Bortezomib, Isatuximab, Cyclophosphamide and Dexamethasone Induction in Transplant-Eligible Multiple Myeloma Patients With Renal Insufficiency

Inclusion Criteria:

1. Voluntary written consent must be given before performance of any study relatedprocedure not part of standard medical care, with the understanding that consent maybe withdrawn by the subject at any time without prejudice to future medical care.

2. Male or female subjects ≥18 years.

3. Patients must be eligible for high-dose therapy and autologous stem celltransplantation as per institutional guidelines.

4. No prior multiple myeloma (MM) -directed therapy except for dexamethasone (up to 160mg), bortezomib (up to 5.2 mg/m^2) and/or cyclophosphamide up to 500 mg/m^2administered for management of acute manifestations of MM (hypercalcemia, renalimpairment, pain) for no longer than four weeks prior to enrollment. If subjectreceived any prior therapy, pretreatment parameters necessary for diseasecharacterization and response assessment (at least one of the following: Serumprotein electrophoresis (SPEP)/Immunofixation electrophoresis (IFE), 24-hour urineprotein with urine protein electrophoresis (UPEP)/ IFE, serum free light chains andbone marrow procedure) must be available.

5. Patients must have documented multiple myeloma as defined by the criteria below (a,b, and c):

6. Monoclonal plasma cells in the bone marrow of ≥10% or presence of a biopsyproven plasmacytoma AND

7. Evidence of organ damage or myeloma-defining events (MDE) that can beattributed to the underlying proliferative plasma cell disorder (at least oneof the following): • Hypercalcemia: corrected serum calcium >1 mg/dL higher than the upper limitof normal (ULN) or >11 mg/Dl.OR • Anemia: hemoglobin value of >2.0 g/dL below the lower limit of normal, or ahemoglobin value <10.0 g/dL.OR

• Bone marrow plasma cells of >60%. OR
• Involved/uninvolved light chain ratio ≥100 OR
• Renal insufficiency: eGFR < 40 mL/min/1.73m^2 (based on the Modificationof Diet in Renal Disease MDRD formula). [Cohort A subjects must meet thiscriterion.] If the patient is enrolled in the renal impaired (RI) A cohortbut Cycle 1 Day 1 labs do not meet RI definition, the patient will beconsidered RI (reconsent and rescreening are not required).

3. Measurable disease as defined (at least one of the following):

• Serum M-protein level ≥0.5 g/dL; OR
• Urine M-protein level ≥200 mg/24 hours; OR
• Light chain multiple myeloma without measurable disease in the urine:serum immunoglobulin (Ig) free light chains (FLC) ≥10 mg/dL and abnormalserum Ig kappa/lambda FLC ratio.

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

7. Female subjects who:

8. Are postmenopausal for at least one year before the screening visit, OR

9. Are surgically sterile, OR

10. Females of childbearing potential or male subjects with female partners ofchildbearing potential shall be required to use effective contraceptive methods (double barrier method, intrauterine device, oral contraception or abstinence)starting two weeks before first study drug(s) administration, while on therapyand for 16 weeks following the last dose of study drug(s). A woman isconsidered of childbearing potential, i.e., fertile, following menarche anduntil becoming postmenopausal unless permanently sterile. The following highlyeffective methods of contraception are accepted:

• Established use of oral, intravaginal, or transdermal combined (estrogenand progestogen containing) hormonal contraception associated withinhibition of ovulation.
• Established use of oral, injectable, or implantable progestogen-onlyhormonal contraception associated with inhibition of ovulation.
• Placement of an intrauterine device or intrauterine hormone-releasingsystem.
• Barrier methods of contraception: male condom with either cap, diaphragmor sponge with spermicide (double-barrier methods). The use ofdouble-barrier methods should always be supplemented with the use of aspermicide. Female condom and male condom should not be used together.
• Male sterilization (provided that the partner is the sole sexual partnerof the patient and that the sterilized partner has received medicalassessment of the surgical success).
• Sexual abstinence.
• Female subjects must agree not to donate eggs (ova, oocytes) for thepurposes of assisted reproduction starting two weeks before first studydrug(s) administration, while on therapy and for 16 weeks following thelast dose of study drug(s).

8. Male subjects, even if surgically sterilized (i.e., status postvasectomy), who:

9. Agree to practice effective barrier contraception during the entire studytreatment period from the time of signing the informed consent through andthrough four months after the last dose of study drug(s) (female and malecondoms should not be used together), or

10. Agree to practice true abstinence during the entire study treatment period fromthe time of signing the informed consent through 16 weeks after the last doseof study drug(s), when this is in line with the preferred and usual lifestyleof the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal,postovulation methods for the female partner] withdrawal, spermicides only, andlactational amenorrhea are not acceptable methods of contraception.)

