REAL World IMROZ OutcomEs (REALIZE Study)

Isatuximab (Isa) is an IgG1 monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In the Phase 3 multicentre randomised study IMROZ, Isa in combination with velcade, lenalidomide and dexamethasone (VRD) was compared to VRD in transplant-ineligible (TIE) patient with newly diagnosed multiple myeloma (MM). Eligible participants were adult patients \<80 years of age with newly diagnosed symptomatic MM who were TIE either due to age, fitness, and/or comorbidities. All participants had an Eastern Co-operative Oncology Group (ECOG) performance status of 0-2. Patients were excluded if they had estimated glomerular filtration rate (eGFR) less than 30 ml/minute/1.73m2 (1).

The primary end point of the study was progression-free survival (PFS). Secondary endpoints included the complete response (CR) rate, minimal residual disease (MRD) negativity rate (assessed by NGS at a sensitivity level of 10-5) in patients in CR, ≥very good partial response (VGPR) rate and overall survival (OS) (1).

Patients were randomised 3:2 between Isa-VRD and VRD and stratified by revised international staging system (R-ISS) score, age (\<70 vs. ≥ 70 years) and country. Four induction cycles, each lasting six weeks, were given followed by Isa-Rd in the Isa-VRD group or Rd in the VRD group until disease progression or intolerance. During induction, all patients received subcutaneous bortezomib (BTZ) (1.3 mg/m2 on days 1,4, 8, 11, 22, 25, 29 and 32), oral lenalidomide (25mg per day (or 10mg per day if eGFR was 30-59 ml/minute/1.73m2) on days 1-14 and 22 to 35), and oral or intravenous dexamethasone (Dex) (20 mg per day on days 1,2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, 33 (or on days 1, 4, 8, 11, 15, 22, 25, 29 and 32 in patients ≥75 years of age)). Patients in the Isa-VRD group also received Isa intravenously (10mg/Kg once weekly in cycle one, and once every two weeks in subsequent cycles). During the continuous maintenance treatment, all patients received lenalidomide (25 mg per day (or 10mg per day if eGFR was 30-59 ml/minute/1.73m2) on days 1-21) and Dex (20mg once weekly). Patients in the Isa-VRD group also received intravenous Isa (10mg/Kg once every two weeks until the end of cycle 17, then once every 4 weeks continuously until progression or intolerance) (1).

Between December 2017 and March 2019, 446 patients were randomly assigned to treatment. 265 patients were randomised to the Isa-VRD group and 181 patients were randomised to the VRD group. After a median follow-up duration of 59.2 months (interquartile range (IQR) 56.0-63.2), disease progression or death had occurred in 162 patients (83/265 (31.7%) and 78/181 (43.1%) in the Isa-VRD and VRD groups respectively). The median PFS was not reached (NR) (95% CI, NR to NR) in the Isa-VRd group versus 54.3 months (95% CI, 45.2 to NR) in the VRD group. The hazard ratio for progression or death for Isa-VRD vs. VRD was 0.60 (98.5% CI, 0.41-0.88), p\<0.001. The proportion of patients achieving ≥CR was significantly higher in the Isa-VRD group (74.7% vs. 64.1%, p=0.001). The MRD negative rate in patients in CR was also significantly higher in the patients treated with Isa-VRD (55.5% vs 40.9%, p=0.003) with 46.8% of Isa-VRD treated patients have sustained MRD-negativity for at least 12 months (1).

The most frequent ≥grade 3 adverse events (AEs) (grade ≥3; Isa-VRD vs VRD) were neutropenia (60.1% vs. 53.0%), thrombocytopenia (30.0% vs. 27.6%), pneumonia (20.2% vs. 12.7%), and cataracts (15.6% vs. 11.0%). AEs with a fatal outcome were reported in 29/263 (11.0%) patients in the Isa-VRD arm vs. 10/181 (5.5%) in the VRD arm (1).

These results led to Isa-VRD becoming the first quadruplet therapy to be approved by the National Institute of Clinical Excellence (NICE) for TIE patients with newly diagnosed MM.

