Randomized phase II trial for patients with newly diagnosed low-risk multiple myeloma to evaluate the benefit of 6 cycles of isatuximab with lenalidomide/bortezomib/dexamethasone (I-VRD) followed by maintenance therapy with lenalidomide and isatuximab randomized in comparison with therapy consisting of 3 cycles of I-VRD followed by one cycle of high-dose therapy and maintenance therapy with lenalidomide and isatuximab

Trial ID: 2022-500453-16-00
Protocol: UZL22_01
Sponsor: Universitaetsklinikum Schleswig-Holstein AöR

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Diseases & Conditions

Plasma cell myeloma

Objectives

The primary objective of this randomized phase II trial is to determine the non-inferiority of the experimental arm B compared to the standard of care treatment arm A regarding **minimal residual disease (MRD)** negativity combined with complete response (≥CR) at week 40. This is assessed using flow cytometry and next-generation sequencing according to the International Myeloma Working Group (IMWG) criteria. The clinical relevance of this objective lies in its potential to establish a less intensive treatment regimen that maintains efficacy in achieving MRD negativity, which is a critical prognostic marker in **multiple myeloma**.

Secondary objectives include:

Detecting possible differences in MRD negativity at week 40, year 1, and year 2.
Detecting possible differences in MRD negativity combined with ≥CR at year 1 and year 2.
Detecting possible differences in sustained MRD negativity at 1 year and 2 years after the start of treatment.
Characterizing both arms with respect to overall survival (OS), progression-free survival (PFS), PFS-2, time to next treatment, and overall response rate (ORR).
Characterizing the safety profile of both arms concerning adverse events (AE) and toxicities.

Participants

The clinical trial involves participants diagnosed with **Multiple Myeloma**, specifically targeting individuals who are newly diagnosed, untreated, and symptomatic. The study population includes both male and female subjects, aged between 18 and 70 years, who are in generally good health as indicated by a WHO performance status of 0-2, provided the status of 2 is due to Multiple Myeloma and not other co-morbid conditions. The trial does not include vulnerable populations. Participants must have adequate vascular access for leukapheresis and be suitable for high-dose melphalan and stem cell retransfusion. Lifestyle considerations include the requirement for male participants to use contraception and refrain from donating sperm, while female participants must not be pregnant or breastfeeding and adhere to strict contraceptive measures. The trial population was selected based on specific inclusion criteria, such as the presence of measurable disease and a standard gene expression pattern of isolated plasma cells. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of a treatment regimen for patients with newly diagnosed low-risk **multiple myeloma**. The trial aims to compare the non-inferiority of an experimental arm against a standard of care treatment arm, focusing on achieving minimal residual disease (MRD) negativity combined with complete response (CR) at week 40. The study will utilize a combination of **lenalidomide**, **isatuximab**, **bortezomib**, and **dexamethasone** in various treatment cycles, followed by maintenance therapy. The trial is expected to run from October 2022 to September 2028, with participant involvement lasting up to 36 months, depending on the treatment arm and response.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, disease stage, and overall health status. Following randomization, participants will attend regular follow-up visits to monitor treatment response, side effects, and overall health. These visits will include assessments such as blood tests, imaging studies, and physical examinations. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination, where final evaluations will be conducted to assess the primary and secondary endpoints.

The expected length of participant involvement is contingent upon the treatment arm assignment and individual response to therapy, with a maximum duration of 36 months. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure participant safety and data integrity throughout the study duration.

Treatment

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Lenalidomide** is provided in the form of hard capsules, available in dosages of 5 mg, 10 mg, 15 mg, and 25 mg. The capsules are administered orally, with a maximum daily dose of 25 mg and a maximum treatment period of 24 to 36 months, depending on the specific dosage. The active substance, lenalidomide, is of chemical origin and is manufactured by HEXAL AG.

**Isatuximab** is administered as a concentrate for solution for infusion, with a concentration of 20 mg/mL. The route of administration is intravenous infusion, with a maximum daily dose of 10 mg/kg and a maximum total dose of 370 mg/kg. The treatment period is up to 24 months. Isatuximab is a protein-based substance produced by SANOFI-AVENTIS GROUPE.

**Dexamethasone**, also referred to as betamethasone sodium phosphate Ph. Eur, is used in the trial as a chemotherapy substance. It is administered both orally and intravenously, with a maximum daily dose of 20 mg and a total dose of 2040 mg over a treatment period of 36 months. The active substance is classified under specified substance group 3.

