Phase 3 Study of Isatuximab, Lenalidomide, and Dexamethasone ± Bortezomib in Non-Frail, Transplant-Ineligible Elderly Patients with Newly Diagnosed Multiple Myeloma

Trial ID: 2024-517215-67-00
Protocol: IFM2020-05-BENEFIT
Sponsor: Centre Hospitalier Universitaire De Poitiers

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Diseases & Conditions

Plasma cell myeloma

Objectives

The primary objective of this study is to evaluate the **Minimal Residual Disease (MRD)** rate at 10^-5 at 18 months in patients with newly diagnosed non-frail transplant ineligible multiple myeloma, comparing the treatment regimens of Isatuximab plus Lenalidomide and Dexamethasone with or without Bortezomib. This objective is clinically relevant as achieving a lower MRD rate is associated with improved patient outcomes and can serve as a prognostic marker for long-term survival in multiple myeloma.

Secondary objectives include:

To determine safety in either arm.
To determine the best response to the treatment at 6, 12, 18 months, and yearly in either arm according to the International Myeloma Working Group (IMWG).
To evaluate the MRD rate at 10^-5 at 12 months, and yearly (and at 10^-6).
To determine the sustained MRD rate at 10^-5.
To determine the rate of loss of MRD at 10^-5 at each time point.
To determine the time to reach MRD negative rate at 10^-5 and loss of MRD negative rate at 10^-5.
To determine Overall Survival (OS), Progression Free Survival (PFS), Time to Progression (TTP), Time to Next Therapy (TTNT), and Event Free Survival (EFS) in either arm.
To assess high-risk multiple myeloma.
To compare the efficacy of originator and generic bortezomib.
To compare the efficacy of originator and generic lenalidomide.
To assess apixaban exposure.
To determine the correlation between apixaban plasma level and myeloma treatments.

Participants

The clinical trial involves participants who are **newly diagnosed** with non-frail, transplant ineligible **Multiple Myeloma** and are elderly patients. The study population includes both male and female subjects aged between 65 and 79 years. Participants are required to have a life expectancy of more than six months and must not be considered candidates for high-dose chemotherapy with stem cell transplantation. The trial does not include a vulnerable population. Participants must have adequate organ and bone marrow function, as well as measurable disease. The sponsor has not provided information regarding the total number of participants. The selection criteria emphasize the ability to understand and comply with the study protocol, including adherence to a pregnancy prevention plan for those of childbearing potential. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed as a **randomized**, open-label, Phase III study to evaluate the efficacy of **isatuximab** in combination with **lenalidomide** and **dexamethasone**, with or without **bortezomib**, in the treatment of newly diagnosed non-frail, transplant-ineligible elderly patients with **multiple myeloma**. The primary objective is to assess the Minimal Residual Disease (MRD) rate at 10^-5 at 18 months. The trial is expected to run from August 2021 to August 2026, with a total duration of approximately five years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, organ function, and disease status. Following randomization, participants will attend regular follow-up visits to monitor treatment response, adverse events, and laboratory parameters. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. The expected length of participant involvement is up to 60 months, depending on the treatment arm and individual response to therapy.

Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants must adhere to the study visit schedule and protocol requirements, including compliance with the lenalidomide pregnancy prevention plan. The trial will utilize a combination of oral and intravenous administration routes for the investigational products, with dosing regimens tailored to each participant's treatment arm. The study aims to provide comprehensive data on the efficacy and safety of the treatment regimens, contributing to the optimization of therapeutic strategies for this patient population.

Treatment

The clinical trial involves the administration of several medications, each with specific roles and administration protocols. **Dexamethasone** is utilized in multiple forms, including an **oral solution** and **tablet** form. The maximum daily dose for dexamethasone is 20 mg, with a total maximum dose of 960 mg over a treatment period of 12 weeks. The route of administration is oral, and it is classified as a chemical substance. Dexamethasone is not a pediatric formulation and is not designated as an orphan drug.

**Isatuximab**, marketed as SARCLISA, is provided as a 20 mg/mL concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 10 mg and a total maximum dose of 2920 mg over a 60-week treatment period. Isatuximab is a humanized monoclonal antibody against CD38, classified as a protein of other origin. It is not a pediatric formulation and is not designated as an orphan drug.

**Lenalidomide**, marketed as Revlimid, is provided in 25 mg hard capsules. The maximum daily dose is 25 mg, with a total maximum dose of 31,500 mg over a 60-week treatment period. The route of administration is oral, and it is classified as a chemical substance. Lenalidomide is not a pediatric formulation and is not designated as an orphan drug.

