Study of Early Relapsed, Lenalidomide-refractory Subjects Eligible for Carfilzomib Triplet

Study Overview
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Brief Summary
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A Study Evaluating Treatment of Multiple Myeloma with Carfilzomib in Combination with Pomalidomide and Dexamethasone

Detailed Description
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An Open-label, Phase 2 Study Treating Subjects with First or Second Relapse of Multiple Myeloma with Carfilzomib, Pomalidomide, and Dexamethasone (KPd) This trial is designed to estimate the efficacy of a carfilzomib-based triplet in first or second relapse of multiple myeloma for subjects refractory to lenalidomide. The study is an open-label, phase 2 trial. Subjects may receive treatment until progression. Myeloma disease status will be monitored locally for response and progression per International Myeloma Working Group (IMWG) criteria (Kumar et al, 2016) every 28 ± 7 days from cycle 1 day 1 until confirmed progressive disease (PD), death, lost to follow-up, or withdrawal of full consent (whichever occurs first), regardless of cycle duration, dose delays or treatment discontinuation. Subjects with a suspected complete response (CR) or better will have a bone marrow for minimal residual disease (MRD) assessment at 12 and 24 months (± 4 weeks) from start of treatment (unless a MRD assessment was performed within 4 months before planned assessment). Subjects who end study drug(s) without confirmed PD are required to complete disease response assessments and report new anti-myeloma treatment every 28 ± 7 days until first subsequent anti-myeloma treatment, death, lost to follow-up, withdrawal of full consent, confirmed PD, or end of study, whichever occurs first. Subjects who discontinue treatment and either start new anti-myeloma treatment or have PD will enter long-term follow-up every 12 weeks until death or end of study. Approximately one-third of subjects enrolled in the study will be in first relapse and two-thirds in second relapse. This study will enroll adults ≥ 18 years of age with first or second relapse multiple myeloma. Eligible subjects will have relapsed multiple myeloma after receiving 1 or 2 prior lines of therapy. Subjects must be refractory to lenalidomide. Subjects may not have received prior pomalidomide. Prior exposure to a proteasome inhibitor is allowed. Subjects previously exposed to carfilzomib must have responded with at least a partial response to carfilzomib, must not have discontinued carfilzomib due to toxicity, may not have relapsed while receiving or within 60 days of the last dose of carfilzomib, and must have at least a 6 month carfilzomib treatment-free interval since their last dose of carfilzomib. Subjects must have measurable disease per IMWG consensus criteria, Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2, and at least partial response to 1 line of therapy.

Official Title
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An Open-label, Phase 2 Study Treating Subjects With First or Second Relapse of Multiple Myeloma With Carfilzomib, Pomalidomide, and Dexamethasone (KPd)

Conditions
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Relapsed or Refractory Multiple Myeloma

Intervention / Treatment
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* Drug: Carfilzomib
* Drug: Dexamethasone
* Drug: Pomalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Subject has provided informed consent prior to initiation of any study specific activities or procedures. Male or female subjects age ≥ 18 years First or second relapse of multiple myeloma by IMWG criteria (subjects refractory to the most recent line of therapy, excluding carfilzomib, are eligible) Refractory to lenalidamide Measurable disease with at least 1 of the following assessed within 28 days prior to enrollment: IgG multiple myeloma: serum monoclonal protein (M-protein) level ≥ 1.0 g/dL IgA, IgD, IgE multiple myeloma: serum M-protein level ≥ 0.5 g/dL urine M-protein ≥ 200 mg per 24 hours in subjects without measurable serum or urine M-protein, serum-free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum kappa lambda ratio Must have at least a PR to at least 1 line of prior therapy Prior therapy with proteasome inhibitors is allowed. Subjects receiving prior carfilzomib therapy must have achieved at least a PR, was not removed due to toxicity, did not relapse within 60 days from discontinuation of carfilzomib, and must have at least a 6 month carfilzomib treatment-free interval from their last dose of carfilzomib ECOG PS of 0 to 2 Exclusion Criteria Primary refractory multiple myeloma Waldenström macroglobulinemia Multiple myeloma of IgM subtype POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) Plasma cell leukemia ( greater than 2.0 × 109/L circulating plasma cells by differential). If automated differential shows ≥ 20% of other cells, obtain manual differential to identify other cells. Primary amyloidosis (patients with multiple myeloma with asymptomatic deposition of amyloid plaques found on biopsy would be eligible if all other criteria are met) Previous diagnosis of amyloidosis associated with myeloma Myelodysplastic syndrome Toxicity requiring discontinuation of lenalidomide therapy Prior treatment with pomalidomide

