PHASE III STUDY OF ISATUXIMAB-CARFILZOMIB-LENALIDOMIDE-DEXAMETHASONE (Isa-KRd) VERSUS CARFILZOMIB-LENALIDOMIDE-DEXAMETHASONE (KRd) IN NEWLY DIAGNOSED MYELOMA PATIENTS ELIGIBLE FOR AUTOLOGOUS STEM CELL TRANSPLANTATION (IsKia TRIAL)

1. Patient with newly diagnosed multiple myeloma and eligible to ASCT, for whom
the standard treatment it is not, according to investigator, the best treatment
available.
2. Patient is, in the investigator*s opinion, willing and able to comply with
the study visits and procedures required per protocol.
3. Patient has provided written informed consent. Subject does not have kind of
condition that, in the opinion of the Investigator, may compromise the ability
of the subject to give written informed consent and patient is, in the
investigator(s) opinion, willing and able to comply with the protocol
requirements.
4. Monoclonal plasma cells in the bone marrow >=10% or presence of a biopsy
proven plasmacytoma and documented multiple myeloma satisfying at least one of
the calcium, renal, anemia, bone (CRAB) criteria or biomarkers of malignancy
criteria:
CRAB criteria:
- Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than upper limit
of normal (ULN) or >2.75 mmol/L (>11 mg/dL)
- Renal insufficiency: creatinine clearance <40mL/min or serum creatinine >177
µmol/L (>2 mg/dL)
- Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10
g/dL
- Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or
PET-CT
Biomarkers of Malignancy:
- Clonal bone marrow plasma cell percentage >=60%
- Involved: uninvolved serum FLC ratio >=100
- >1 focal lesion on magnetic resonance imaging (MRI) studies
5. Patient is 18 - 70 years old and is eligible for autologous stem cell
transplantation
6. Patient has measurable disease as defined by any one of the following:
- Serum monoclonal paraprotein (M-protein) level >=1.0 g/dL or urine M-protein
level >=200 mg/24 hours; or
- Light chain multiple myeloma without measurable disease in the serum or the
urine: Serum immunoglobulin FLC >=10 mg/dL and abnormal serum immunoglobulin
kappa lambda FLC ratio.
7. Life expectancy >= 3 months
8. ECOG status <=2
9. Clinical laboratory values meeting the following criteria during the
Screening Phase:
o Adequate hepatic function, with serum ALT <= 2.5 times ULN, AST <= 2.5 x the
ULN
o Serum direct bilirubin <= 1.5 ULN (except in subjects with congenital
bilirubinemia, such as Gilbert syndrome, direct bilirubinemia <= 1.5 ULN)
o Absolute neutrophil count (ANC) >= 1.0 × 109/L
o Platelet count >= 75× 109/L (>= 50× 109/L if myeloma involvement in the bone
marrow is > 50%) and no platelet infusion in the 1 week prior to screening
platelet count
o Creatinine clearance (CrCl) >= 30 mL/minute. Creatinine clearance should be
calculated using eGFR (Modified Diet in Renal Disese [MDRD])
o Corrected serum calcium <= 13.5 mg/dL (3.4 mmol/L)
o LVEF >= 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method
of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not
available.
10. Females of childbearing potential (FCBP)* complies with the conditions of
the Pregnancy Prevention Plan, including confirmation that she has an adequate
level of understanding and must agree to ongoing pregnancy testing and to
practice contraception or true abstinence. FCBP must use a highly effective and
an additional barrier contraception method simultaneously for 4 weeks before
starting therapy, during treatment and dose interruptions and for 5 months
after the last dose of study drugs.
11. Male subjects must agree to practice contraception if sexually active with
FCBP during the treatment and for at least 5 months after the last dose of
study drugs. Males must agree to refrain from donating sperm for at least 90
days after the last dose of carfilzomib and for at least 5 months after the
last dose of isatuximab.

1. Previous treatment with anti-myeloma therapy (does not include radiotherapy,
biphosphonates, or a single short course of steroid <= to the equivalent of
dexamethasone 40 mg/day for 4 days).
2. Patients with non-secretory MM unless serum free light chains are present
and the ratio is abnormal or a plasmacytoma with minimum largest diameters of >
2 cm.
