Newly Diagnosed Multiple Myeloma (NDMM)

Primary objective: To demonstrate the benefit of isatuximab in combination with bortezomib, lenalidomide and dexamethasone in the prolongation of progression free survival (PFS) as compared to bortezomib, lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM) not eligible for transplant.

Isatuximab

Isatuximab

30 ml glass vial

20

Primary endpoint:
The primary endpoint is PFS defined as the time from the date of randomization to the date
of first documentation of PD (as determined by the IRC) or the date of death from any
cause, whichever occurs first. Response will be determined according to IMWG criteria.
Progression based on paraprotein assessments will be confirmed based on 2 consecutive
assessments.

Inclusion criteria:
Main study: patients will be considered eligible for randomization in the IVRd or VRd arms
if they meet all of the following criteria:
I 01. Symptomatic multiple myeloma, as defined by the IMWG criteria.
I 02. Evidence of measurable disease:
- Serum monoclonal (M)-protein •1.0 g/dL measured using serum protein
immunoelectrophoresis
and/or
- Urine M-protein •200 mg/24 hours measured using urine protein
immunoelectrophoresis
and/or
- Light chain multiple myeloma without measurable M-protein in serum or
urine as per previous criteria (serum immunoglobulin free light chain (sFLC)
•10 mg/dL and abnormal serum immunoglobulin kappa lambda free light
chain ratio <0.26 or >1.65).
I 03. Patients who are newly diagnosed and not considered for
high-dose chemotherapy due to: being age •65 years; or <65 years with
important comorbidities likely to have a negative impact on tolerability of high
dose chemotherapy with SCT.
I 04. Patient has given voluntary written informed consent before performance of any
study related procedures not part of normal medical care, with the understanding
that consent may be withdrawn by the patient at any time without prejudice to
his/her medical care.
Crossover part: patients will be considered eligible for crossover if they meet all of the
following criteria:
I 801. Patient with confirmed PD in the VRd control arm prior to crossover.
I 802. Patient has not received any other systemic anticancer therapy(ies) other than the
VRd arm.

