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

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

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

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 antimyeloma 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 (PR) to 1 line of therapy.

Multiple Myeloma, RRMM, Open-label, First Relapse Multiple Myeloma, Second Relapse Multiple Myeloma, Refractory to Lenalidomide, Triplicate Treatment Regimen, Dexamethasone, Carfilzomib, Pomalidomide

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.

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.

Objective response defined as the best overall confirmed response of partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR) by Independent Review Committee (IRC) per International Myeloma Working Group Uniform Response Criteria (IMWG-URC).

Number of participants with a minimal residual disease negative complete response (MRD[-]CR) in participants with multiple myeloma at first or second relapse after treatment with lenalidomide

MRD[-]CR at a sensitivity of 10^-5 using next generation sequencing (NGS)-based method in the bone marrow at 12 months +/-4 weeks from start of treatment.

Number of participants who achieve minimal residual disease negative (MRD[-]) after treatment with pomalidomide and dexamethasone (KPd)

MRD(-) at a sensitivity of 10^-5 using next generation sequencing (NGS)-based method in the bone marrow.

Sustained MRD[-]CR response at a sensitivity of 10^-5 using NGS-based method in the bone marrow defined as subjects that maintain MRD[-]CR 12 months or more after achieving MRD[-]CR status, disregarding when the first MRD[-]CR was reached.

Sustained MRD[-]CR response at a sensitivity of 10^-5 using NGS-based method in the bone marrow at 24 months ± 4 weeks from start of treatment and calculated only within the subjects who reached MRD[-]CR in the time window for key secondary endpoint assessment.

Estimate a landmark overall response by 12 months, defined as the best overall confirmed response of partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR) by 12 months from start of treatment.

Estimate duration of response, defined as time from first date of partial response (PR) or better to date of disease progression or death due to any cause.

Estimate time to response, defined as time from start of treatment to first date of partial response (PR) or better.

Estimate Progression-free survival (PFS) defined as time from start of treatment until progression or death from any cause.

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 International Myeloma Working Group (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 partial response (PR) to at least 1 line of prior therapy Prior therapy with PI 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 Eastern Cooperative Oncology Group (ECOG) Performance Status (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

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.

Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.