This is a phase I-II open-label, multicenter, non-randomized study aiming to evaluate the efficacy and safety of belantamab mafodotin in combination with carfilzomib (Kyprolis®) and dexamethasone (Kd). Since this is the first time that this combination is being evaluated in a clinical trial, a first dose escalation part will be developed following the classic 3+3 design, to establish the maximum tolerated dose (MTD) of the combination. Once the MTD will be defined, a dose expansion phase will be open to recruit up to 60 patients.~The study comprises the following phases:~Phase 1 (Lead-in): 3+3 Dose escalation~In the phase 1 of the study, aiming to establish the recommended phase 2 dose (RP2D), patients will be included following the classic 3 + 3 design. Dose levels will be as follows:~Dose level -1~Belantamab-Mafodotin 1.9 mg/kg day 1, Q8W~Carfilzomib 20/45 mg/m2 on days 1, 8, and 15, Q4W.~Dexamethasone 40 mg weekly (days 1, 8, 15 and 22) or 20 mg in patients > 75 years old, Q4W Dose level 1~Belantamab-Mafodotin 2.5 mg/kg day 1, Q8W~Carfilzomib 20/45 mg/m2 days 1, 8, and 15, Q4W.~Dexamethasone 40 mg weekly (days 1, 8, 15 and 22) or 20 mg in patients > 75 years old., Q4W Dose level 2~Belantamab-Mafodotin 2.5 mg/kg on day 1, Q8W~Carfilzomib 20/56 mg/m2 on days 1, 8, and 15, Q4W.~Dexamethasone 40 mg weekly (days 1, 8, 15 and 22) or 20 mg in patients > 75 years old, Q4W. Dose level 3~Belantamab-Mafodotin 2.5 mg/kg on day 1, every 4 weeks (Q8W)~Carfilzomib 20/70 mg/m2 on days 1, 8, and 15, Q4W.~Dexamethasone 40 mg weekly (days 1, 8, 15 and 22) or 20 mg in patients > 75 years old., Q4W~The rules applied for the Lead-in phase are as follows:~An initial cohort of 3 subjects is enrolled at the first dose level (DL1).~If 1/3 subjects develop a DLT, 3 additional patients will be included at the same dose level (DL1)~If 0/3 subjects develop a DLT, 3 additional patients will be included at the next dose level (DL2, dose level 2).~If 1/3 subjects develop a DLT, 3 additional patients will be included at the same dose level (DL2, dose level 2).~If 0 of the 3 new subjects develops a DLT (for a total of 0-1/6 patients with a DLT at this dose level), 3 new subjects will be included in DL3 (dose level 3).~If 1 of the 3 new subjects develops a DLT (for a total of 0-1/6 patients with a DLT at this dose level), 3 new subjects will be included at the same dose level (DL3, dose level 3)~If 0 out of the 3 new subjects develops a DLT, 3 additional subjects will be included in the same dose level. If 0-1 out of 6 patients developed a DLT, this dose will be considered the maximum tolerated dose (MTD) and will be explored in the expansion phase (phase 2).~If ≥2/3 subjects develop a DLT, dose level will be de-escalated (previous dose level) with the same rules as described above.~Dose limiting toxicities (DLTs) will be evaluated during the DLT evaluation period. The DLT evaluation period will be defined as the first 4-weeks treatment cycle for each cohort.~Patients participating in the Lead-In-Phase must undergo a complete ophthalmologic examination at the end of the DLT evaluation period (4-weeks) and before starting Cycle 2.~Subjects will be considered evaluable for the assessment of DLT if they:~Received at least 1 dose of belantamab mafodotin + Kd and experience a DLT, OR~Received at least 1 dose of belantamab mafodotin, 3 doses of Carfilzomib and 3 doses of Dexamethasone and complete the safety follow-up through the end of the DLT evaluation period.~Non-evaluable subjects will be replaced.~Phase 2 (Expansion Phase, n= up to 60 patients)~Combination treatment will be administered at the RP2D based on the results of the phase 1 dose escalation part of the study:~Belantamab mafodotin on day 1 at the RP2D, every 8 weeks, intravenously (IV).~Carfilzomib will be given at the RP2D weekly IV on days: 1, 8, and 15 of every 4-week cycle (Q4W).~Dexamethasone will be given at the dose of 40 mg (or 20 mg if patient > 75 years old) on days: 1, 8, 15 and 22 Q4W.~From month 13 onwards carfilzomib treatment will be given on day 1 and 15 of every 4-weeks cycles. Belantamab will be given at the RP2D every 8 weeks and Dexamethasone 40mg on days 1, 8, and 15 of every 4-week cycle.~The trial has the following objectives:~Primary objectives (PO):~Phase 1 PO1: To determine the maximum tolerated dose, and the recommended phase 2 dose of belantamab mafodotin in combination with carfilzomib and dexamethasone.~Phase 2 PO2: To evaluate the efficacy in terms of complete response rate and rates of minimal residual negativity after 12 months of therapy with belantamab mafodotin combined with carfilzomib and dexamethasone.~PO3: To evaluate safety and tolerability of the combination of belantamab mafodotin plus carfilzomib and dexamethasone.~Secondary Objectives (SO):~SO1: To determine time to event data of the combinations: Progression-free survival, progression-free survival at 12 months, duration of response, time to response, and overall survival.~SO2: Evaluate deepening of response during continuous therapy at 12, and 24 months.~SO3: Evaluate sustained MRD rate at 1 and 2 years. SO4: Evaluate the rate of conversion from MRD positivity to MRD negativity during the treatment (yearly).~SO5: To assess the safety of the combination of belantamab mafodotin + Kd, as well as the incidence of corneal and ophthalmologic adverse events.
This is a phase I-II open-label, multicenter, non-randomized study aiming to evaluate the efficacy and safety of belantamab mafodotin in combination with carfilzomib (Kyprolis®) and dexamethasone (Kd). Since this is the first time that this combination is being evaluated in a clinical trial, a first dose escalation part will be developed following the classic 3+3 design, to establish the maximum tolerated dose (MTD) of the combination. Once the MTD will be defined, a dose expansion phase will be open to recruit up to 60 patients.~Patients will receive treatment with belantamab-mafodotin + Kd, until unacceptable toxicity, disease progression, patient withdrawal, loss to follow-up, end of study, or death.