**Bortezomib** is included as a non-experimental chemotherapy substance in the trial. It is provided as a powder for solution for injection, administered subcutaneously. The maximum daily dose is 1.3 mg/m², with a total dose of 62.4 mg/m² over a 36-month treatment period. Bortezomib is of chemical origin.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of these treatments in patients with newly diagnosed low-risk multiple myeloma, comparing different therapeutic approaches involving these medications.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the evaluation of **minimal residual disease (MRD)** negativity combined with complete response (≥CR) at week 40. This primary endpoint will be measured using flow cytometry according to EuroFlow standards, with MRD negativity defined as lower than 1:10^-5, and ≥CR determined according to the International Myeloma Working Group (IMWG) criteria. Secondary endpoints include overall survival (OS) since randomization and since week 40 based on MRD negativity, progression-free survival (PFS) from randomization to disease progression after first-line treatment, and the frequency of partial response (PR), very good partial response (VGPR), near complete response (nCR), complete response (CR), stringent complete response (sCR), as well as overall response rate (ORR) at specified time points.

Additional secondary endpoints involve PFS since week 40 based on MRDneg+≥CR, OS and PFS stratified by cytogenetic findings, PFS-2, time to onset of further relapse therapy, and global quality of life (QoL) scores using the EORTC QLQ-30 every six months post-randomization. The trial will also assess MRD negativity and sustained MRD negativity combined with ≥CR response at one and two years after the start of induction therapy. The type and frequency of adverse events, particularly Grade III and IV with a focus on secondary malignancies, will also be monitored. These efficacy parameters will be collected and analyzed at various time points, including week 40, one year, and two years after the start of treatment, to determine the non-inferiority of the experimental arm compared to the standard of care treatment arm.

Inclusion and Exclusion Criteria

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Inclusion Criteria

newly diagnosed, untreated, symptomatic, documented myeloma (according to the revised CRAB criteria 2014) with clonal bone marrow (BM) plasma cells ≥10% or biopsy-proven osseous or extramedullary plasmacytoma and any one or more of the following myeloma defining events: I. Hypercalcemia: serum calcium >0,25 mmol/L (>1 mg/dl) higher than the upper limit of normal or >2,75 mmol/L (>11 mg/dL); II. Renal insufficiency: serum creatinine >177 μmol/l (>2 mg/dl); III. Anemia: hemoglobin value of >20 g/l below the lower limit of normal, or a hemoglobin value lower than 10g/dl; IV. Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT; V. Clonal BM plasma cell percentage ≥60%; VI. Involved: uninvolved serum free light chain ratio ≥100; VII. >1 focal lesions on MRI examination
Presence of measurable disease: I. Serum M-protein ≥ 0.5 g/dL or urine M-protein ≥ 200 mg/24 hours. II. Involved FLC level ≥ 10 mg/dl, provided sFLC ratio is abnormal
R-ISS stage I
Standard gene expression pattern of isolated plasma cell based on SKY92 GEP assay
Must be ≥ 18 and ≤70 years at the time of signing the informed consent form
Must be able to adhere to the study visit schedule and other protocol requirements in the investigator's opinion
WHO performance status 0-2 (WHO=2 is allowed only if caused by MM and not by co-morbid conditions)
Ability to understand and willingness to sign written informed consent. Signed informed consent must be obtained before any study specific procedure
Suitable for high-dose melphalan and stem cell retransfusion
Subjects must have adequate vascular access for leukapheresis
A male participant must agree to use contraception during the intervention period and for at least 5 months after the last dose of isatuximab treatment and refrain from donating sperm during this period. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: i) Not a Female of childbearing potential (FCBP), OR ii) A FCBP who must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 28 days prior to and again within 24 hours prior to starting study medication and then every 21 days during each cycle of induction as well as experimental arm consodilation and every 28 days during maintenance therapy and other therapy cycles and must either commit to continue abstinence from heterosexual intercourse or apply a highly effective method of birth control during the intervention period and for at least 5 months after the last dose of isatuximab treatment. In case of more frequent menstruation, a test will be applied every 14 days. In case of unexpected heavy bleeding or delay of menstruation, additional tests will be applied. Of note: contraception duration should take also into consideration any backbone therapy. All females: Must understand the damages and hazards lenalidomide can cause to an unborn fetus and the necessary precautions associated with the use of lenalidomide. Females of childbearing potential (FCBPs) must understand the need for effective contraception, without interruption. [...]
All subjects must: I. Agree to abstain from donating blood while taking lenalidomide, during dose interruptions and for at least 5 months after the last dose of lenalidomide and/or isatuximab. II. Agree never to give lenalidomide to another person. III. Agree to return all unused lenalidomide capsules to the investigator (with exception of prescribed lenalidomide capsules) IV. Be aware that no more than a 28-day lenalidomide supply may be dispensed with each cycle of lenalidomide during induction and consolidation therapy and be prescribed during maintenance therapy.

