Inclusion Criteria:
1. The patient has signed an informed consent form (ICF), stating that he or she
understands the purpose of the procedures required for the study and is willing to
participate in the study. The patient must be willing and able to adhere to the
prohibitions and restrictions specified in this protocol, as stated in the ICF.
2. Male or female patients aged 18 years or older at the time of the ICF signature.
3. Patients diagnosed with MM based on the International Myeloma Working Group (IMWG)
criteria (see Appendix H).
4. Patients with severe RI defined as estimated glomerular filtration rate (eGFR) <30
ml/min/1.73m2 (calculated with the Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) formula) or in need for dialysis (see Appendix E).
5. Patients with current evidence of measurable disease defined as:
- - Serum monoclonal protein (M-protein) levels ≥0.5 g/dL, measured using serum
protein electrophoresis (SPEP) and/or.
- - Urine M-protein levels ≥200 mg/24 hours, measured using urine protein
electrophoresis (UPEP), or.
- - Serum immunoglobulin free light chain (FLC) ≥10 mg/dL and abnormal serum
immunoglobulin kappa lambda FLC ratio.
6. Adequate bone marrow and hepatic function as defined by ALL the laboratory criteria:
- - Absolute Neutrophil Count (ANC) ≥1.0 x 109/L (Granulocyte colony-stimulating
factor (GCSF) administration is not allowed to reach this level)
- Hemoglobin levels ≥7.5 g/dL (≥4.65 mmol/L)
- Platelet count ≥75 x 109/L in patients in whom <50% of bone marrow nucleated
cells are plasma cells OR platelet count ≥50 x 109/L in patients in whom ≥ 50% of
bone marrow nucleated cells are plasma cells (transfusions are not allowed to
reach this level)
- Alanine aminotransferase (ALT) levels ≤2.5 x the upper limit of normal (ULN)
- Aspartate aminotransferase (AST) levels ≤2.5 x ULN.
- - Total bilirubin levels ≤1.5 x ULN (except for Gilbert Syndrome: direct bilirubin
≤1.5 x ULN)
- Serum calcium corrected for albumin ≤14.0 mg/dL (≤3.5 mmol/L), or free ionized
calcium ≤ 6.5 mg/dL (≤1.6 mmol/L)
7.
Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2 (see Appendix C).
8. For patients experiencing toxicities resulting from previous therapy, the toxicities
must be resolved or stabilized to ≤ Grade 1.
Exclusion Criteria:
1. Prior or current systemic therapy or stem-cell transplantation for any plasma cell
dyscrasia, with the exception of emergency use of a short course (the equivalent of
dexamethasone 40 mg/day for a maximum of 4 days) of corticosteroids before treatment.
2. History of malignancy (other than MM) within three years before Cycle 1, Day 1
(exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of
the cervix or breast, or other non-invasive lesion that in the opinion of the
Investigator, with concurrence with the Sponsor's medical monitor, are considered
cured with minimal risk of recurrence within three years).
3. Clinical signs of meningeal involvement of MM.
4. Clinically significant cardiac disease, including:
1. Myocardial infarction within six months before Cycle 1, Day 1, or unstable or
uncontrolled condition (e.g., unstable angina, congestive heart failure, New York
Heart Association Class III-IV)
2. Cardiac arrhythmia (Common Terminology Criteria for Adverse Events Grade 3 or
higher) or clinically significant electrocardiogram (ECG) abnormalities. 3. ECG showing a baseline QT interval as corrected QTc >470 msec. 5. Known:
1. Active hepatitis A. 2. To be seropositive for hepatitis B (defined by a positive test for hepatitis B
surface antigen). Patients with resolved infection (i.e., patients who are
positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies
to hepatitis B surface antigen [anti-HBs]) must be screened using real-time
polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA
levels. Those who are PCR positive will be excluded.
Exception: Patients 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.
3. To be seropositive for hepatitis C (except in the setting of a sustained
virologic response, defined as aviremia at least 12 weeks after the completion of
the antiviral therapy).
4. Known to be seropositive for human immunodeficiency virus.
6. Patient has plasma cell leukemia (>2.0 × 109/L circulating plasma cells by standard
differential) or Waldenström's macroglobulinemia or POEMS syndrome (polyneuropathy,
organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis.
7. Any concurrent medical or psychiatric condition or disease (e.g., active systemic
infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that
is likely to interfere with the study procedures or results or that, in the opinion of
the investigator, would constitute a hazard for participating in this study.
8. Ongoing ≥Grade 2 peripheral neuropathy.
9. Patient has had major surgery within two weeks before C1D1, or has not fully recovered
from an earlier surgery, or has a surgery planned during the time the patient is
expected to participate in the study or within two weeks after the last dose of study
drug administration. Note: patients with planned surgical procedures to be conducted
under local anesthesia may participate. Kyphoplasty or vertebroplasty are not
considered major surgery.
10. Patient has known allergies, hypersensitivity, or intolerance to any of the study
drugs, monoclonal antibodies, human proteins, or their excipients (refer to isatuximab
Investigator's Brochure) or known sensitivity to mammalian-derived products.
11. Patient was vaccinated with live vaccines within four weeks prior to C1D1.
12. Pregnant or nursing women.
13. a. Females of childbearing potential (FCBP) unwilling to prevent pregnancy with the
use of two reliable methods of contraception for ≥four weeks before the start of study
treatment, during treatment (including dose interruptions), and up to five months
following the last dose of isatuximab or three months following the last dose of the
rest of the study treatment, whichever is longer. This includes one highly effective
form of contraception (tubal ligation, intrauterine device, hormonal [birth control
pills, injections, hormonal patches, vaginal rings or implants] or partner's
vasectomy) and one additional effective contraceptive method (male latex or synthetic
condom, diaphragm, or cervical cap).
b. FCBP who are unwilling or unable to be tested for pregnancy: a) twice before study
treatment initiation (one 10-14 days prior to start of study drug and one within 24
hours prior to start of study drug. Urine tests must have a sensitivity of ≥25
mIU/mL), b) weekly during 1st month of treatment and then prior to each treatment
cycle administration or c) every two weeks in case of irregular menstrual cycles, and
d) up to five months following the last dose of isatuximab or three months following
the last dose of the rest of the study treatment, whichever is longer.
14. Male participants who refuse to practice abstinence or use a condom during sexual
contact with a pregnant female or an FCBP while participating in the study, during
dose interruptions and at least five months following the last dose of isatuximab or
three months following the last dose of the rest of the study treatment, whichever is
longer, even if they have undergone a successful vasectomy.
Note 1: an FCBP is a female who: 1) has achieved menarche at some time point, 2) has not
undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing
potential) for at least 24 consecutive months (i.e., has had menses at any time in the
preceding 24 consecutive months).
Note 2: True abstinence is acceptable when this is in line with the preferred and usual
lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of contraception.
