Trial on the Effect of Isatuximab to Lenalidomide/Bortezomib/Dexamethasone (RVd) Induction and Lenalidomide Maintenance in Patients With Newly Diagnosed Myeloma (GMMG HD7)

Study Overview
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Brief Summary
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Trial in patients with newly diagnosed myeloma to evaluate the effect of isatuximab in induction therapy with lenalidomide/bortezomib/dexamethasone (RVd) and in lenalidomide maintenance treatment

Detailed Description
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Prospective, multicentre, randomised, parallel group, open, phase III clinical trial, for patients with confirmed diagnosis of untreated multiple myeloma requiring systemic therapy. Investigational Medicinal Products: Isatuximab, Lenalidomide Randomization: Patients are randomized in one of 2 study arms (IA or IB) before induction therapy. Patients randomized in arm IA will receive 3 cycles RVd (Bortezomib (Velcade®), Lenalidomide (Revlimid®, each cycle is 42 days), Dexamethasone). Patients in arm IB will additionally receive the monoclonal antibody Isatuximab in the 3 cycles RVd. After induction therapy patients undergo intensifying therapy according to GMMG standard (usually mobilization therapy followed by stem cell collection and autologous stem cell transplantation). Randomization: Before maintenance treatment patients are randomized in one of 2 study arms (IIA and IIB): Patients in arm IIA receive Lenalidomide maintenance therapy for three years, patients in arm IIB receive additional Isatuximab. There are two primary objectives: to compare the induction regimen (IA vs IB) regarding minimal residual disease (MRD) negativity after induction (assessed by flow cytometry; sensitivity at least 1e-5) to compare the maintenance strategies (arms IIA vs IIB) regarding progression-free survival (PFS), defined as time from 2nd randomization (prior to maintenance therapy) to progression or death from any cause whichever occurs first. The duration of the trial for each patients is expected to be 45-48 months (induction and intensification treatment: 6-9 months, 3 months rest between intensification and start of maintenance phase 36 months).

Official Title
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A Randomized Phase III Trial Assessing the Benefit of the Addition of Isatuximab to Lenalidomide / Bortezomib / Dexamethasone (RVd) Induction and Lenalidomide Maintenance in Patients With Newly Diagnosed Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Lenalidomide
* Drug: Bortezomib
* Drug: Dexamethasone
* Drug: Isatuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of untreated multiple myeloma requiring systemic therapy (diagnostic criteria (IMWG updated criteria (2014)1) see appendix IA. For some patients systemic therapy may be required though these diagnostic criteria are not fulfilled. In this case the GMMG study office has to be consulted prior to inclusion.) Patient is eligible for high dose therapy and autologous stem cell transplantation. Measurable disease, defined as any quantifiable monoclonal protein value, defined by at least one of the following three measurements:2 Serum M-protein ≥ 10g/l (for IgA ≥ 5g/l) Urine light-chain (M-protein) of ≥ 200 mg/24 hours Serum FLC assay: involved FLC level ≥ 10 mg/dl provided sFLC ratio is abnormal Age 18 - 70 years inclusive WHO performance status 0-2 Negative pregnancy test at inclusion (females of childbearing potential) All patients must agree on the requirements regarding the lenalidomide pregnancy prevention plan described in section 6. For all men and females of childbearing potential: patients must be willing and capable to use adequate contraception during the complete therapy. All patients must agree to abstain from donating blood while taking lenalidomide and for 28 days following discontinuation of lenalidomide therapy agree not to share study drug lenalidomide with another person and to return all unused study drug to the investigator or pharmacist Ability of patient to understand character and individual