Exclusion criteria:
Main study: patients who meet all the inclusion criteria will be screened for the following
exclusion criteria:
E 01. Less than 18 years (or country’s legal age of majority if the legal age is >18 years)
and more than 80 years of age.
E 02. Diagnosis of peripheral neuropathy Grade >1 or Grade 1 with pain.
E 03. Diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined
significance, or smoldering multiple myeloma (asymptomatic multiple myeloma
with absence of related organ or tissue impairment end organ damage).
E 04. Diagnosis of Waldenström's disease, or other conditions in which IgM M-protein is
present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
E 05. Prior or current systemic therapy, or SCT for symptomatic multiple myeloma, with
the exception of an emergency use of a short course (equivalent of
dexamethasone 40 mg/day for 4 days) of corticosteroids, if completed within 14 days prior to randomization.
E 06. Concomitant plasma cell leukemia.
E 07. Any major procedure within 14 days before the initiation of the study treatment:
plasmapheresis, major surgery (kyphoplasty is not considered a major
procedure), radiotherapy.
E 08. ECOG PS >2.
E 09. Hemoglobin <8 g/dL.
E 10. Platelets <70 × 109/L if <50% of bone marrow (BM) nucleated cells are plasma
cells, and 30 × 109/L if •50% of BM nucleated cells are plasma cells. Platelet
transfusion is not allowed within 3 days before the screening hematological test.
E 11. Absolute neutrophil count (ANC) <1000/μL (1 × 109/L). The use of granulocyte
colony-stimulating factor (G-CSF) is not allowed to reach this level.
E 12. Creatinine clearance <30 mL/min/1.73 m² (modification of diet in renal disease
>MDRD@ formula).
E 13. Total bilirubin >1.5 × upper limit of normal (ULN), except for known Gilbert
syndrome.
E 14. Corrected serum calcium >14 mg/dL (>3.5 mmol/L).
E 15. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)
>3 × ULN.
E 16. Hypersensitivity (or contraindication) to dexamethasone, sucrose histidine (as
base and hydrochloride salt), boron, mannitol, and polysorbate 80 or any of the
components of study therapy that are not amenable to premedication with
steroids, or H2 blockers that would prohibit further treatment with these agents.
E 17. Any of the following within 6 months prior to randomization:
- Second/third degree heart block
- Poorly controlled hypertension
- Myocardial infarction
- Severe/unstable angina pectoris
- Coronary/peripheral artery bypass graft
- New York Heart Association class III or IV congestive heart failure
- Grade •3 arrhythmias
- Stroke or transient ischemic attack.
E 18. Left-ventricular ejection fraction <40%.
E 19. Prior malignancy. Adequately treated basal cell or squamous cell skin, or
superficial (pTis, pTa, and pT1) bladder cancer, or low risk prostate cancer, or any
in situ malignancy after curative therapy are allowed, as well as any other cancer
for which cytotoxic chemotherapy has been completed •5 years prior to
enrollment and from which the patient has been disease-free for •5 years.
E 20. Known acquired immunodeficiency syndrome (AIDS-related illness) or known HIV
disease requiring antiviral treatment or active hepatitis A, B, or C infection.
E 21. Malabsorption syndrome or any condition that can significantly impact the
absorption of lenalidomide.
E 22. Unable or unwilling to undergo thromboprophylaxis as per local clinical practice.
E 23. Daily requirement for corticosteroids (equivalent to •10 mg/day of prednisone) for
more than 7 days (except for inhalation corticosteroids).
E 24. Any of the following within 3 months prior to randomization: treatment resistant
peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory
bowel disease, diverticulitis, pulmonary embolism, or other uncontrolled
thromboembolic event.
E 25. Any severe acute or chronic medical condition which could impair the ability of the
patient to participate in the study or interfere with interpretation of study results
(eg, systemic infection unless anti-infective therapy is employed), or inability of
the patient to comply with the study procedures.
E 26. Pregnant or breastfeeding woman or woman who intends to become pregnant
during the participation in the study. Woman of childbearing potential (WOCBP)
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 for 3 months after discontinuation of isatuximab or bortezomib
treatment, whichever occurs last, and/or who are unwilling or unable to be tested
for pregnancy before study treatment initiation (2 negative tests), weekly during
the first 6 weeks of treatment, every 21 days for induction Cycles 2 to 4, and then
every 28 days while on therapy (or every 14 days in case of irregular menstrual
cycles) and, for at least 30 days following discontinuation of study lenalidomide
(14 and 30 days for in case of irregular menstrual cycles), or monthly for 3 months
after discontinuation of isatuximab or bortezomib treatment, whichever occurs
last.
Note 1: a WOCBP is a woman 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
(ie, 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 (eg, calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable
methods of contraception.
E 27. Male participants who disagree to practice true abstinence or disagree to use a
condom during sexual contact with a pregnant woman or a WOCBP while
participating in the study, during dose interruptions, and for at least 28 days
following discontinuation of study lenalidomide, or for 3 months after
