Multiple Myeloma
Conditions
Brief summary
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
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 1. 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). 2. 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: 1. 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) 2. 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).
Interventions
DRUGLenalidomide
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)
DRUGBortezomib
all arms: 1,3 mg/m\^2 subcutaneous on day 1, 4, 8, 11, 22, 25, 29 32 in 3 induction cycles
DRUGDexamethasone
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.
DRUGIsatuximab
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)
Sponsors
University of Heidelberg Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
2 x 2 arms, 1. randomization before induction therapy (arm IA and IB), 2. randomization before maintenance therapy (arm IIA and IIB)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. 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.) 2. Patient is eligible for high dose therapy and autologous stem cell transplantation. 3. 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 4. Age 18 - 70 years inclusive 5. WHO performance status 0-2 6. Negative pregnancy test at inclusion (females of childbearing potential) 7. 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. 8. 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 9. Ability of patient to understand character and individual consequences of the clinical trial 10. Provide written informed consent (must be available before enrolment in the trial)
Exclusion criteria
1. 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. 2. Systemic AL amyloidosis (except for AL amyloidosis of the skin or the bone marrow) 3. Plasma cell leukemia 4. 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 5. Severe cardiac dysfunction (NYHA classification III-IV), ejection fraction \< 40% 6. 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. 7. Patients with active or history of hepatitis B or C 8. HIV positivity 9. Patients with active, uncontrolled infections 10. Patients with severe renal insufficiency (Creatinine Clearance \< 30ml/min) 11. 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) 12. 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 13. Patients with acute diffuse infiltrative pulmonary and/or pericardial disease 14. Autoimmune hemolytic anemia with positive Coombs test or immune thrombocytopenia 15. Platelet count \< 75 x 109/l 16. Haemoglobin \< 8.0 g/dl, unless related to myeloma 17. Absolute neutrophil count (ANC) \< 1.0 x 109/l (the use of colony stimulating factors within 14 days before the test is not allowed) 18. Corrected serum calcium \> 14 mg/dl (\> 3.5 mmol/l) 19. Unable or unwilling to undergo thromboprophylaxis 20. Pregnancy and lactation 21. 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. 22. 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. \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MRD negativity after induction Treatment (comparison of arms IA and IB) | 18 weeks after start of study treatment | Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5) |
| Progression Free Survival (PFS) after second randomization (arms IIA and IIB) | time from 2. randomization to progression or death from any cause whichever comes first, censored after three years of maintenance therapy | Response Evaluation by IMWG criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| to compare the four treatment arms (IA-IIA, IA-IIB, IB-IIA, IB-IIB) regarding Progression free survival (PFS) | time from 1. randomization (study inclusion) to progression or death whichever comes first (assessed up to 79 months) | Response evaluation by IMWG criteria |
| to compare all 4 treatment arms (IA-IIA, IA-IIB, IB-IIA, IB-IIB) regarding overall survival (OS) from time of 1.randomization | time from randomisation to time of death from any cause (assessed up to 79 months) | survival status |
| Overall survival from second randomization | time from 2. randomization to time of death from any cause (assessed up to 75 months) | survival status |
| Complete Response (CR) rates after induction therapy | After induction treatment (18 weeks after start of treatment) | Response Evaluation by IMWG criteria |
| Complete Response (CR) after high dose therapy | After high dose therapy (9 or 12 months after start of therapy) | Response Evaluation by IMWG criteria |
| Complete Response (CR) during/after maintenance therapy | During/after maintenance therapy (6 months after start of therapy up to 36 months of maintenance therapy) | Response Evaluation by IMWG criteria |
| MRD negativity after high dose therapy | After high dose therapy (9 or 12 months after start of therapy) | Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5) |
| MRD negativity during and after maintenance therapy | up to 36 months after start of maintenance therapy | Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5) |
| Best response to treatment during the trial | 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 | Response evaluation by IMWG criteria |
| PFS 2 (PFS after next line of therapy) from 2. randomization | time from 2. randomization to time of overall end of trial (up to 75 months) | Response evaluation by IMWG criteria |
| 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 | : 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 | toxicity according CTCAE Version v5.0 |
| Quality of Life Assessment | 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) | 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. |
| Pharmakokinetic analyses of Isatuximab in induction treatment of patients in Arm IB (selected sites only) | 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 | Determination of serum concentration of isatuximab at different timepoints before, during and after isatuximab infusion |
| Pharmakokinetic analyses of Isatuximab in maintenance treatment of patients in Arm IIB (selected sites only) | 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 | Determination of serum concentration of isatuximab at different timepoints |
Countries
Germany
Contacts
PRINCIPAL_INVESTIGATORHartmut Goldschmidt, Prof. Dr.
Med. Klinik V, University Hospital Heidelberg
Outcome results
None listed