consequences of the clinical trial Provide written informed consent (must be available before enrolment in the trial) Exclusion Criteria Patient has known 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. Systemic AL amyloidosis (except for AL amyloidosis of the skin or the bone marrow) Plasma cell leukemia Previous chemotherapy or radiotherapy during the past 5 years except local radiotherapy in case of local myeloma progression. (Note: patients may have received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency therapy.) Previous therapy due to smouldering myeloma may be acceptable. In this case the GMMG study office has to be consulted prior to inclusion Severe cardiac dysfunction (NYHA classification III-IV), ejection fraction < 40% Significant hepatic dysfunction (ASAT and/or ALAT ≥ 3 times normal level and/or serum bilirubin ≥ 1.5 times normal level if not due to hereditary abnormalities as Gilbert's disease), unless related to myeloma. Patients with active or history of hepatitis B or C HIV positivity Patients with active, uncontrolled infections Patients with severe renal insufficiency (Creatinine Clearance < 30ml/min) Patients with peripheral neuropathy or neuropathic pain, CTC grade 2 or higher (as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0) Patients with a history of active malignancy during the past 5 years with the exception of following malignancies after curative therapy: basal cell carcinoma of the skin, squamous cell skin carcinoma, stage 0 cervical carcinoma or any in situ malignancy Patients with acute diffuse infiltrative pulmonary and/or pericardial disease Autoimmune hemolytic anemia with positive Coombs test or immune thrombocytopenia Platelet count < 75 x 109/l Haemoglobin < 8.0 g/dl, unless related to myeloma Absolute neutrophil count (ANC) < 1.0 x 109/l (the use of colony stimulating factors within 14 days before the test is not allowed) Corrected serum calcium > 14 mg/dl (> 3.5 mmol/l) Unable or unwilling to undergo thromboprophylaxis Pregnancy and lactation Participation in other clinical trials. This does not include long-term follow-up periods without active drug treatment of previous studies during the last 6 months. Prisoners or subjects who are legally institutionalized, or those unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions. No patients will be allowed to enrol in this trial more than once. -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 2 x 2 arms, 1. randomization before induction therapy (arm IA and IB), 2. randomization before maintenance therapy (arm IIA and IIB)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IA<br>Patients in arm IA are treated with 3 cycles RVd (lenalidomide 25 mg/d p.o. d1 - 14 and d22 - 35; bortezomib 1.3 mg/m2 s.c. d1, 4, 8, 11, 22, 25, 29, 32; dexamethasone p.o. 20 mg/d d1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, 32-33).Treatment repeats every 42 days (d43 = cycle 2 d1). Standard intensification: For all patients, stem cells are mobilized by GMMG Standard protocols (CAD: cyclophosphamide, doxorubicin, dexamethasone) and G-CSF. At least 7.5x106 CD34+ cells/kg body weight are harvested. High dose treatment (melphalan 200mg/m², HDT) followed by autologous stem cell transplantation (ASCT) is started 4 - 6 weeks after CAD. For patients not in CR after HDT1, a second HDT is performed within 3 months. | Drug: Lenalidomide<br>* 25 mg per os on day 1-14 and d22-35 in induction cycle 1-3 (Arms IA and IB) 10 mg p.o. on day 1-28 in maintenance cycle 1-3, 15 mg p.o. on day 1-28 in maintenance cycle 4-39 (Arms IIA and IIB)<br>* Other names: Revlimid;Drug: Bortezomib<br>* all arms: 1,3 mg/m^2 subcutaneous on day 1, 4, 8, 11, 22, 25, 29 32 in 3 induction cycles<br>* Other names: Velcade;Drug: Dexamethasone<br>* 20 mg per os on day 1,2 and 4,5 and 8,9 and 11,12 and 15 and 22,23 and 25,26 and 29,30 and 32,33 in induction cycles 1-3 (Arms IA and IB). Maintenance cycle 1 on day 1, 8, 15, 22 Dexamethasone 20 mg/d per os (Arm IIA). In Arm IIB Dexamethasone 20 mg i.v. on days of Isatuximab infusion in the first maintenance cycle (d 1, 8, 15, 22), dexamethasone will be administered intravenously as part of the premedication. If an isatuximab dose is skipped or discontinued dexamethasone should be administered orally.<br>|