In the phase 3 BENEFIT trial, this quadruplet regimen achieved a higher ≥CR rate (58% v. 33%) and MRD negativity at 10-5 in in a higher proportion of patients in ≥CR (37% v. 17%%) compared to triplet therapy with Isa, lenalidomide and Dex (IsaRD) (2). Crucially the comparator used in BENEFIT has comparable in efficacy to the current UK standard of care for newly diagnosed TIE MM patients (daratumumab, lenalidomide and dex (DRD)). However, both large phase 3 studies comparing Isa-VRD to triplet therapy (IMROZ and BENEFIT) only enrolled patients up to the age of 80 years of age (1, 2), leaving uncertainty about the tolerability of quadruplet therapy for older and/or frailer patients. It is crucial that this knowledge gap is addressed, so that a greater understanding of where the divide between patients suitable for quadruplet therapy versus those better suited to triplet therapy should fall.

Within the IMROZ trial, 26% of patients were classified as frail using the simplified International Myeloma Working Group frailty score (sIMWG FS). Encouraging efficacy results were seen in this subgroup, including improved median PFS (NR v. 28.9 months) and MRD negativity rate (48% v. 22%) compared to patients treated with triplet therapy (3), demonstrating that the benefits are quadruplet therapy are not restricted to non-frail patients. The pragmatic dose adjustment approach adopted by many UK clinicians, particularly in the dosing of lenalidomide and Dex for older and/or frailer patients, may expand the patient cohort to which quadruplet therapy could be given. However, there are currently no published data to confirm this hypothesis and to demonstrate the impact of this approach on depth of response and treatment discontinuation rates for TIE MM patients treated with quadruplet therapy. This study will address this knowledge gap and patients above the age of 75 years of age and/or with a sIMWG FS ≥2 will form a subgroup of special interest. The outcomes of these patients will be compared to propensity matched patients treated with VRD in the IMROZ trial.

In addition to uncertainty about the upper age limit and frailty score of patients who will be treated with quadruplet therapy, the high efficacy of these regimens continues to raise questions about the upper age limit at which consolidation with high dose chemotherapy and autologous stem cell transplantation (ASCT) should still be applied. Since the introduction of DRD for TIE patients, at large transplant centres such as University Hospitals Birmingham NHS Foundation Trust, a reduction in the number of patients over 70 years of age being referred for ASCT has been observed. Isa-VRD may challenge this upper age limit even further. Patients under the age of 70 receiving Isa-VRD will therefore form a second subgroup of special interest in this study.

Given the depths of responses observed with modern MM regimens, MRD has become the desired biomarker for characterising deep treatment response, and it projects long-term disease control in multiple myeloma. Importantly, the U.S. Food and Drug Administration (FDA) now recognizes MRD at 10-5 sensitivity threshold in CR as a clinically meaningful endpoint for accelerated approvals in MM clinical trials (measured at 9 months, 12 months, MRD negative CR at any time) (4).

In the UK however, bone marrow (BM)-based MRD testing is not routinely available and poorly utilised in everyday practice. Limited access, the need for repeated invasive procedures, and service capacity constraints hinder widespread, longitudinal BM MRD assessment - particularly for TIE, newly diagnosed MM patients treated outside of specialised centres. As a result, routine monitoring often relies on conventional serum tests (serum protein electrophoresis, immunofixation electrophoresis and serum free light chain assays), which lack the analytical sensitivity to consistently detect very low-level disease.

The EXENT GAM assay is a technology that can potentially address this gap. Emerging evidence from international trials demonstrate that peripheral blood residual disease (PRD) negativity by mass spectrometry carries similar prognostic performance to sustained BM MRD negativity at the 10-5 threshold (5). As a serum-based, highly sensitive assay for patient specific M-protein, the EXENT GAM assay enables minimally invasive, repeatable PRD assessment with greater sensitivity than conventional serology. It is also much less susceptible to interference from therapeutic monoclonal antibodies (TMAB) and therefore does not require additional testing, such as the HYDRASHIFT assay, to differentiate between residual positivity due to disease versus TMAB interference in patients with IgG kappa MM (6). The EXENT GAM assay is available within the UK at the Botnar Institute, Oxford, as part of the UKCHART network, and provides a practical, scalable platform for standardized PRD monitoring across participating sites.

