Expression-linked and R-ISS-adapted Stratification for First Line Therapy in Multiple Myeloma Patients

Inclusion Criteria:

1. newly diagnosed, untreated, symptomatic, documented myeloma (according to therevised Hypercalcaemia, renal dysfunction, anaemia and bone lesions (CRAB) criteria 2014, see Appendix 1) with clonal bone marrow (BM) plasma cells ≥10% orbiopsy-proven osseous or extramedullary plasmacytoma and any one or more of thefollowing myeloma defining events: I. Hypercalcemia: serum calcium >0,25 mmol/L (>1mg/dl) higher than the upper limit of normal or >2,75 mmol/L (>11 mg/dL) II. Renalinsufficiency: serum creatinine > 177 μmol/l (>2 mg/dl) III. Anemia: hemoglobinvalue of >20 g/l below the lower limit of normal or a hemoglobin value lower than 10g/dl. IV. Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, orPET- CT (positron emission tomography) V. Clonal BM plasma cell percentage ≥60% VI.Involved: uninvolved serum free light chain ratio ≥100 VII. >1 focal lesion on MRIexamination

2. Presence of measurable disease: I. Serum M-protein ≥ 0.5 g/dL or urine M-protein ≥ 200 mg/24 hours. II. Involved FLC (free light chain) level ≥ 10 mg/dl, provided sFLC (free light chain) ratio isabnormal.

3. R-ISS stage I33 (see appendix 2)

4. Standard gene expression pattern of isolated plasma cell based on SKY92 GEP assay

5. Must be ≥ 18 and ≤70 years at the time of signing the informed consent form.

6. Must be able to adhere to the study visit schedule and other protocol requirementsin the investigator's opinion.

7. WHO (see Appendix 3) performance status 0-2 (WHO=2 is allowed only if caused by MMand not by co-morbid conditions).

8. Ability to understand and willingness to sign written informed consent. Signedinformed consent must be obtained before any study specific procedure.

9. Suitable for high-dose melphalan and stem cell retransfusion.

10. Subjects must have adequate vascular access for leukapheresis

.

11. Male or Female

Male participants:

A male participant must agree to use contraception during the intervention period and for at least 5 months after the last dose of isatuximab treatment and refrain from donating sperm during this period.

Female participants:

A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

i) Not a Female of childbearing potential (FCBP), OR ii) A FCBP who must have a negative serum or urine pregnancy test with a sensitivity of at least 25 milliliter units (mIU)/mL within 28 days prior to and again within 24 hours prior to starting study medication and before each cycle of study treatment as well as day 21 of induction and experimental arm consolidation as well as every 28 days during all other cycles. If heavy menstruation appears or a menstruation is delayed, additional tests have to be performed. Participants must either commit to continue abstinence from heterosexual intercourse or apply a highly effective method of birth control during the intervention period and for at least 5 months after the last dose of isatuximab treatment Of note: contraception duration should take also into consideration any backbone therapy

All females:

Must understand the damages and hazards lenalidomide can cause to an unborn fetus and the necessary precautions associated with the use of lenalidomide.

Females of childbearing potential (FCBPs) must understand the need for effective contraception, without interruption. This should be 28 days before starting lenalidomide, isatuximab, throughout the entire duration of study and at least 5 months after the last dose of lenalidomide or isatuximab.

All female and male patients with fertile partners must adhere to the following recommendations:

I. If the female patients are permanently sterile or post-menopausal, they are considered to have no childbearing potential. Permanent sterilization methods include hysterectomy, bilateral salpingectomy. The postmenopausal state is defined as the absence of menstruation within 12 months without alternative medical reasons.

II. Female patients with fertility (and male patients with fertile partners) must agree to use an effective method of contraception (pearl index <1) throughout the study period and for 12 months thereafter.

III. According to the "Recommendations Related to Contraception and Pregnancy Tests in Clinical Trials" (Clinical Trial Facilitation Group, 2014-09-15), birth control methods considered to be very effective include:

• Combined (including estrogen and progesterone) hormonal contraception related toovulation suppression*:

• oral

• In the vagina

• Transdermal *Due to the increased risk of venous thromboembolism in subjectswith multiple myeloma taking lenalidomide and dexamethasone, the use ofcombined oral contraceptive pills are not recommended and the method should bechanged

• Progesterone-only hormone contraception associated with inhibition of ovulation*:

• oral

• Injectable

• Implantable

• Intrauterine device (IUD)

• Intrauterine Hormone-releasing System (IUS)

• Vasectomized partner (with confirmed surgical success)

• Sexual abstinence (when consistent with the subject's usual lifestyle) IV.Investigational medicial product (IMP) may interact with hormonal contraceptives andmay reduce the effectiveness of contraceptive methods V. Women using hormonalcontraceptives should add a barrier method as a second form of contraception,because it is currently unknown whether lenalidomide, isatuximab, bortezomib ordexamethasone may reduce the effectiveness of hormonal contraceptives.

VI. Breast-feeding lenalidomide and its metabolites are excreted in human milk. It is unknown whether isatuximab is secreted in milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with lenalidomide and isatuximab VII. Must adhere to regular pregnancy tests (at least every 21 days during induction and consolidation (experimental arm) and 28 days during maintenance and other therapy cycles, in case of irregular menstruation at least every two weeks, if heavy menstruation appears or menstruation is delayed, additional tests have to be performed).

