| Eligibility |
Inclusion Criteria:
1. Must be able to understand and voluntarily sign an informed consent form
2. Must be able to adhere to the study visit schedule and other protocol requirements
3. Patient able to swallow the various oral treatments
4. Life expectancy > 6 months
5. Subject, male or female, must be at least = 65 years of age
6. Must have a Newly diagnosed Multiple Myeloma requiring therapy (SLiM CRAB criteria)
(see appendix 18.2) 6.1. Monoclonal plasma cells in the bone marrow =10% or presence
of a biopsy proven plasmacytoma 6.2. Revised International Myeloma Working Group
diagnostic criteria for multiple myeloma
Myeloma defining events:
- Evidence of end organ damage that can be attributed to the underlying plasma cell
proliferative disorder, specifically: • Hypercalcemia: serum calcium >0.25 mmol/L
(>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL) •
Renal insufficiency: creatinine clearance =40 mL per min† or serum creatinine
=177 µmol/L (=2 mg/dL)
†Measured or estimated by validated equations
- Anemia: hemoglobin value of = 20 g/L below the lower limit of normal, or
hemoglobin value =100 g/L
- 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 than one bone
lesion is required to distinguish from solitary plasmacytoma with minimal
marrow involvement
- Any one or more of the following biomarkers of malignancy:
- Clonal bone marrow plasma cell percentage* =60%
- Involved/uninvolved serum free light chain ratio =100
- >1 focal lesion on MRI studies (Each focal lesion must be 5 mm or more in
size.)
7. Must have measurable disease as defined by any of the following:
Serum monoclonal paraprotein (M-protein) level =5 g/L or urine M- protein level =200
mg/24 hours; or Serum immunoglobulin free light chain =100 mg/L and abnormal serum
immunoglobulin kappa lambda free light chain ratio (any method)*
* The same method must be used along the study for a given patient.
8. Must be nontransplant eligible 8.1. Newly diagnosed and not considered candidate for
high- dose chemotherapy with SCT. 8.2. Subject must have Charlson comorbidity index =1
8.3. ECOG =2
9. Adequate bone marrow function, documented within 72 hours and without transfusion 72
hours prior to the first intake of investigational product (C1J1) with no growth
factor support (one week), defined as:
- Absolute neutrophils = 1 x109/L,
- Untransfused Platelet count = 75 x109/L,
- Hemoglobin =8.5 g/dL.
10. Adequate organ function documented within one week prior to the first intake of
investigational product (C1J1) defined as:
- Serum total bilirubin < 2x upper limit of normal (ULN),
- Creatinine clearance = 30ml/min calculated with MDRD formula,
- Serum SGOT/AST or SGPT/ALT < 3x upper limit of normal (ULN).
11. Person affiliated to the French social security system or equivalent
12. A man who is sexually active with a pregnant woman or a woman of childbearing
potential must agree to use a barrier method of birth control e.g., condom with
spermicidal foam/gel/film/cream/suppository during the study and for at least 5 months
after the last dose of treatment, even he has had a vasectomy.
13. A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:
13.1. Not a female of childbearing potential Or 13.2. A FCBP* who must have a negative
serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14
days prior to and again within 24 hours prior to starting study medication and before
each cycle of study treatment.
A FCBP* must understand and agree to continue abstinence from heterosexual intercourse
or to use 2 reliable effective methods of contraception (a very effective method and
an effective additional method) simultaneously without interruption:
13.2.1. For at least 28 days before starting experimental treatments, 13.2.2.
Throughout the entire duration of experimental treatments, 13.2.3. During dose
interruptions, 13.2.4. And for at least 5 months after the last dose of experimental
treatments.
14. All patients must understand and accept to comply with the conditions of the
Lenalidomide pregnancy prevention plan
Exclusion Criteria :
1. Subject has a diagnosis of primary systemic amyloidosis, monoclonal gammopathy of
undetermined significance, or smouldering multiple myeloma.
2. Subject has a diagnosis of Waldenstro¨m'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.
3. Subject has prior or current systemic therapy or SCT for multiple myeloma, with the
exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day
for a maximum 4 days) of corticosteroids before treatment.
4. Subject has a history of ongoing malignancy (other than multiple myeloma) within 3
years (date of diagnosis of the malignancy) before inclusion in the study treatment
(exceptions are malignancies considered cured with minimal risk of recurrence within 3
years, even though the patient receives treatment).
5. Subject has had radiation therapy within 7 days study treatment*
* unless done for antalgic reason or in case of functional risk for the patient.
6. Subject has had plasmapheresis within 7 days study treatment *
* unless patient disease is still measurable (inclusion criteria n°6) after the
plasmapheresis.
7. Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.
8. Known to be seropositive for history of human immunodeficiency virus (HIV).
9. Known to have hepatitis B active or uncontrolled infection (positive HBsAg and/or HBV
DNA)
10. Known to have hepatitis C active infection (positive HCV RNA and negative anti-HCV)
11. Subject has any clinically significant medical or psychiatric condition or disease
(e.g., uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) in the
investigator's opinion, would expose the patient to excessive risk or may interfere
with compliance or interpretation of the study results.
12. Subject has active systemic infection and severe infections requiring treatment with a
parenteral administration of antibiotics.
13. Subject has clinically significant cardiac disease, including:
- myocardial infarction within 6 months before study treatment, or an unstable or
uncontrolled disease/condition related to or affecting cardiac function (e.g.,
unstable angina, congestive heart failure, New York Heart Association Class
III-IV)
- uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology
Criteria for Adverse Events [NCI CTCAE] Version 5 Grade =2) or clinically
significant ECG abnormalities or LVEF < 40 % 14. Subject has known allergies,
hypersensitivity, or intolerance to steroids, mannitol, pregelatinized starch,
sodium stearyl fumarate, histidine (as base and hydrochloride salt), arginine
hydrochloride, poloxamer 188, sucrose or any of the other components of study
intervention that are not amenable to premedication with steroids and H2 blockers
or would prohibit further treatment with these agents, monoclonal antibodies or
human proteins, or their excipients (refer to respective package inserts or
Investigator's Brochure).
15. Known hypersensitivity, allergy to one of the study product (isatuximab,
lenalidomide, bortezomib), dexamethasone, boron or to one of the excipients.
Allergy to bandages or adhesives (acrylic).
16. Acute diffuse infiltrative pneumopathy, pericardial disease 17. Subject has
plasma cell leukemia (according to World Health Organization [WHO] criterion:
=20% of cells in the peripheral blood with an absolute plasma cell count of more
than 2 × 109/L) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,
monoclonal protein, and skin changes).
18. Subject is known or suspected of not being able to comply with the study
protocol (e.g., because of alcoholism, drug dependency, or psychological
disorder). Subject has any condition for which, in the opinion of the
investigator, participation would not be in the best interest of the subject
(e.g., compromise the well-being) or that could prevent, limit, or confound the
protocol- specified assessments. Subject is taking any prohibited medications.
19. Subject has had major surgery within 2 weeks before study treatment or has
not fully recovered from surgery, excluding surgery related to myeloma.
20. Subject has received an investigational drug (including investigational
vaccines) within 14 days or 5 half-lives of the investigational drug prior to
initiation of study intervention, whichever is longer, or used an invasive
investigational medical device within 4 weeks before study treatment or is
currently enrolled in an interventional investigational study.
21. Persons referred to in Articles L1121-5 to L1121-8 of the CSP 22. Subject has
contraindications to required prophylaxis for deep vein thrombosis and pulmonary
embolism.
23. Incidence of gastrointestinal disease that may significantly alter the
absorption of oral drugs.
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