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Exclusion Criteria

Direct Coombs test positive hemolytic anemia
Involvement of the central nervous system (CNS)
History or presence of clinically relevant CNS pathology such as clinically relevant epilepsy, seizure, paresis, aphasia, stroke, subarachnoid hemorrhage or other CNS bleed, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis
Subject with active or history of plasma cell leukemia, Waldenström's macroglobulinemia, POEMS syndrome or clinically significant amyloidosis
Patients having nonsecretory MM
Systemic AL amyloidosis (with exception of AL amyloidosis of BM)
Previous chemotherapy or radiotherapy during the past 5 years except local radiotherapy for myeloma treatment or benign diseases, such as nonmalignant thyroid diseases. (Note: patients may have received a cumulative dose of up to 320 mg of dexamethasone or equivalent as emergency therapy.) Previous therapy due to smouldering myeloma or a single dose of bortezomib may be acceptable. In this case the coordinating investigator or his deputy has to be consulted prior to inclusion
Patients with any of the following laboratory abnormalities: I. Absolute neutrophil count (ANC) < 1,000/μL. II. Platelet count < 50,000 / μL (Platelet transfusions are not permitted to improve platelet count one week prior to study inclusion.) III. Serum Creatinine Clearance (CrCl) < 30 mL/min / 1,73m2. IV. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × upper limit of normal (ULN) (unless due to liver infiltration by myeloma cells), serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with documented Gilbert’s syndrome. V. International ratio (INR) or partial thromboplastin time (PTT) > 1.5 × ULN, or history of Grade ≥ 2 hemorrhage within 30 days, or subject requires ongoing treatment with chronic, therapeutic dosing of anticoagulants (e.g., warfarin, low molecular weight heparin, or Factor Xa inhibitors)
Echocardiogram (ECHO) with left ventricular ejection fraction < 45%
An inadequate pulmonary function defined as oxygen saturation (Sa02) < 92 % on room air
Known to be HIV+ or to have uncontrolled or active hepatitis A, B, or C infection [...]
Subject with prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years
Subjects with severe polyneuropathy with accompanying pain
Hypersensitivity or allergy against any of the study drugs
Contraindications against any of the study drugs as outlined in the Investigator brochure or equivalent
Prisoners or subjects who are legally institutionalized, or those unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions
Participation in another interventional clinical trial during this trial or within 4 weeks before entry into this trial. There may be exceptions at the discretion of the (coordinating) investigator
Active systemic infection and severe infections requiring treatment with a parenteral administration of antibiotics
Any clinically significant, uncontrolled medical conditions that, in the Investigator's opinion, would expose the patient to excessive risk or may interfere with compliance or interpretation of the study results
Hypersensitivity or history of 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

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Germany	Not Recruiting	01 Oct 2022	78

Sites & Investigators

Research sites

Marien Gesellschaft Siegen gGmbH Klinikum Nuernberg Carl Von Ossietzky Universitaet Oldenburg Charite Universitaetsmedizin Berlin KöR

Investigators

Carsten S.Amin T.Elisabeth M.Henry S.

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	INTRAVENIOUS INFUSION	10	24	PRD8587472
SARCLISA 20mg/mL concentrate for solution for infusion	Test	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENIOUS INFUSION	10	24	PRD8132765
LENALIDOMIDE	Test	—	ORAL	25	36	SUB25389
DEXAMETHASONE	Test	PHF00231MIG	ORAL AND IV	20	36	SCP1977137
SARCLISA 20mg/mL concentrate for solution for infusion	Test	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENIOUS INFUSION	10	24	PRD8132767
LENALIDOMIDE	Test	—	ORAL	25	36	SUB25389
LENALIDOMIDE	Test	—	ORAL	25	36	SUB25389
LENALIDOMIDE	Test	—	ORAL	25	36	SUB25389
BORTEZOMIB	Test	—	SUBCUTANEOUS	1.3	36	SUB20020
LENALIDOMIDE	Test	—	ORAL	25	36	SUB25389