| Experimental: IB<br>Patients in arm IB are treated with 3 cycles RVd + Isatuximab (lenalidomide 25 mg/d p.o. d1 - 14 and d22 - 35; bortezomib 1.3 mg/m2 s.c. d1, 4, 8, 11, 22, 25, 29, 32;dexamethasone p.o. 20 mg/d d1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, 32-33).Isatuximab (10 mg/kg i.v. C1: d 1, 8, 15, 22, 29; C2-3: d 1, 15, 29).Treatment repeats every 42 days (d43 = cycle 2 d1). Standard intensification: For all patients, stem cells are mobilized by GMMG Standard protocols (CAD: cyclophosphamide, doxorubicin, dexamethasone) and G-CSF. At least 7.5x106 CD34+ cells/kg body weight are harvested. High dose treatment (melphalan 200mg/m², HDT) followed by autologous stem cell transplantation (ASCT) is started 4 - 6 weeks after CAD. For patients not in CR after HDT1, a second HDT is performed within 3 months. | Drug: Lenalidomide<br>* 25 mg per os on day 1-14 and d22-35 in induction cycle 1-3 (Arms IA and IB) 10 mg p.o. on day 1-28 in maintenance cycle 1-3, 15 mg p.o. on day 1-28 in maintenance cycle 4-39 (Arms IIA and IIB)<br>* Other names: Revlimid;Drug: Bortezomib<br>* all arms: 1,3 mg/m^2 subcutaneous on day 1, 4, 8, 11, 22, 25, 29 32 in 3 induction cycles<br>* Other names: Velcade;Drug: Dexamethasone<br>* 20 mg per os on day 1,2 and 4,5 and 8,9 and 11,12 and 15 and 22,23 and 25,26 and 29,30 and 32,33 in induction cycles 1-3 (Arms IA and IB). Maintenance cycle 1 on day 1, 8, 15, 22 Dexamethasone 20 mg/d per os (Arm IIA). In Arm IIB Dexamethasone 20 mg i.v. on days of Isatuximab infusion in the first maintenance cycle (d 1, 8, 15, 22), dexamethasone will be administered intravenously as part of the premedication. If an isatuximab dose is skipped or discontinued dexamethasone should be administered orally.<br>Drug: Isatuximab<br>* 10 mg/kg in the vein( i.v) on day 1,8,15, 22, 29 in induction cycle 1 on day 1, 15 and 29 in induction cycle 2 and 3 (Arm IB). 10 mg/kg i.v. on day 1,8, 15 and 22 in maintenance cycle 1, 10 mg/kg i.v. on day 1 and 15 in maintenance cycle 2 and 3, 10 mg/kg i.v. on day 1 in maintenance cycle 4 - 39 (Arm IIB)<br>|
| Active Comparator: IIA<br>maintenance treatment with Lenalidomide 10mg/d (increased to 15mg/d after 3 months) repeated every 28d. Maintenance treatment is planned for up to 36 months or until progression if progression occurs first. | Drug: Lenalidomide<br>* 25 mg per os on day 1-14 and d22-35 in induction cycle 1-3 (Arms IA and IB) 10 mg p.o. on day 1-28 in maintenance cycle 1-3, 15 mg p.o. on day 1-28 in maintenance cycle 4-39 (Arms IIA and IIB)<br>* Other names: Revlimid;|
| Experimental: IIB<br>maintenance treatment with Lenalidomide 10mg/d (increased to 15mg/d after 3 months) + Isatuximab (10 mg/kg; C1: d1, 8, 15, 22; C2-C3: d1 + 15; C4-39:d1, repeated every 28d). Within the trial, maintenance treatment is planned for up to 36 months or until progression if progression occurs first. | Drug: Lenalidomide<br>* 25 mg per os on day 1-14 and d22-35 in induction cycle 1-3 (Arms IA and IB) 10 mg p.o. on day 1-28 in maintenance cycle 1-3, 15 mg p.o. on day 1-28 in maintenance cycle 4-39 (Arms IIA and IIB)<br>* Other names: Revlimid;Drug: Isatuximab<br>* 10 mg/kg in the vein( i.v) on day 1,8,15, 22, 29 in induction cycle 1 on day 1, 15 and 29 in induction cycle 2 and 3 (Arm IB). 10 mg/kg i.v. on day 1,8, 15 and 22 in maintenance cycle 1, 10 mg/kg i.v. on day 1 and 15 in maintenance cycle 2 and 3, 10 mg/kg i.v. on day 1 in maintenance cycle 4 - 39 (Arm IIB)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRD negativity after induction Treatment (comparison of arms IA and IB) | Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5) | 18 weeks after start of study treatment | 
