Expression-linked and R-ISS-adapted stratification for first line therapy in multiple myeloma patients (ELIAS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University Medical Centre Schleswig-Holstein

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Cardiovascular Diseases [C14], Diseases [C] - Hemic and Lymphatic Diseases [C15], Diseases [C] - Immune System Diseases [C20]

Trial duration

30 Oct 2023 → ongoing

Decision date (initial)

2022-11-03

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Sanofi-Aventis Deutschland GmbH · Sanofi-Aventis Deutschland GmbH

External identifiers

EU CT number

2022-500453-16-00

ClinicalTrials.gov

NCT05665140

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To determine non-inferiority of the experimental arm B compared to standard of care treatment arm A regarding minimal residual disease (MRD) negativity combined with ≥CR (MRDneg+≥CR) at week 40, as determined by flow cytometry and next-generation sequencing and according to IMWG criteria

Secondary objectives 5

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

Conditions and MedDRA coding

Multiple Myeloma

Study design 4 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 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
2. 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
3. R-ISS stage I
4. Standard gene expression pattern of isolated plasma cell based on SKY92 GEP assay
5. Must be ≥ 18 and ≤70 years at the time of signing the informed consent form
6. Must be able to adhere to the study visit schedule and other protocol requirements in the investigator's opinion
7. WHO performance status 0-2 (WHO=2 is allowed only if caused by MM and not by co-morbid conditions)
8. Ability to understand and willingness to sign written informed consent. Signed informed consent must be obtained before any study specific procedure
9. Suitable for high-dose melphalan and stem cell retransfusion
10. Subjects must have adequate vascular access for leukapheresis
11. 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. [...]
12. 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.

Exclusion criteria 20

1. Direct Coombs test positive hemolytic anemia
2. Involvement of the central nervous system (CNS)
3. 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
4. Subject with active or history of plasma cell leukemia, Waldenström's macroglobulinemia, POEMS syndrome or clinically significant amyloidosis
5. Patients having nonsecretory MM
6. Systemic AL amyloidosis (with exception of AL amyloidosis of BM)
7. 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
8. 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)
9. Echocardiogram (ECHO) with left ventricular ejection fraction < 45%
10. An inadequate pulmonary function defined as oxygen saturation (Sa02) < 92 % on room air
11. Known to be HIV+ or to have uncontrolled or active hepatitis A, B, or C infection [...]
12. Subject with prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years
13. Subjects with severe polyneuropathy with accompanying pain
14. Hypersensitivity or allergy against any of the study drugs
15. Contraindications against any of the study drugs as outlined in the Investigator brochure or equivalent
16. 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
17. 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
18. Active systemic infection and severe infections requiring treatment with a parenteral administration of antibiotics
19. 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
20. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. MRD negativity combined with ≥CR (MRDneg+≥CR) at week 40 (MRD negativity measured by flow cytometry according to EuroFlow and lower than 1:10-5, ≥CR according to IMWG criteria)

Secondary endpoints 14

1. OS since randomization
2. OS since week 40 based on MRD negativity at week 40
3. PFS, defined as time since randomization to disease progression after first-line treatment (study treatment)
4. Frequency of PR, VGPR, nCR, CR, sCR as well as ORR (ORR defined as: proportion of all patients reaching PR or VGPR or nCR or CR or sCR) in arm A and B at week 40, one year after start of treatment and two years after start of treatment
5. PFS since week 40 based on MRDneg+≥CR at week 40
6. OS, PFS based and stratified by cytogenetic findings
7. PFS-2, defined as the time since start of second line treatment due to relapse to disease progression in relapsed patients
8. Time to onset of further relapse therapy after progression during first-line treatment
9. Global QoL score (EORTC QLQ-30) every six month after randomization
10. MRD negativity combined with ≥CR (MRDneg+≥CR) according to IMWG criteria at one year, and at two years after the start of induction therapy
11. MRD negativity at week 40 and 1 and 2 years after the start of treatment
12. Sustained MRD negativity between week 40 and one year, and two years after the start of induction therapy
13. Sustained MRD negativity combined with ≥CR response between week 40 and one year, and two years after the start of induction therapy
14. Type and frequency of adverse events Grade III and IV with special attention to secondary malignancies

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 10

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University Medical Centre Schleswig-Holstein

Sponsor organisation

University Medical Centre Schleswig-Holstein

Address

Ratzeburger Allee 160

City

Luebeck

Postcode

23538

Country

Germany

Scientific contact point

Organisation

University Medical Centre Schleswig-Holstein

Contact name

Prof. Cyrus Khandanpour

Public contact point

Organisation

University Medical Centre Schleswig-Holstein

Contact name

Prof. Cyrus Khandanpour

Third parties 8

Locations

1 EU/EEA country · 23 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 22 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications