Trattamento

Active Comparator: Control Arm: isatuximab + pomalidomide + dexamethasone (Substudy 1)

• Isatuximab dose, intravenous (IV) weekly (QW) x 4 weeks (Cycle 1), followed by Q2W (subsequent cycles).
• Pomalidomide dose os (PO) daily Day 1 to Day 21.
• Dexamethasone dose PO QW.

Part 1: Belantamab Mafodotin in combination with isatuximab and dexamethasone

1 dose level (DL) of intravenous (IV) Belantamab Mafodotin in Part 1 and de-escalation dose DL-1:

• DL1 Belantamab Mafodotin dose QW4 or de-escalation dose DL-1 QW8
• Isatuximab dose, intravenous (IV) weekly (QW) x 4 weeks (Cycle 1), followed by Q2W (subsequent cycles).
• Dexamethasone fixed dose and schedule: QW PO.

Part 2:

• Isatuximab dose, intravenous (IV) weekly (QW) x 4 weeks (Cycle 1), followed by Q2W (subsequent cycles).
• Belantamab Mafodotin dose IV Q4W or Q8W
• Dexamethasone fixed dose and schedule: QW PO

Obiettivo primario 

Part 1 (dose finding, experimental substudies): Determination of recommended dose of novel agents in combination with isatuximab [ Time Frame: Through the end of cycle 1 (approximately 6 weeks) ]

Determination or confirmation of the dose will be based on: safety and tolerability in terms of TEAEs/SAEs, dose-limiting toxicity occurrence, and laboratory parameters available information on PK (if appropriate) and biomarkers.

1. VGPR Rate (Rate of Very Good Partial Response Rate or Better) in experimental substudies [ Time Frame: Up to approximately 28 months after the First patient in or scheduled assessment ]

VGPR or better rate is defined as the percentage of participants with a VGPR or better as defined by the 2016 IMWG response criteria, assessed by Investigator based on central laboratory values and local imaging.

Criteri di inclusione

• Participant must be 18 years of age inclusive or older
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Participants with relapsed or refractory MM who have received at least 3 prior lines of therapy for MM, including PIs and IMiDs or at least 2 prior lines if at least one of these lines consisted of 2 or more multiagent regimens (eg, Induction regimen with autologous stem cell transplant followed by maintenance).
• RRMM with measurable disease:
• Serum M protein ≥0.5 g/dL measured using serum protein immunoelectrophoresis and/or
  • Urine M protein ≥200 mg/24 hours measured using urine protein immunoelectrophoresis and/or
  • Serum free light chain (sFLC) MM without measurable M protein in serum or urine per previous criteria (serum Ig free light chain ≥10 mg/dL and abnormal serum Ig kappa lambda free light chain ratio <0.26 or >1.65).
• Men or woman or childbearing potential should agree to use contraception.

Substudy 01 and 03: Anti-CD38 therapy naive or prior exposure to such drugs without being refractory but with a wash out of at least 6 months after the last dose. “Refractory” is defined as progressing within 60 days of last dose of anti-CD38 targeting therapy.

Criteri di esclusione

• Primary systemic amyloid light chain amyloidosis, plasma cell leukemia, monoclonal gammopathy of undetermined significance, or smoldering myeloma.
• Uncontrolled infection within 14 days prior to randomization.
• Clinically significant cardiac (including valvular) or vascular disease within bypass graft, percutaneous coronary intervention) or peripheral artery revascularization, left ventricular ejection fraction <40%, heart failure New York Heart Association Classes III and IV, stroke, transient ischemic attack, pulmonary embolism, other thromboembolic event, or cardiac arrhythmia (Grade 3 or higher by NCI CTCAE Version 5.0).
• Known acquired immunodeficiency syndrome-related illness or known human immunodeficiency virus (HIV) disease requiring antiviral treatment or active hepatitis A.
• Uncontrolled or active hepatitis B virus (HBV) infection.
• Active hepatitis C virus (HCV) infection.
• Any of the following within 3 months prior to randomization: treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease.
• Second malignancy other than basal cell or squamous cell carcinoma of the skin or in situ carcinoma, unless they are successfully treated with curative intent for more than 3 years before randomization.
• Any anti-MM drug treatment within 14 days before randomization, including dexamethasone.
• Participants with a contraindication to treatment.
• Vaccination with a live vaccine 4 weeks before the start of the study.
• Hemoglobin <8 g/dL.
• Platelets <50 x 10^9/L.
• Absolute neutrophil count <1.5 x 10^9/L.
• Creatinine clearance <30 mL/min.
• Total bilirubin >1.5 x ULN, except for known Gilbert syndrome in which direct bilirubin should be ≤2.5 x ULN.
• 3 months prior to randomization, eg, myocardial infarction, unstable angina, coronary (eg, coronary artery
• Aspartate aminotransferase and/or alanine aminotransferase >3 x ULN.
• Patients with grade 3 or 4 hypercalcemia.
• Substudy 01:
  • Malabsorption syndrome or any condition that can significantly impact the absorption of pomalidomide.
  • For the first 10 participants: Body weight ≤70 kg
• Substudy 03:
  • Current corneal epithelial disease except mild punctate keratopathy
  • Patients who have received prior therapy with Belantamab Mafodotin