| Progression Free Survival (PFS) after second randomization (arms IIA and IIB) | Response Evaluation by IMWG criteria | time from 2. randomization to progression or death from any cause whichever comes first, censored after three years of maintenance therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| to compare the four treatment arms (IA-IIA, IA-IIB, IB-IIA, IB-IIB) regarding Progression free survival (PFS) | Response evaluation by IMWG criteria | time from 1. randomization (study inclusion) to progression or death whichever comes first (assessed up to 79 months) | 
| to compare all 4 treatment arms (IA-IIA, IA-IIB, IB-IIA, IB-IIB) regarding overall survival (OS) from time of 1.randomization | survival status | time from randomisation to time of death from any cause (assessed up to 79 months) | 
| Overall survival from second randomization | survival status | time from 2. randomization to time of death from any cause (assessed up to 75 months) | 
| Complete Response (CR) rates after induction therapy | Response Evaluation by IMWG criteria | After induction treatment (18 weeks after start of treatment) | 
| Complete Response (CR) after high dose therapy | Response Evaluation by IMWG criteria | After high dose therapy (9 or 12 months after start of therapy) | 
| Complete Response (CR) during/after maintenance therapy | Response Evaluation by IMWG criteria | During/after maintenance therapy (6 months after start of therapy up to 36 months of maintenance therapy) | 
| MRD negativity after high dose therapy | Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5) | After high dose therapy (9 or 12 months after start of therapy) | 
| MRD negativity during and after maintenance therapy | Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5) | up to 36 months after start of maintenance therapy | 
| Best response to treatment during the trial | Response evaluation by IMWG criteria | response assessment after 3 months, 4,5 months, 5,5 months, 9 months (if applicable: 3 months later after 2. high dose therapy) subsequently every 3 months during maintenance treatment, up to 48 months after start of study treatment | 
| PFS 2 (PFS after next line of therapy) from 2. randomization | Response evaluation by IMWG criteria | time from 2. randomization to time of overall end of trial (up to 75 months) | 
| Toxicity during induction and maintenance with respect to adverse events of CTC grade >3 (and specific adverse events of CTC grade > 2 as defined in the protocol and serious adverse events | toxicity according CTCAE Version v5.0 | : from first administration of study drug until 30 days after last administration of study drug or any drug of the study treatment or upon start of a new subsequent chemotherapy, whichever occurs first | 
| Quality of Life Assessment | EORTC (European Organization of Research and Treatment of Cancer) -QLQC30 Questionnaire to assess the quality of life of cancer patients. Impairment of daily life is asked in 4 scales from not at all (best) to very much (worst scale), EORTC-QLQMY20 questionnaire to assess health-related quality of life in patients with multiple myeloma with 4 scales from not at all (best scale) to very much (worst scale); EQ(EuroQol Group)-5D-5L Health questionnaire comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. Additionally a visual analogue scale from 100 (best) to 0 (worst scale) is used to assess the quality of health questionnaires. | assessed at baseline, after ca. 4.5 months, 9 months, (additionally after 12 months,if a second high dose therapy is administered) after 12 months of maintenance and at end of study (up to 50 months) | 
| Pharmakokinetic analyses of Isatuximab in induction treatment of patients in Arm IB (selected sites only) | Determination of serum concentration of isatuximab at different timepoints before, during and after isatuximab infusion | Up to 18 weeks in induction treatment (C1: D1, before infusion, at end of infusion, 1 h after infusion, C1 D8,15,22,29 before infusion; C2 and 3:D1 before infusion | 
| Pharmakokinetic analyses of Isatuximab in maintenance treatment of patients in Arm IIB (selected sites only) | Determination of serum concentration of isatuximab at different timepoints | Up to 9 months (C1: D1, before infusion, at end of infusion, 1 h after infusion, C1 D8,15,22 before infusion, C2 -9, D1: before infusion |