discontinuation of isatuximab or bortezomib treatment, whichever occurs last,
even if he has undergone a successful vasectomy.
Crossover part: patients will be considered eligible for crossover if they do not meet any of
the following criteria:
E 801. Diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined
significance, or smoldering multiple myeloma (asymptomatic multiple myeloma
with absence of related organ or tissue impairment end organ damage).
E 802. Diagnosis of Waldenström's disease, or other conditions in which IgM M-protein is
present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
E 803. Concomitant plasma cell leukemia.
E 804. Any major procedure within 14 days before the initiation of the study treatment:
plasmapheresis, major surgery (kyphoplasty is not considered a major
procedure), radiotherapy.
E 805. ECOG PS >2.
E 806. Hemoglobin <8 g/dL.
E 807. Platelets <50 × 109/L if <50% of BM nucleated cells are plasma cells, and
30 × 109/L if •50% of BM nucleated cells are plasma cells. Platelet transfusion
is not allowed within 3 days before the screening hematological test.
E 808. Absolute neutrophil count <1000/μL (1 × 109/L). The use of
G-CSF is not allowed to reach this level.
E 809. Creatinine clearance <30 mL/min/1.73 m² (MDRD formula).
E 810. Total bilirubin >1.5 × ULN except for known Gilbert syndrome.
E 811. Corrected serum calcium >14 mg/dL (>3.5 mmol/L).
E 812. Aspartate aminotransferase and/or ALT >3 × ULN.
E 813. Hypersensitivity (or contraindication) to dexamethasone, sucrose histidine (as
base and hydrochloride salt), boron, mannitol, and polysorbate 80 or any of the
components of study therapy that are not amenable to premedication with
steroids, or H2 blockers that would prohibit further treatment with these agents.
E 814. Any of the following within 6 months prior to first investigational medicinal product
(IMP) dosing in the crossover arm:
- Second/third degree heart block.
- Poorly controlled hypertension.
- Myocardial infarction.
- Severe/unstable angina pectoris.
- Coronary/peripheral artery bypass graft.
- New York Heart Association class III or IV congestive heart failure.
- Grade •3 arrhythmias.
- Stroke or transient ischemic attack.
E 815. Left-ventricular ejection fraction <40%.
E 816. Prior malignancy. Adequately treated basal cell or squamous cell skin, or
superficial (pTis, pTa, and pT1) bladder cancer, or low risk prostate cancer, or any
in situ malignancy after curative therapy are allowed, as well as any other cancer
for which cytotoxic chemotherapy has been completed •5 years prior to first
dosing and from which the patient has been disease-free for •5 years.
E 817. Known acquired immunodeficiency syndrome (AIDS-related illness) or known HIV
disease requiring antiviral treatment, or active hepatitis A, B, or C infection.
E 818. Malabsorption syndrome or any condition that can significantly impact the
absorption of lenalidomide.
E 819. During the main study, premature discontinuation of lenalidomide and
dexamethasone due to a related AE occurring less than 6 months before the start
of crossover part, consent withdrawal, or for any reason other than PD.
E 820. Unable or unwilling to undergo thromboprophylaxis as per local clinical practice.
E 821. Daily requirement for corticosteroids (equivalent to •10 mg/day of prednisone) for
more than 7 days (except for inhalation corticosteroids).
E 822. Any of the following, within 3 months prior to first IMP dosing in the crossover
arm: treatment resistant peptic ulcer disease, erosive esophagitis or gastritis,
infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism, or
other uncontrolled thromboembolic event.
E 823. Any severe acute or chronic medical condition which could impair the ability of the
patient to participate in the study or interfere with interpretation of study results
(eg, systemic infection unless anti-infective therapy is employed), or inability of
the patient to comply with the study procedures.
E 824. Pregnant or breastfeeding woman or woman who intends to become pregnant
during participation in the crossover part. Woman of childbearing potential
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 for 3 months after discontinuation of isatuximab treatment,
whichever occurs last, and/or who are unwilling or unable to be tested for
pregnancy before study treatment initiation (2 negative tests), weekly during the
first 4 weeks of treatment, and every 28 days while on therapy (or every 14 days
in case of irregular menstrual cycles), and for at least 30 days following
discontinuation of study lenalidomide (14 and 30 days for in case of irregular menstrual cycles), or monthly for 3 months after discontinuation of isatuximab
treatment, whichever occurs last.
Note 1: a WOCBP is a woman 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
(ie, 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 (eg, calendar, ovulation,
symptothermal, and post-ovulation methods) and withdrawal are not acceptable
methods of contraception.
E 825. Male participants who disagree to practice true abstinence or disagree to use a
condom during sexual contact with a pregnant woman or a WOCBP while
participating in the crossover part, during dose interruptions, and for at least
30 days following discontinuation of study lenalidomide, or for 3 months after
discontinuation of isatuximab treatment, whichever occurs last, even if he has
undergone a successful vasectomy.