**Bortezomib**, marketed as VELCADE, is provided as a 3.5 mg powder for solution for injection. It is administered subcutaneously with a maximum daily dose of 1.3 mg/m² and a total maximum dose of 249.6 mg/m² over a 60-week treatment period. Bortezomib is classified as a chemical substance. It is not a pediatric formulation and is not designated as an orphan drug.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of these medications in treating newly diagnosed non-frail transplant-ineligible multiple myeloma in elderly patients.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the evaluation of **Minimal Residual Disease (MRD)** rate at a sensitivity of 10^-5 at 18 months. This will be measured in bone marrow aspirate samples from patients with newly diagnosed non-transplant eligible (NTE) **Multiple Myeloma**. The primary endpoint is defined as the proportion of patients achieving MRD negativity at this threshold.

Secondary endpoints include a range of clinical and laboratory parameters, adverse events, and vital signs, assessed according to CTCAE 5.0. Additional efficacy measures will include the overall response rate, defined as the proportion of patients achieving a very good partial response (VGPR) or better, and the duration of response, which is the time from the first response to the first documentation of disease progression. The trial will also evaluate the time to first response and the rate of primary refractory disease, defined as the proportion of patients with stable disease (SD) or disease progression (DP).

Further assessments will involve the MRD rate at 12 months and annually, sustained MRD rate between evaluations, and the rate of loss of MRD negativity. Time to reach and lose MRD negativity will also be analyzed. Survival outcomes such as overall survival (OS), time to progression (TTP), progression-free survival (PFS), time to next treatment (TTNT), and event-free survival (EFS) will be measured. The study will also explore the correlation between genomic abnormalities in bone marrow tumor plasma cells and response, MRD rate, and survival rate.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Must be able to understand and voluntarily sign an informed consent form
Must be able to adhere to the study visit schedule and other protocol requirements
Life expectancy of > 6 months
Subject, male or female, must be at least ≥ 65 years of age and < 80 years of age
Newly diagnosed multiple myeloma requiring therapy 5.1. Monoclonal plasma cells in bone marrow ≥ 10% or presence of biopsy-proven plasmacytoma 5.2. Revised International Myeloma Working Group diagnostic criteria for multiple myeloma
Must have measurable disease o IgG myeloma: M-protein ≥1.0 g/dL or urine M- protein≥200 mg/24 hours; or o IgA, IgM, IgD, or IgE multiple myeloma: serum M-protein ≥0.5 g/dL or urine M- protein ≥200 mg/24 hours; or o Light chain multiple myeloma: urine M- protein ≥200 mg/24 hours or Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio
Must be non-transplant eligible and not frail o Newly diagnosed and not considered candidate for high-dose chemotherapy with SCT. o Subject must be not frail
performance status ECOG ≤ 2
Adequate bone marrow function, documented within 72 hours and without transfusion 72 hours prior to the first intake of investigational product (C1J1) with no growth factor support (one week), defined as: o Absolute neutrophils ≥ 1 x109/L, o Untransfused Platelet count ≥ 75 x109/L, o Hemoglobin ≥ 8.5 g/dL.
Adequate organ function documented within one week prior to the first intake of investigational product (C1J1) defined as: o Serum total bilirubin < 2x upper limit of normal (ULN), o Creatinine clearance ≥ 30ml/min, calculated with MDRD formula, o Serum SGOT/AST or SGPT/ALT < 3x upper limit of normal (ULN).
Subjects affiliated with an appropriate social security system
A man who is sexually active with a pregnant woman or a woman of childbearing potential must agree to use a barrier method of birth control e.g., condom with spermicidal foam/gel/film/cream/suppository during the study and for at least 8 months after the last dose of treatment, even he has had a vasectomy
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a female of childbearing potential Or A FCBP* who must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 – 14 days prior to and again within 24 hours prior to starting study medication and before each cycle of study treatment. A FCBP* must agree to continue abstinence from heterosexual intercourse or to use 2 reliable effective methods of contraception simultaneously without interruption: o For at least 28 days before starting experimental treatments, o Throughout the entire duration of experimental treatments, o During dose interruptions, o And for at least 8 months after the last dose of experimental treatments.
All patients must understand and accept to comply with the conditions of the lenalidomide pregnancy prevention plan