VIII. Notify investigator if method of contraception is changed. IX. Notify investigator immediately in case of pregnancy

Male subjects must agree:

I. to use a condom during sexual contact with a pregnant female or a FCBP while taking lenalidomide or isatuximab, during any dose interruptions and for 5 months after the last dose of lenalidomide or isatuximab, II. Not donate semen or sperm while receiving lenalidomide, during dose interruptions and for at least 5 months after the last dose of lenalidomide and/or isatuximab.

III. Receive counseling about pregnancy precautions and the potential risks of fetal exposure to lenalidomide at a minimum of every 28 days l) All subjects must: I. Agree to abstain from donating blood while taking lenalidomide, during dose interruptions and for at least 5 months after the last dose of lenalidomide and/or Isatuximab.

II. Agree never to give lenalidomide to another person. III. Agree to return all unused lenalidomide capsules to the investigator (with exception of prescribed lenalidomide capsules) IV. Be aware that no more than a 28-day lenalidomide supply may be dispensed with each cycle of lenalidomide during induction and consolidation therapy and be prescribed during maintenance therapy.

Exclusion Criteria:

1. Direct Coombs test positive hemolytic anemia.

2. Involvement of the central nervous system (CNS).

3. History or presence of clinically relevant CNS pathology such as clinically relevantepilepsy, seizure, paresis, aphasia, stroke, subarachnoid hemorrhage or other CNSbleed, severe brain injuries, dementia, Parkinson's disease, cerebellar disease,organic brain syndrome, or psychosis.

4. Subject with active or history of plasma cell leukemia, Waldenström'smacroglobulinemia, POEMS syndrome or clinically significant amyloidosis.

5. Patients having nonsecretory MM.

6. Systemic AL amyloidosis (with exception of AL amyloidosis of BM).

7. Previous chemotherapy or radiotherapy during the past 5 years except localradiotherapy in case of local myeloma progression or benign diseases, such asnonmalignant thyroid diseases. (Note: patients may have received a cumulative doseof up to 320 mg of dexamethasone or equivalent as emergency therapy.) Previoustherapy due to smouldering myeloma or a single dose of bortezomib may be acceptable.In this case the coordinating investigator or his deputy has to be consulted priorto inclusion.

8. Patients with any of the following laboratory abnormalities: I. Absolute neutrophil count (ANC) < 1,000/μL. II. Platelet count < 50,000/µL (Platelet transfusions are not permitted to improve platelet count one week prior tostudy inclusion.) III. Serum Creatinine Clearance (CrCl) < 30 mL/min/1,73m2. IV.Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 ×upper limit of normal (ULN) (unless due to liver infiltration by myeloma cells),serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with documentedGilbert's syndrome. V. International ratio (INR) or partial thromboplastin time (PTT) > 1.5 × ULN, orhistory of Grade ≥ 2 hemorrhage within 30 days, or subject requires ongoingtreatment with chronic, therapeutic dosing of anticoagulants (e.g. warfarin, lowmolecular weight heparin, or Factor Xa inhibitors).

9. Echocardiogram (ECHO) with left ventricular ejection fraction < 45%.

10. An inadequate pulmonary function defined as oxygen saturation (Sa02) < 92 % on roomair

11. Known to be HIV+ or to have hepatitis A, B, or C active infection. Uncontrolled or active hepatitis B virus (HBV) infection: Patients with positiveHBsAg and/or HBV DNA Of note: Patient can be eligible if anti-HBc immunoglobulin G (IgG) positive (with or withoutpositive anti-HBs) but HBsAg and HBV DNA are negative. If anti-HBV therapy in relation with prior infection was started before initiationof IMP, the anti-HBV therapy and monitoring should continue throughout the studytreatment period. Patients with negative HBsAg and positive HBV DNA observed during screening periodwill be evaluated by a specialist for start of anti-viral treatment: study treatmentcould be proposed if HBV DNA becomes negative and all the other study criteria arestill met. Active HCV infection: positive HCV RNA and negative anti-HCV Of note: Patients with antiviral therapy for HCV started before initiation of IMP andpositive HCV antibodies are eligible. The antiviral therapy for HCV should continuethroughout the treatment period until seroconversion. Patients with positive anti-HCV and undetectable HCV RNA without antiviral therapyfor HCV are eligible.

12. Subjects with prior history of malignancies, other than MM, unless the subject hasbeen free of the disease for ≥ 5 years.

13. Subjects with severe polyneuropathy with accompanying pain

14. Hypersensitivity or allergy against any of the study drugs.

15. Contraindications against any of the study drugs as outlined in the Investigatorbrochure or equivalent.

16. Prisoners or subjects who are legally institutionalized, or those unwilling orunable to comply with scheduled visits, drug administration plan, laboratory tests,other study procedures, and study restrictions.

17. Participation in another interventional clinical trial during this trial or within 4weeks before entry into this trial. There may be exceptions at the discretion of the (coordinating) investigator.

18. Active systemic infection and severe infections requiring treatment with aparenteral administration of antibiotics.

19. Any clinically significant, uncontrolled medical conditions that, in theInvestigator's opinion, would expose the patient to excessive risk or may interferewith compliance or interpretation of the study results.

20. Hypersensitivity or history of intolerance to steroids, mannitol, pregelatinizedstarch, sodium stearyl fumarate, histidine (as base and hydrochloride salt),arginine hydrochloride, poloxamer 188, sucrose or any of the other components ofstudy intervention that are not amenable to premedication with steroids and H2blockers or would prohibit further treatment with these agents.