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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.

Once the DLT assessment period is completed and the MTD is defined, the recruitment will continue in the expansion phase 2.

Combination treatment will be administered at the recommended Phase 2 dose (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.

In phase 1:

* Dose level -1: Belantamab-Mafodotin 1.9 mg/kg day 1, Q8W
* Dose level 1,2,3: Belantamab-Mafodotin 2.5 mg/kg day 1, Q8W In phase 2: maximum tolerated dose (MTD) of the combination

Belantamab mafodotin

In phase 1:

* Dose level -1, 1: Carfilzomib 20/45 mg/m2 days 1, 8, and 15, Q4W.
* Dose level 2: Carfilzomib 20/56 mg/m2 on days 1, 8, and 15, Q4W
* Dose level 3: Carfilzomib 20/70 mg/m2 on days 1, 8, and 15, Q4W.

In phase 2: maximum tolerated dose (MTD) of the combination

Carfilzomib

Description: Dexamethasone 40 mg weekly (days 1, 8, 15 and 22) or 20 mg in patients \> 75 years old., Q4W

Carmen López-Carrero

Roberto Maldonado

Albert Oriol Rocafiguera

Laura Rosiñol

Anna Sureda

Anna S

Cristina Encinas

Joaquín Martínez

Felipe de Arriba

Mª Pilar González Rodríguez

Joan Bargay

Paula Rodríguez

Mariví Mateos

Miguel Teodoro Hernández García

Enrique Ocio

Marta Sonia González Pérez

Estrella Carrillo

Javier de la Rubia

Paula Rodríguez Otero

María-Victoria Mateos

Jesús San Miguel Izquierdo

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.

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:

1. An initial cohort of 3 subjects is enrolled at the first dose level (DL1).
2. If 1/3 subjects develop a DLT, 3 additional patients will be included at the same dose level (DL1)
3. If 0/3 subjects develop a DLT, 3 additional patients will be included at the next dose level (DL2, dose level 2).
4. If 1/3 subjects develop a DLT, 3 additional patients will be included at the same dose level (DL2, dose level 2).
5. 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).
6. 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)
7. 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).
8. 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.

A phase I classic 3+3 design, to establish the maximum tolerated dose (MTD) of the combination. Once the MTD will be defined, a dose expansion phase II will be open to recruit up to 60 patients.

Study of Belantamab Mafodotin in Combination With Kd for the Treatment of Relapsed Myeloma Patients, Refractory to Lenalidomide

An Open Label, Multicenter, Phase I/II Study of Belantamab Mafodotin in Combination With Kd for the Treatment of Relapsed Myeloma Patients, Refractory to Lenalidomide.

To determine the maximum tolerated dose, and the recommended phase 2 dose of belantamab mafodotin in combination with carfilzomib and dexamethasone, number of participants with adverse events (AEs) during the triplet-therapy in phase 1 will be evaluated.

Percentage of participants with a confirmed partial response (PR) or better (PR, VGPR, CR, sCR).

The percentage of participants who are MRD negative by next-generation flow cytometry (NGF).

The percentage of participants with a confirmed complete response (CR) or better (stringent complete response (CR, sCR)).

Frequency and percentage of deaths and primary cause of death.

Percentage of patients who present differences in hematologic laboratory parameters from baseline values .

Percentage of patients who present differences in blood chemistry panel from baseline values.

Time from first documented evidence of PR or better until progressive disease (PD) or death due to PD among participants who achieved PR or better.

Time from the start of treatment until the earliest date of documented disease progression or death due to any cause.

Time from the start of treatment and the first documented evidence of response (PR or better) among participants who achieve confirmed PR or better.

Time from the start of treatment until the date of death due to any cause

Percentage of patients upgrading/deepening the response (converting from partial response to VGPR, etc.)

Percentage of patients achieving minimal residual disease negativity using EuroFlow Panel with a sensitivity of 10\*(-6)

Percentage of patients converting from positive MRD to undetectable MRD following EuroFlow panel with a sensitivity of 10-6

Frequency and percentage of Treatment related adverse events

Percentage of patients discontinuing therapy due to AEs.

Percentage of patients requiring dose modifications.

Spots Global Cancer Trial Database for refractoriness to lenalidomide