3. Patients with plasma cell leukemia, amyloidosis, Waldenstrom Disease, POEMS
syndrome
4. Meningeal involvement of multiple myeloma
5. Patient ineligible for autologous transplantation
6. Pregnant or lactating females
7. Acute active infection requiring treatment (systemic antibiotics,
antivirals, or antifungals) within 14 days prior to randomization
8. Known human immunodeficiency virus infection (HIV)
9. Active hepatitis A, B or C infection. Hepatitis C infection (subjects with
hepatitis C that achieve a sustained virologic response after antiviral therapy
are allowed), or hepatitis B infection (subjects with hepatitis B surface
antigen or core antibody that achieve sustained virologic response with
antiviral therapy are allowed). Tests to be performed if required per local
country regulations (in Czech Republic
testing for HIV and hepatitis B and C is required at screening). In fact it is
not possible to avoid the risk of virological reactivation with the study
treatments.
Uncontrolled or active HBV infection: Patients with positive HBsAg and/or HBV
DNA
- Patient can be eligible if anti-HBc IgG positive (with or without positive
anti-HBs) but HBsAg
and HBV DNA are negative. If anti-HBV therapy in relation with prior infection
was started
before initiation of IMP, the anti-HBV therapy and monitoring should continue
throughout the
study treatment period.
- Patients with negative HBsAg and positive HBV DNA observed during screening
period will
be evaluated by a specialist for start of anti-viral treatment: study treatment
could be proposed
if HBV DNA becomes negative and all the other study criteria are still met.
Active HCV infection: positive HCV RNA and negative anti-HCV
- Patients with antiviral therapy for HCV started before initiation of IMP and
positive HCV
antibodies are eligible. The antiviral therapy for HCV should continue
throughout the treatment
period until seroconversion.
- Patients with positive anti-HCV and undetectable HCV RNA without antiviral
therapy for HCV
are eligible.
10. Unstable angina or myocardial infarction within 4 months prior to
randomization, NYHA Class III or IV heart failure, uncontrolled angina,
uncontrolled hypertension, (Uncontrolled hypertension, defined as an average
systolic blood pressure >= 160 mmHg or diastolic >= 100 mmHg despite optimal
treatment, in the last 5 years pulmonary embolia, history of severe coronary
artery disease, severe uncontrolled ventricular arrhythmias, sick sinus
syndrome, or electrocardiographic evidence of acute ischemia or Grade 3
conduction system abnormalities unless subject has a pacemaker
11. Non-hematologic or hematological malignancy within the past 3 years with
the exception of a) adequately treated basal cell carcinoma, squamous cell skin
cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c)
prostate cancer of Gleason Grade 6 or less with stable prostate-specific
antigen levels; or d) cancer considered cured by surgical resection or unlikely
to impact survival during the duration of the study, such as localized
transitional cell carcinoma of the bladder or benign tumors of the adrenal or
pancreas
12. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days
prior to randomization as defined by National Cancer Institute Common Toxicity
Criteria (NCI CTCAE) 5.0
13. Known history of allergy to Captisol® (a cyclodextrin derivative used to
solubilize carfilzomib) and to PS80; prior hypersensitivity to sucrose,
histidine (as base and hydrochloride salt), or known intolerance or
hypersensitivity to infused protein products or any of the components (active
substance or excipients) of study treatments that are not amenable to
premedication with steroids, or H2 blockers, that would prohibit further
treatment with these agents.
14. Contraindication to any of the required concomitant drugs or supportive
treatments, including hypersensitivity to all anticoagulation and antiplatelet
options, antiviral drugs, or intolerance to hydration due to preexisting
pulmonary or cardiac impairment
15. Any other clinically significant medical disease or condition that, in the
Investigator*s opinion, may interfere with protocol adherence or a subject*s
ability to give informed consent
16. Received any investigational drug within 14 days or 5 half-lives of the
investigational drug,
prior to initiation of study intervention, whichever is longer.
17. Pregnant or breastfeeding woman or woman who intends to become pregnant
during the participation in the study. FCBP unwilling to prevent pregnancy by
the use of 2 reliable methods of contraception for >=4 weeks before the start of
study treatment, during treatment (including dose interruptions), and for at
least 28 days following discontinuation of study lenalidomide, or 30 days
following discontinuation of carfilzomib or for 5 months after discontinuation
of isatuximab treatment, whichever occurs last,
18. Male participants who disagree to practice true abstinence or disagree to
use a condom during sexual contact with a pregnant woman or a FCBP while
participating in the study, during dose interruptions, and for at least 28 days
following discontinuation of study lenalidomide, or 3 months following
discontinuation of carfilzomib, or for 5 months after discontinuation of
isatuximab treatment, whichever occurs last, even if he has undergone a
successful vasectomy.