Isa-RVD Study in Patients With Newly Diagnosed Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
This study aims to evaluate the stringent Complete Response (sCR) rate by the end of two cycles of induction treatment, defined as the proportion of patients who have achieved sCR, according to International Myeloma Working Group (IMWG) criteria, by the end of two cycles of induction treatment.

Official Title
-----------------
Isa-RVD Study: Phase II, Multi-centre, Single-Arm, Open-Label Study to Evaluate the Efficacy and Safety of the Combination Regimen Isatuximab, Lenalidomide, Bortezomib, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: Isatuximab
* Drug: Bortezomib
* Drug: Lenalidomide
* Drug: Dexamethasone (IV)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants must have a diagnosis of MM according to Revised International Myeloma Working Group diagnostic criteria (Rajkumar 2014): Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events: End organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: Hypercalcaemia: 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) Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or a 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 Patient has received no prior treatment with any systemic therapy for the treatment of multiple myeloma. Prior treatment of hypercalcaemia or spinal cord compression with corticosteroids does not disqualify the patient (the dose should not exceed the equivalent of 160 mg of dexamethasone in a 2 week period) Bisphosphonates are permitted Patients treated with local radiotherapy with or without concomitant exposure to steroids, for pain control or management of cord/nerve root compression, are eligible. Two weeks must have lapsed since last date of radiotherapy, which is recommended to be a limited field. Patients who require concurrent radiotherapy should have entry to the protocol deferred until the radiotherapy is completed and 2 weeks have passed since the last date of therapy. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. Age ≥ 18 years at the time of signing Informed Consent. Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Lenalidomide Pregnancy Prevention Risk Management Plan. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25mlU/mL 10 to14 days prior to therapy and repeated again within 24 hours prior to prescribing lenalidomide for induction Cycle 1 (prescriptions must be filled within 7 days as required by the Lenalidomide Pregnancy Prevention Risk Management Plan) and must either commit to complete abstinence from heterosexual contact or begin TWO acceptable methods of birth control, one highly effective method and one additional effective (barrier) method, AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must practice complete abstinence or agree to use a condom during sexual contact with a FCBP even if they have had a successful vasectomy. All study participants must be registered into the mandatory Lenalidomide Pregnancy Prevention Risk Management Plan, and be willing and able to comply with the requirements of the Lenalidomide Pregnancy Prevention Risk Management Plan.*A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months). All necessary baseline studies for determining eligibility must be obtained within 21 days prior to enrolment. Subject has an ECOG performance status of < 2 or Karnofsky performance status of ≥ 60 (Appendix E). Subject must be able to adhere to the study visit schedule and other protocol requirements. Participants must also have measurable disease according to the Standard Diagnostic Criteria (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. Patient has ≥ Grade 2 peripheral neuropathy on clinical examination within 14 days before enrolment. Renal insufficiency (serum creatinine levels > 2.5 mg/dL/221μmol/L, calculated creatinine clearance with Cockcroft-Gault formula (see Appendix G) < 45 ml/min). Subjects with evidence of mucosal or internal bleeding and/or platelet refractory (i.e. unable to maintain a platelet count 50,000 cells/mm3). Subjects with an absolute neutrophil count (ANC) < 1000 cells/mm3. Growth factors may not be used to meet ANC eligibility criteria. Subjects with a haemoglobin < 8.0 g/dL. AST (SGOT) and ALT (SGPT) > 2 x ULN, bilirubin levels > 1.5 ULN. Concomitant therapy medications that include corticosteroids (except as indicated in inclusion criteria). Myocardial infarction within 6 months prior to enrolment or has New York Heart Association (NYHA) Class III or IV heart failure (Appendix G), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischaemia or active conduction system abnormalities. Clinically relevant active infection requiring treatment (antibiotics, antivirals, antifungals). Any serious co-morbid condition, including laboratory abnormalities, that in the opinion of the Investigator places the subject at unacceptable risk if he/she were to participate in the study. Female subject is pregnant or breast-feeding. Serious psychiatric illness or addiction likely to interfere with participation in this clinical study. Uncontrolled diabetes mellitus. Contraindication to any required concomitant drugs or supportive therapies including hypersensitivity to all anticoagulation and antiplatelet options or hypersensitivity to acyclovir or similar anti-viral drug. History of allergic reaction/hypersensitivity attributed to compounds containing boron, mannitol, polysorbate 80 or sodium citrate dehydrate. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes). Known seropositive for or active HIV infection active hepatitis B or C viral infection. Patients who are seropositive because of hepatitis B virus vaccine are eligible. Known intolerance to steroid therapy. Patient has hypersensitivity to bortezomib, boron, or mannitol. Diagnosed or treated for another malignancy within 2 years of enrolment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy. Participation in clinical trials with other anti-myeloma investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial. Radiation therapy within 2 weeks before randomization. Enrolment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 2 weeks have elapsed since the last date of therapy.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Isa-RVD<br>Isatuximab (IV): 10 mg/kg on Days 1, 8, 15, 22, 29 in Cycle 1; from Cycle 2 onwards, it will be given on Days 1, 15, 29. Bortezomib (SQ): 1.3 mg/m² on Days 1, 4, 8, 11, 22, 25, 29, and 32. Lenalidomide (PO): 25 mg/day (10 mg/day for patients with creatinine clearance [CrCl] ≥30 to <60 mL/min) from Day 1 to Day 14 and from Day 22 to Day 35 of each cycle. Dexamethasone (IV on the days of Isatuximab and PO on other days): 20 mg/day on Days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, 23, 25, 26, 29, 30, 32, and 33. If patients are ≥75 years old, dexamethasone will be administered on Days 1, 4, 8, 11, 15, 16, 22, 25, 29 and 32. | Drug: Isatuximab<br>* Isatuximab (IV): 10 mg/kg on Days 1, 8, 15, 22, 29 in Cycle 1; from Cycle 2 onwards, it will be given on Days 1, 15, 29.<br>Drug: Bortezomib<br>* Bortezomib (SQ): 1.3 mg/m² on Days 1, 4, 8, 11, 22, 25, 29, and 32.<br>Drug: Lenalidomide<br>* Lenalidomide (PO): 25 mg/day (10 mg/day for patients with creatinine clearance [CrCl] ≥30 to <60 mL/min) from Day 1 to Day 14 and from Day 22 to Day 35 of each cycle.<br>Drug: Dexamethasone (IV)<br>* Dexamethasone (IV on the days of Isatuximab and PO on other days): 20 mg/day on Days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, 23, 25, 26, 29, 30, 32, and 33. If patients are ≥75 years old, dexamethasone will be administered on Days 1, 4, 8, 11, 15, 16, 22, 25, 29 and 32.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the stringent Complete Response (sCR) rate by the end of two cycles of induction treatment | To evaluate the stringent Complete Response (sCR) rate by the end of two cycles of induction treatment, defined as the proportion of patients who have achieved sCR, according to International Myeloma Working Group (IMWG) criteria, by the end of two cycles of induction treatment. | 84 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate complete response (CR) and sCR rate following induction, ASCT and maintenance treatment. |  | 3.5 years | 
| To evaluate overall response rate and rate of very good partial response (VGPR) or better following induction, ASCT, and maintenance treatment. |  | 3.5 years | 
| To evaluate duration of and time to sCR and time to CR. |  | 3.5 years | 
| To evaluate time to VGPR or better. |  | 3.5 years | 
| To evaluate time to partial response (PR) or better. |  | 3.5 years | 
| To assess negative minimal residual disease (MRD) rate following induction, ASCT and maintenance treatment. |  | 3.5 years | 
| To evaluate clinical outcomes including time to progression (TTP). |  | 3.5 years | 
| To evaluate clinical outcomes including progression-free survival (PFS). |  | 3.5 years | 
| To evaluate clinical outcomes including overall survival (OS). |  | 3.5 years | 
| To evaluate clinical outcomes including duration of response (DOR). |  | 3.5 years | 
| To assess the safety of the Isa-RVD treatment regime based on reported adverse events and toxicity. |  | 3.5 years | 
| To assess the tolerability of the Isa-RVD treatment regime based on reported adverse events and toxicity. |  | 3.5 years | 
| To evaluate stem cell yield after mobilization. |  | 90 days |