Isa-RVD Study in Patients With Newly Diagnosed Multiple Myeloma

Inclusion Criteria:

1. Participants must have a diagnosis of MM according to Revised International MyelomaWorking Group diagnostic criteria (Rajkumar 2014):

• Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullaryplasmacytoma and any one or more of the following myeloma defining events:

• End organ damage that can be attributed to the underlying plasma cellproliferative disorder, specifically:

• Hypercalcaemia: serum calcium >0·25 mmol/L (>1 mg/dL) higher than theupper limit of normal or >2·75 mmol/L (>11 mg/dL)

• Renal insufficiency: creatinine clearance <40 mL per min or serumcreatinine >177 μmol/L (>2 mg/dL)

• Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, ora haemoglobin value <100 g/L

• Bone lesions: one or more osteolytic lesions on skeletal radiography, CT,or PET-CT

• 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 lesions on MRI studies

2. Patient has received no prior treatment with any systemic therapy for the treatmentof multiple myeloma.

3. Prior treatment of hypercalcaemia or spinal cord compression withcorticosteroids does not disqualify the patient (the dose should not exceed theequivalent of 160 mg of dexamethasone in a 2 week period)

4. Bisphosphonates are permitted

5. Patients treated with local radiotherapy with or without concomitant exposureto steroids, for pain control or management of cord/nerve root compression, areeligible. Two weeks must have lapsed since last date of radiotherapy, which isrecommended to be a limited field. Patients who require concurrent radiotherapyshould have entry to the protocol deferred until the radiotherapy is completedand 2 weeks have passed since the last date of therapy.

6. Voluntary written informed consent before performance of any study-related procedurenot part of normal medical care, with the understanding that consent may bewithdrawn by the subject at any time without prejudice to future medical care.

7. Age ≥ 18 years at the time of signing Informed Consent.

8. Females of reproductive potential must adhere to the scheduled pregnancy testing asrequired in the Lenalidomide Pregnancy Prevention Risk Management Plan. Females ofchildbearing potential (FCBP) must have a negative serum or urine pregnancy testwith a sensitivity of at least 25mlU/mL 10 to14 days prior to therapy and repeatedagain within 24 hours prior to prescribing lenalidomide for induction Cycle 1 (prescriptions must be filled within 7 days as required by the LenalidomidePregnancy Prevention Risk Management Plan) and must either commit to completeabstinence from heterosexual contact or begin TWO acceptable methods of birthcontrol, one highly effective method and one additional effective (barrier) method,AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP mustalso agree to ongoing pregnancy testing. Men must practice complete abstinence oragree to use a condom during sexual contact with a FCBP even if they have had asuccessful vasectomy. All study participants must be registered into the mandatoryLenalidomide Pregnancy Prevention Risk Management Plan, and be willing and able tocomply with the requirements of the Lenalidomide Pregnancy Prevention RiskManagement Plan.*A female of childbearing potential is a sexually mature female who:

1. has not undergone a hysterectomy (the surgical removal of the uterus) orbilateral oophorectomy (the surgical removal of both ovaries) or 2) has not beennaturally postmenopausal (amenorrhea following cancer therapy does not rule outchildbearing potential) for at least 24 consecutive months (i.e., has had menses atany time during the preceding 24 consecutive months).

6. All necessary baseline studies for determining eligibility must be obtained within 21 days prior to enrolment.

7. Subject has an ECOG performance status of < 2 or Karnofsky performance status of ≥ 60 (Appendix E).

8. Subject must be able to adhere to the study visit schedule and other protocolrequirements.

9. Participants must also have measurable disease according to the Standard DiagnosticCriteria (Rajkumar 2009):

• Serum IgG, IgA, or IgM M-protein ≥ 0.5 g/dL, or

• Serum IgD M-protein ≥ 0.05 g/dL, or

• Urinary M-protein excretion of more than 200 mg/24 hours, or

• Serum free light chains of at least 100 mg/L with an abnormal FLC ratio

Exclusion Criteria:

Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study.

1. Patient has ≥ Grade 2 peripheral neuropathy on clinical examination within 14 daysbefore enrolment.

2. Renal insufficiency (serum creatinine levels > 2.5 mg/dL/221μmol/L, calculatedcreatinine clearance with Cockcroft-Gault formula (see Appendix G) < 45 ml/min).

3. Subjects with evidence of mucosal or internal bleeding and/or platelet refractory (i.e. unable to maintain a platelet count 50,000 cells/mm3).

4. Subjects with an absolute neutrophil count (ANC) < 1000 cells/mm3. Growth factorsmay not be used to meet ANC eligibility criteria.

5. Subjects with a haemoglobin < 8.0 g/dL.

6. AST (SGOT) and ALT (SGPT) > 2 x ULN, bilirubin levels > 1.5 ULN.

7. Concomitant therapy medications that include corticosteroids (except as indicated ininclusion criteria).

8. Myocardial infarction within 6 months prior to enrolment or has New York HeartAssociation (NYHA) Class III or IV heart failure (Appendix G), uncontrolled angina,severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence ofacute ischaemia or active conduction system abnormalities.

9. Clinically relevant active infection requiring treatment (antibiotics, antivirals,antifungals).

10. Any serious co-morbid condition, including laboratory abnormalities, that in theopinion of the Investigator places the subject at unacceptable risk if he/she wereto participate in the study.

11. Female subject is pregnant or breast-feeding.

12. Serious psychiatric illness or addiction likely to interfere with participation inthis clinical study.

13. Uncontrolled diabetes mellitus.

14. Contraindication to any required concomitant drugs or supportive therapies includinghypersensitivity to all anticoagulation and antiplatelet options or hypersensitivityto acyclovir or similar anti-viral drug. History of allergicreaction/hypersensitivity attributed to compounds containing boron, mannitol,polysorbate 80 or sodium citrate dehydrate.

15. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly,endocrinopathy, monoclonal protein (M-protein) and skin changes).

16. Known seropositive for or active HIV infection active hepatitis B or C viralinfection. Patients who are seropositive because of hepatitis B virus vaccine areeligible.

17. Known intolerance to steroid therapy.

18. Patient has hypersensitivity to bortezomib, boron, or mannitol.

19. Diagnosed or treated for another malignancy within 2 years of enrolment, with theexception of complete resection of basal cell carcinoma or squamous cell carcinomaof the skin, an in situ malignancy, or low-risk prostate cancer after curativetherapy.

20. Participation in clinical trials with other anti-myeloma investigational agents notincluded in this trial, within 14 days of the start of this trial and throughout theduration of this trial.

21. Radiation therapy within 2 weeks before randomization. Enrolment of subjects whorequire concurrent radiotherapy (which must be localized in its field size) shouldbe deferred until the radiotherapy is completed and 2 weeks have elapsed since thelast date of therapy.