Real-World Outcomes of Standard-of-Care Treatments and Safety of CAR T and Bispecific Antibody Therapies in Adult Patients with Triple-Class Exposed Relapsed/Refractory Multiple Myeloma: Evidence from a Multicenter Retrospective Study (MMIRROR-2)

Objectif(s) de la recherche et intérêt pour la santé publique

Finalité de l'étude

Objectifs poursuivis

Domaines médicaux investigués

Bénéfices attendus

Multiple myeloma (MM) is generally an incurable hematological malignancy in which there is clonal proliferation of malignant plasma cells and the excessive production of monoclonal protein (M-protein), an abnormal immunoglobulin. This cancer exhibits significant heterogeneity in its clinical presentation, with varying severity and progression. Patients experience a relapse and remitting course of the disease where each line of therapy results in shorter duration of response.

MM poses a considerable clinical burden and is responsible for about 1% of all cancers globally, constituting approximately 10% of hematological neoplasms. In the United States (US) and the European Union (EU), around 50,000 individuals receive a diagnosis of MM annually, resulting in the loss of 30,000 lives due to the disease each year.

Anitocabtagene autoleucel is a novel BCMA-directed chimeric antigen receptor CAR T-cell therapy that is being evaluated in the investigational ARC-112A (iMMagine-1) trial (NCT05396885) in patients with triple-class exposed RRMM. To contextualize the results of the single-arm iMMagine-1 trial, a multi-center non-interventional retrospective study (MMIRROR-1) was conducted in adult patients with RRMM who had received at least 3 systemic treatments and were refractory at the last line of therapy. MMIRROR-1 analyzed patients with index LOTs initiated between 01 January 2018 and 31 December 2022.

With the advent and availability of innovative treatment modalities such as BCMA-directed therapies in recent years, current evidence on clinical outcomes in routine clinical practice that includes the newer therapies is limited, including in MMIRROR-1. To address this gap, a subsequent study (MMIRROR-2) is planned to primarily assess clinical outcomes for patients with triple-class exposed RRMM who received real-world standard of care treatments, including newer treatment options such as CAR T-cell therapies, BsAbs, and antibody-drug conjugates. Given uptake of these newer therapies has been heterogenous across markets and in some cases limited in the late line setting, this study will oversample patients who received CAR T-cell and BsAb therapies.

This will ensure that an adequate sample of patients receiving these newer treatments (rather than a representative sample of actual real-world usage) will be included in the study to enable a robust characterization of outcomes in these subgroups. MMIRROR-2 will include patients with triple-class exposed RRMM who have initiated their index LOTs between 01 January 2018 and 31 December 2024 and will use individual patient-level data from multiple medical centers across the US and EU. Efficacy analyses will concern the ITT population. The study also aims to characterize the safety profile of patients who have received standard of care CAR T-cell or BsAb treatments. To support the comparative analysis of the iMMagine-1 trial, weighted ECA cohorts for efficacy and safety will be constructed from the pooled real-world dataset and will be used to contextualize the efficacy and safety outcomes of anitocabtagene autoleucel, respectively.

Primary Objective

Objective 1:

To estimate the overall response rate (ORR) of standard of care treatments in current real-world clinical practice among adult patients with RRMM who were treated with at least 3 prior regimens of systemic therapy, including proteasome inhibitor (PI), immunomodulatory drugs (IMiD), and anti-CD38 antibody, i.e., triple-class exposed, were refractory to the last line of therapy (LOT), and meet iMMagine-1 eligibility criteria (Eligible RRMM Cohort)

Secondary Objectives

Objective 2a:

To estimate ORR at 4th line (4L, subjects limited to three lines of prior treatment) of standard of care in current real-world clinical practice in adult patients with triple-class exposed RRMM who meet iMMagine-1 eligibility criteria (Eligible RRMM Cohort)

Objective 2b:

To evaluate ORR in an external control arm weighted to patients in ITT iMMagine1 Cohort 2B (ITT iMMagine1 RW Cohort) and compare to ORR for patients in ITT iMMagine1 Cohort 2B

To evaluate ORR at 4L in an external control arm weighted to patients in ITT iMMagine1 Cohort 2B (ITT iMMagine1 RW Cohort) and compare to ORR at 4L for patients in ITT iMMagine1 Cohort 2B

To evaluate additional key clinical outcomes including OS, PFS, CR/sCR rate, and DOR in an external control arm weighted to patients in ITT iMMagine1 Cohort 2B (ITT iMMagine1 RW Cohort) and compare to outcomes for patients in ITT iMMagine1 Cohort 2B

To evaluate other clinical outcomes including VGPR rate, PR rate, and TTNT in an external control arm weighted to patients in ITT iMMagine1 Cohort 2B (ITT iMMagine1 RW Cohort) and compare to outcomes for patients in ITT iMMagine1 Cohort 2B

Objective 2c:

To estimate safety outcomes, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), non-ICANS delayed neurotoxicity (NT), neutropenia, thrombocytopenia, non-relapse mortality, hypogammaglobulinemia and infection rates of CAR T and bispecific antibody (BsAb) treatments in current real-world clinical practice in patients with triple-class exposed RRMM who meet iMMagine-1 eligibility criteria (Eligible RRMM Safety CAR T Cohort and Eligible RRMM Safety BsAb Cohort, respectively)

Exploratory Objectives

Objective 3:

To describe healthcare resource utilization (HRU) in the cohort of triple-class exposed RRMM patients who received CAR T or bispecific antibody (BsAb) treatments in current real-world clinical practice and who meet iMMagine-1 eligibility criteria (Eligible RRMM Safety CAR T Cohort and Eligible RRMM Safety BsAb Cohort, respectively)

Objective 4:

To evaluate safety outcomes, including CRS, ICANS, non-ICANS delayed NT, neutropenia, thrombocytopenia, non-relapse mortality, hypogammaglobulinemia, and infection in the external control safety cohorts weighted to mITT iMMagine-1 Cohort 2B (iMMagine-1 RW Safety CAR T Cohort and iMMagine-1 RW Safety BsAb Cohort, respectively) and compare to outcomes for patients in mITT iMMagine-1 Cohort 2B.

Methods
MMIRROR-2 will be a real-world, non-interventional, retrospective study. Data will be sourced from EMR records from 15 medical centers in the US and EU and then merged into a common data model (CDM). The data will be in a pseudonymized format.

Study population
The study population for this analysis will be patients with triple-class exposed RRMM who meet the study eligibility criteria which are adapted from iMMagine-1, adult patients with RRMM who have received at least 3 prior systemic regimens, including a PI, an IMiD and ananti-CD38 antibody, and were refractory to the last LOT.