Demonstrating the real-world effectiveness of Isa-VRD in routine NHS care is the key aim for this proposal. Incorporating EXENT PRD assessments provides a minimally invasive, regulator-aligned measure of deep response that overcomes limited access to BM MRD in the UK. Serial EXENT testing will deliver precise estimates of the PRD negativity rate at 12 months, and sustained PRD negativity rate at 24 months in TIE patients treated with Isa-VRD under real-world conditions. In parallel, the harmonised longitudinal dataset will enable a rigorous comparison of an EXENT-anchored monitoring algorithm versus standard serology testing to quantify clinical utility, cost-effectiveness and a gap analysis to routine implementation. This integrated strategy enhances feasibility across NHS settings and positions the study to generate actionable diagnostic-supported implementation of Isa-VRD in routine UK practice.

Project Objectives

1. Overall response rate (ORR) at 12 months according to International Myeloma Working Group (IMWG) uniform response criteria when Isa-VRD is delivered using a pragmatic frailty adjusted dosing
2. Treatment discontinuation rate at 12 months
3. Relative dose intensity (RDI) of Isa-VRD in the first 12 months
4. 12-month PFS
5. 12-month OS
6. Subgroup analysis of patient outcomes according to:

1. sIMWG frailty score
2. Patients with and without eGFR \<30 ml/minute/1.73 m2
3. Deprivation score and ethnicity
4. Age ≥75 and/or sIMWG frailty score ≥2
7. Rate of PRD negativity, as defined by EXENT GAM assay negativity at 12 months from the start of treatment.
8. Proportion of patients maintaining sustained PRD-negative status for a minimum duration of 12 months, as confirmed by EXENT GAM testing.
9. To evaluate the clinical utility and health resource analysis of a disease monitoring algorithm incorporating quarterly EXENT GAM testing, compared with standard-of-care assessments (monthly serum electrophoresis, serum free light chain quantification, serum immunofixation, and bone marrow biopsy as per standard of care).

This study has two parts. The real-world data collection is a non-interventional retrospective multi-centre evaluation of TIE Patients with newly diagnosed symptomatic MM who have received Isa-VRD. The second part of study will evaluate the PRD testing using the EXENT GAM MS-based assay in patients being treated with Isa-VRD. Only patients who have achieved ≥VGPR and a have an M-protein ≤1 g/L at 12 months from the start of Isa-VRD will participate in the PRD sub study.

Time frame: within 12 months

Responses will be evaluated using the IMWG 2016 uniform response criteria and the ORR will be calculated by evaluating the number and proportion of patients who achieve ≥partial response

Time frame: within 12 months of receiving their first dose of Isa-VRD

Treatment discontinuation rate at 12 months will be analysed by collecting data on the number and proportion of patients who discontinued treatment within 12 months of receiving their first dose of Isa-VRD

Time frame: within 12 months of receiving their first dose of Isa-VRD

RDI within the first 12 months of treatment for each agent within Isa-VRD will be calculated by collecting the number and dose of each treatment delivered within the 12 month timeframe following their firs dose of Isa-VRD. Data on renal function will also be collected to ensure the lenalidomide dose intensity is calculated taking into account the adjusted dosing schedule for lenalidomide according to the summary of product characteristics for lenalidomide (7)

Time frame: 12-months from their first dose of Isa-VRD

12-month PFS will be calculated as the proportion of patients alive and progression free at 12-months from their first dose of Isa-VRD

Time frame: 12 months from their first dose of Isa-VRD

12-month OS defined as the proportion patients alive at 12 months from their first dose of Isa-VRD

Time frame: 12-months from the start of Isa-VRD

Rate of PRD negativity, as defined by EXENT GAM assay negativity, will be assessed at 12-months from the start of Isa-VRD

Time frame: 24-months from the start of Isa-VRD

Proportion of patients maintaining sustained PRD-negative status for a minimum duration of 12 months, will be assessed by evaluating how many patients who are PRD-negative at 12-months from initiation of Isa-VRD remain PRD-negative at 24-months from the start of Isa-VRD

Time frame: 12 months after the start of Isa-VRD.

Peripheral residual disease (PRD) negativity is defined as a negative result using the EXENT GAM mass-spectrometry assay. The number and percentage of eligible PRD substudy participants with a negative EXENT GAM result at 12 months after starting Isa-VRD will be reported.

Time frame: From 12 months to 24 months after the start of Isa-VRD

Sustained PRD negativity is defined as EXENT GAM assay negativity at 12 months after starting Isa-VRD followed by maintained PRD negativity through 24 months. The number and percentage of participants meeting this definition will be reported.

REAL World IMROZ OutcomEs (REALIZE Study)