulative dose of ≤ 160 mg dexamethasone or equivalent during screeningis permitted.

• NSAIDs, IV contrast, aminoglycosides, or other potentially nephrotoxic drugs within 2 weeks of enrollment, except aspirin.

• Known hypersensitivity to bortezomib, lenalidomide, dexamethasone, or daratumumab