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carfilzomib combined with pomalidomide and dexamethasone<br>Carfilzomib, pomalidomide, and dexamethasone (KPd) | Drug: Carfilzomib<br>* Carfilzomib will be administered intravenously over 30 ± 5 minutes, on days 1, 8, and 15 (± 2 days) of each 28-day cycle for up to 12 cycles or progression. A dose of 20 mg/m^2 will be administered on day 1 of cycle 1. All subsequent doses will be 56 mg/m^2. The frequency of carfilzomib administration will be reduced to day 1 and 15 per cycle starting with cycle 13 and continued until progression or end of study.<br>* Other names: Kyprolis;Drug: Dexamethasone<br>* Dexamethasone will be administered at least 30 minutes, but no more than 4 hours prior to carfilzomib on days of carfilzomib administration. Dexamethasone will be administered at a dose of 40 mg on days 1, 8, 15, and 22 of each 28-day cycle up to progression during cycles 1 to 12. Dexamethasone will be administered at a dose of 20 mg on days 1 and 15 of each 28-day cycle up to progression during cycles 13 onward. For subjects more than or equal to 75 years of age, the dose will be 20 mg during cycles 1 through 12 and 10 mg from cycles 13 onward.<br>* Other names: Decadron, Ozurdex, DexPak 6, 10, 13 Day, ReadySHarp, LoCort, Maxidex;Drug: Pomalidomide<br>* Pomalidomide dose will be 4 mg per day orally on days 1 to 21 of each cycle until progression.<br>* Other names: Pomalyst;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) As Assessed by the Independent Review Committee (IRC) (PA DCO Only) | Overall response was defined as the best overall confirmed response of: Complete response (CR): Negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, < 5% plasma cells in bone marrow (BM). Stringent CR (sCR): CR and normal serum free light chain ratio and no clonal cells in BM. Very Good Partial Response (VGPR): Serum and urine M-protein detectable by immunofixation or ≥ 90% reduction in serum M-protein (urine M-protein level < 100 mg/24-h). PR: ≥ 50% reduction of serum M-protein and 24-h urinary M-protein by ≥ 90% or to < 200 mg/24-h. Assessment was by IRC per International Myeloma Working Group Uniform Response Criteria (IMWG-URC). The 90% confidence intervals were estimated using the Clopper-Pearson method (1994). | From day 1 cycle 1 until the PA DCO date of 30 November 2022; the median duration of KPd treatment as of the DCO was 32.8 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Minimal Residual Disease Negative Complete Response (MRD[-]CR) as Assessed by the IRC (PA DCO Only) | The MRD[-]CR rate was defined as the number of participants who reached MRD[-]CR at the 12 month landmark (8- to 13-month window). MRD[-]CR was defined as the achievement of CR (including sCR or better) per IMWG-URC by IRC assessment and MRD[-] status at a sensitivity of 10^-5 using next-generation sequencing based method in the bone marrow. The 90% CIs were estimated using the Clopper-Pearson method (1994). | Day 1 cycle 1 to month 12 (8 to 13 month window). PA DCO date of 30 November 2022; the median duration of KPd treatment as of the DCO was 32.8 weeks. | 
| Number of Participants With Treatment-emergent Adverse Events |  | Day 1 cycle 1 up to approximately 60 months | 
| Number of Participants Achieving Minimal Residual Disease Negative MRD[-] Response |  | Day 1 cycle 1 to month 60 | 
| Number of Participants With Sustained MRD[-]CR for at Least 12 Months as Assessed by the IRC |  | Day 1 cycle 1 to month 60 | 
| Number of Participants With Sustained MRD[-]CR at Month 24 as Assessed by the IRC |  | Day 1 cycle 1 to month 26 (19 to 26 month window) | 
| Kaplan-Meier Estimate of Duration of Response as Assessed by the IRC |  | Day 1 cycle 1 to month 60 | 
| Time to Response as Assessed by the IRC |  | Day 1 cycle 1 to month 60 | 
| Kaplan-Meier Estimate of Progression Free Survival as Assessed by the IRC |  | Day 1 cycle 1 to month 60 | 
| Kaplan-Meier Estimate of Overall Survival |  | Day 1 cycle 1 to month 60 | 
| Number of Participants With Best Overall Confirmed Response of CR or Better as Assessed by the IRC |  | Day 1 cycle 1 to month 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, RRMM, Open-label, First Relapse Multiple Myeloma, Second Relapse Multiple Myeloma, Refractory to Lenalidomide, Triplicate Treatment Regimen, Dexamethasone, Carfilzomib, Pomalidomide