newly diagnosed multiple myeloma MedDRA version: 21.0 Level: LLT Classification code 10028228 Term: Multiple myeloma System Organ Class: 100000004864
Conditions
Sponsors
Hellenic Society of Hematology (EAE)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Age = 18 years 2.Monoclonal plasma cells in the BM =10% or presence of a biopsy proven plasmacytoma and documented MM satisfying at least 1 of the CRAB criteria: -Hypercalcemia:serum calcium >0.25 mmol/L higher than ULN or >2.75 mmol/L. - Renal insufficiency:CrCl 177 µmol/L. -Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin 1.65 4.Not a candidate for high-dose chemotherapy with ASCT due to the presence of significant comorbid condition(s) that are likely to have a negative impact on tolerability of high dose chemotherapy with stem cell transplantation. The participants will be assessed by the IMWG frailty index that is recommended by ESMO guidelines. Participants with IMWG frailty index score 1 or 2 will be considered transplant ineligible 5.ECOG performance status: 0–2 6.Adequate organ system function as defined by the below laboratory assessments. oANC =1.25 X 109/L; GCSF use within the past 14 days is NOT permitted Hemoglobin = 8.0 g/dL; transfusions within the past 14 days are NOT permitted PLT = 50 x 109/L if BM is >50% involved in myeloma. Otherwise =75 x 109/L; transfusions within the past 14 days are NOT allowed to reach this level Total bilirubin =1.5xULN ALT = 2.5xULN eGFR =30 mL/min/1.73 m2 Spot urine 1 year b.Participants who have been amenorrhoeic for < 2 years without a history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation c.Post-hysterectomy, post-bilateral oophorectomy or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure. OR •Is a WOCBP and using 2 methods of reliable birth control, beginning 4 weeks before initiating treatment with lenalidomide, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of lenalidomide treatment. Thereafter, WOCBP must use 1 method of reliable birth control that is highly effective for a further 4 months following discontinuation of belantamab mafodotin or 3 months following the discontinuation of daratumumab. WOCBP must also agree not to donate eggs (ova, oocytes) for the purpose of reproduction during treatment, during dose interruptions and for 28-days following the last dose of lenalidomide or 3 months following discontinuation of daratumumab treatment or 4 months following discontinuation of belantamab mafodotin treatment whichever is longer. A WOCBP must have 2 negative pregnan
Exclusion criteria
Exclusion criteria: 1.Prior systemic therapy for MM or SMM. 2.Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the NCI CTCAE Version 5. 3.Major surgery within 2 weeks before the first dose of study drug 4.Presence of active renal condition. Participants with isolated proteinuria resulting from MM are eligible, provided that they fulfil the other inclusion criteria. 5.Any serious and/or unstable pre-existing medical or psychiatric disorder, or other conditions (including laboratory abnormalities) that could interfere with participant’s safety, obtaining informed consent or compliance to the study procedures. 6.Evidence of active mucosal or internal bleeding uncontrolled by local therapy and not explained by reversible coagulopathy. 7.Current active unstable liver or biliary disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. 8.Participants with previous or concurrent malignancies other than MM are excluded. Exceptions are surgically treated cervical carcinoma in situ, or any other malignancy that has been considered medically stable for at least 2 years. The participant must not be receiving active therapy other than hormonal therapy for this disease. 9.Evidence of cardiovascular risk including any of the following: •Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities, second degree or third degree AV block. •Screening 12-lead ECG showing a baseline QT interval >470 msec •History of myocardial infarction, acute coronary syndromes, coronary angioplasty or stenting or bypass grafting within 3 months of Screening. •Class III or IV heart failure as defined by the New York Heart Association functional classification system. •Uncontrolled hypertension. 10.Participant has known COPD 11.Active infection requiring treatment. 12.Known HIV infection, unless the participant can meet all of the following criteria: •Established ART for at least 4 weeks and HIV viral load <400 copies/mL. •CD4+ T-cell (CD4+) count =350 cells/uL. •No history of AIDS-defining opportunistic infections within the last 12 months. 13.To be seropositive for hepatitis B at screening or within 3 months prior to first dose of study treatment. 14.Positive hepatitis C antibody test result or positive hepatitis C RNA test result at screening or within 3 months before the first dose of study treatment unless the participant can meet the following criteria: •RNA test negative •Successful anti-viral treatment is required, followed by a negative HCV RNA test after a washout period of at least 4 weeks. 15.Current corneal epithelial disease except for mild punctate keratopathy. 16.Intolerance or contraindications to anti-viral prophylaxis. 17.Unable to tolerate antithrombotic prophylaxis. 18.Active or history of venous thromboembolism within past 3 months. 19.AL amyloidosis (light chain amyloidosis), active POEMS syndrome or active plasma cell leukemia at the time of screening. 20.Exhibiting clinical signs of or with a known history of meningeal or central nervous system involvement by MM. 21.Known intolerance or immediate or delayed hypersensitivity reaction or idiosyncratic reaction to: drugs chemically related to belantamab mafodotin, or any of the components of the study treatment; daratumumab SC or to any of its excipients; or infused protein products, sucrose, histidine, and polysorbate 80. 22.Use of
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part 1 – Dose finding To determine the safety and tolerability of belantamab mafodotin in combination with daratumumab, lenalidomide, and dexamethasone to establish a recommended dose for participants with TI NDMM. Part 2 – Dose expansion To further evaluate the safety and determine the preliminary clinical activity of belantamab mafodotin RP2D in combination with daratumumab, lenalidomide, and dexamethasone. ;Secondary Objective: To evaluate the effect of combining belantamab mafodotin with daratumumab, lenalidomide, and dexamethasone: •Assess the efficacy of belantamab mafodotin in combination with daratumumab, lenalidomide, and dexamethasone in TI NDMM. •Evaluate alternate corneal AE management approaches using visual acuity changes for belantamab mafodotin dose modifications. •To further characterize the pharmacokinetic (PK) profile of belantamab mafodotin when administered in combination with daratumumab, lenalidomide, and dexamethasone •To evaluate symptomatic AEs measured by the Ocular Surface Disease Index (OSDI) questionnaire as documented by the investigator. Exploratory objectives: •To investigate the relationship between biological characteristics and clinical response. •To explore the exposure-response relationship of belantamab mafodotin with clinical endpoints. ;Primary end point(s): Primary Endpoints Part 1: •The number (%) of participants and 95% CI with the dose-limiting toxicity (DLTs) in each of the cohorts 1-2, using the DLT evaluable population. •The number (%) of participants with AEs and serious adverse events (SAEs) in each of the cohorts 1-2, using the DLT evaluable and Safety populations. Part 2: •Overall Response Rate (ORR) as per IMWG by Investigator assessment; defined as the percentage of participants with a confirmed partial response (PR), very good partial response (VGPR), complete response (CR) or stringent CR (intenetion-to-treat [ITT] set). •Number (%) of participants with AEs and SAEs (Safety set). Both endpoint | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): •Lenalidomide RDI; DLT evaluable population, safety population •Cumulative belantamab mafodotin dose of (DLT evaluable population, safety population) administered in combination with daratumumab, lenalidomide and dexamethasone. The total dose for each participant will be calculated as the sum of all administrated doses •ORR and 95% CI as per IMWG by Investigator Assessment (ITT population) Part 1 only •VGPR+ and 95% CI as per IMWG by Investigator Assessment (ITT population) Part 1 only •TTR as per IMWG by Investigator Assessment (ITT population) •DoR as per IMWG by Investigator Assessment (ITT population). The median DoR will be presented along with the respective 95% CIs and the 1st and 3rd quartiles. •CRR as per IMWG by Investigator Assessment (ITT population).The denominator will be the total number of participants in each population, cohort and group respectively. •MRD negativity rate (ITT population). The denominator will be the total number of participants in each population, cohort and Group respectively. •PFS as per IMWG by Investigator Assessment (ITT population, Safety population). The median PFS will be analyzed with the Kaplan Meier method and presented along with the respective 95% CI and the 1st and 3rd quartiles. •OS (ITT population, Safety population). The median OS will be analyzed using the Kaplan-Meier method and will be presented with the respective 95% CI and the 1st and 3rd quartiles. •Number (%) of participants with abnormal ocular findings (DLT evaluable population, Safety population). •PK analysis (PK population) Concentration-time data: linear and semi-logistic unique profiles of concentration-time and the mean and median profiles will be graphically represented for belantamab mafodotin. PK parameters: Concentration-time data can be presented, considering data from other studies and analyzed using a population PK analysis. Further, the Cmax and AUC will be calculated. •Number of participants with changes from | — |
Countries
Greece
Contacts
Public ContactProf. Evangelos Terpos
Hellenic Society of Hematology (EAE)
Outcome results
None listed