Exclusion Criteria:

1. For renal impaired Cohort A subjects, any subject who requires immediate treatmentfor management of renal failure (including, but not limited to, dialysis). Suchtreatment is allowed once the patient becomes stable, based on investigator'sdiscretion.

2. Diagnosed or treated for malignancy other than multiple myeloma, except:

• Malignancy treated with curative intent and with no known active diseasepresent for ≥3 years before enrollment or documentation that the malignancyrequired/requires no treatment at time of enrollment.

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease.

• Adequately treated carcinoma in situ (e.g., cervical, breast) with no evidenceof disease.

3. Exhibiting clinical signs of or has a known history of meningeal or central nervoussystem involvement by multiple myeloma.

4. Known to be seropositive for human immunodeficiency virus, known to have hepatitis Bsurface antigen positivity, or known to have untreated or active hepatitis C.

5. Concurrent medical condition or disease (e.g., active systemic infection) that islikely to interfere with study procedures or results, or that in the opinion of theinvestigator would constitute a hazard for participating in this study.Specifically, any potential subject who is unsuitable for ASCT would be excludedfrom the study.

6. Clinically significant cardiac disease, including:

• Myocardial infarction within six months before Cycle 1, Day 1, or unstable oruncontrolled disease/condition related to or affecting cardiac function (e.g.,unstable angina, congestive heart failure, New York Heart Association ClassIII-IV).

• Uncontrolled cardiac arrhythmia (National Cancer Institute Common TerminologyCriteria for Adverse Events [NCI-CTCAE] Version 5 Grade 2 or higher) orclinically significant electrocardiogram (ECG) abnormalities.

• Screening 12-lead ECG showing a baseline QT interval as corrected byFridericia's formula (QTcF) >470 msec.

• Uncontrolled hypertension.

7. Any of the following laboratory test results at the time of enrollment:

• Absolute neutrophil count <1.0 × 109/L; no granulocyte colony stimulatingfactor (G-CSF) treatment in the past seven days are allowed.

• Hemoglobin level ≤7.5 g/dL (≤5 mmol/L); blood transfusions to maintainhemoglobin >7.5 g/dL are acceptable.

• Platelet count <75 × 109/L for subjects in whom <50% of bone marrow nucleatedcells are plasma cells; otherwise platelet count <50 × 109/L; no platelettransfusions in the past seven days are allowed.

• Alanine aminotransferase (ALT) level ≥2.5 × ULN

• Aspartate aminotransferase (AST) level ≥2.5 × ULN

• Total bilirubin level ≥1.5 × ULN, (except for Gilbert Syndrome: directbilirubin ≥2 × ULN)

8. Known allergies, hypersensitivity (if not amenable to premedication with steroids,or H2 blockers), or intolerance to monoclonal antibodies or human proteins,isatuximab or its excipients or known sensitivity to mammalian-derived products.

9. Plasma cell leukemia (>2.0 × 10^9/L circulating plasma cells by standarddifferential), Waldenström's macroglobulinemia, POEMS syndrome (polyneuropathy,organomegaly, endocrinopathy, monoclonal protein, and/or skin changes), orlight-chain amyloidosis.

10. Known or suspected of not being able to comply with the study protocol (e.g.,because of alcoholism, drug dependency, or psychological disorder) or the subjecthas any condition for which, in the opinion of the investigator, participation wouldnot be in the best interest of the subject (e.g., compromise their well-being) orthat could prevent, limit, or confound the protocol-specified assessments.

11. Pregnant or breastfeeding or planning to become pregnant starting two weeks beforefirst study drug(s) administration, while on therapy and for 16 weeks following thelast dose of study drug(s).

12. Plans to father a child starting two weeks before first study drug(s)administration, while on therapy and for 16 weeks following the last dose of studydrug(s).

13. Had major surgery within two weeks before Cycle 1, Day 1, or will not have fullyrecovered from surgery, or has surgery planned during the time the subject isexpected to participate in the study or within two weeks after the last dose ofstudy drug administration. Note: Subjects with planned surgical procedures to beconducted under local anesthesia are not excluded. Kyphoplasty is not considered amajor surgery.

14. Patients with pre-existing uncontrolled pulmonary disease will be excluded;uncontrolled refers to patients having had at least one hospitalization due topulmonary disease (for example, asthma, chronic obstructive pulmonary disease)within the six months prior to enrollment in the study; patients with previoushistory of pneumonitis will be excluded.