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Exclusion Criteria

1 Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma. Monoclonal gammopathy of undetermined significance is defined by presence of serum M-protein <3 g/dL; absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the M-protein; and (if determined) proportion of plasma cells in the bone marrow of 10% or less (Kyle 2003). Smoldering multiple myeloma is defined as asymptomatic multiple myeloma with absence of related organ or tissue impairment end organ damage (Kyle 2003, Kyle 2007).
2 Subject has a diagnosis of Waldenström’s disease, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
3 Subject has prior or current systemic therapy or SCT for multiple myeloma, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment.
4 Subject has a history of malignancy (other than multiple myeloma) within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the Coordinator Investigator, is considered cured with minimal risk of recurrence within 3 years).
5 Subject has had radiation therapy within 7 days of randomization unless done for antalgic reason or in case of functional risk for the patient
6 Subject has had plasmapheresis within 7 days of randomization unless patient disease is still measurable (inclusion criteria n° 6) after the plasmapheresis
7 Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.
8 Subject known to be seropositive for history of human immunodeficiency virus (HIV) or to have hepatitis A active infection.
9 Known to have hepatitis B active or uncontrolled infection (positive HBsAg and/or HBV DNA) o Patient can be eligible if anti-HBc IgG positive (with or without positive anti-HBs) but HBsAg and HBV DNA are negative. If anti-HBV therapy in relation with prior infection was started before initiation of IMP, the anti-HBV therapy and monitoring should continue throughout the study treatment period. o • Patients with negative HBsAg and positive HBV DNA observed during screening period will be evaluated by a specialist for start of anti-viral treatment: study treatment could be proposed if HBV DNA becomes negative and all the other study criteria are still met.
10 Known to have hepatitis C active infection (positive HCV RNA and negative anti-HCV) Patients with antiviral therapy for HCV started before initiation of IMP and positive HCV antibodies are eligible. The antiviral therapy for HCV should continue throughout the treatment period until seroconversion. Patients with positive anti-HCV and undetectable HCV RNA without antiviral therapy for HCV are eligible.
11 Subject has any clinically significant medical or psychiatric condition or disease (e.g., uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) in the investigator’s opinion, would expose the patient to excessive risk or may interfere with compliance or interpretation of the study results.
12 Subject has active systemic infection and severe infections requiring treatment with a parenteral administration of antibiotics.
13 Subject has clinically significant cardiac disease, including: o myocardial infarction within 6 months before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV) o uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 5 Grade ≥2) or clinically significant ECG abnormalities or LVEF < 40 %
14 Subject has known allergies, hypersensitivity, or intolerance to steroids, mannitol, pregelatinized starch, sodium stearyl fumarate, histidine (as base and hydrochloride salt), arginine hydrochloride, poloxamer 188, sucrose or any of the other components of study intervention that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents, monoclonal antibodies or human proteins, or their excipients
15 Known hypersensitivity, allergy to one of the study products (isatuximab, lenalidomide, bortezomib), dexamethasone or to one of the excipients
Acute diffuse infiltrative pneumopathy, pericardial disease
17 Subject has plasma cell leukemia (according to World Health Organization [WHO] criterion: ≥20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 109/L) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
18 Subject is known or suspected of not being able to comply with the study protocol (e.g., because of alcoholism, drug dependency, or psychological disorder). Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol- specified assessments. Subject is taking any prohibited medications
19 Subject has had major surgery within 2 weeks before randomization or has not fully recovered from surgery, Kyphoplasty or vertebroplasty is not considered major surgery
20 Subject has received an investigational drug (including investigational vaccines) within 14 days or 5 half-lives of the investigational drug prior to initiation of study intervention, whichever is longer, or used an invasive investigational medical device within 4 weeks before randomization or is currently enrolled in an interventional investigational study. In case of very aggressive disease (i.e. circulating plasma cell) delay could be shortened after agreement between sponsor and investigator, in absence of residual toxicities from previous therapy
21 Refusal to consent or protected by legal regime (under judicial protection, guardianship, trusteeship)
22 Subject has contraindications to required prophylaxis for deep vein thrombosis and pulmonary embolism
23 Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
France	Not Recruiting	17 Aug 2021	270

Sites & Investigators

Research sites

Institut de Cancérologie Hématologie Universitaire de Saint Etienne (iCHUSE)Centre Hospitalier Intercommunal De Cornouaille Centre Hospitalier Emile Muller de Mulhouse Groupe Hospitalier du Havre - Hôpital Jacques Monod

Investigators

Cyrille H.Salomon M.Borhane S.Jean Marc S. D. C.

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name	Role in Trial	Formulation	Administration	Max Daily Dose	Treatment Duration	EU MP Number
SARCLISA 20mg/mL concentrate for solution for infusion.	Test	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS USE	10	60	PRD8132765
DEXAMETHASONE	Other	—	ORAL USE	20	12	SUB07017MIG
DEXAMETHASONE	Other	—	ORAL USE	20	12	SUB07017MIG
VELCADE 3.5 mg powder for solution for injection	Test	POWDER FOR SOLUTION FOR INJECTION	SUBCUTANEOUS USE	1.3	60	PRD3353088
Revlimid 25 mg hard capsules	Test	HARD CAPSULES	ORAL USE	25	60	PRD9264271
DEXAMETHASONE	Other	—	ORAL USE	20	12	SUB07017MIG
DEXAMETHASONE	Other	—	ORAL USE	20	12	SUB07017MIG