Expression-linked and R-ISS-adapted Stratification for First Line Therapy in Multiple Myeloma Patients

NCT05665140 | Recruiting Phase 2 DMC

• 2 other identifiers: UZL22_012022-500453-16-00
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 6

Brief Summary

Multiple myeloma (MM) is a malignant disease of the BM characterized by clonal expansion of plasma cells. Current guidelines recommend that newly diagnosed transplant-eligible patients with multiple myeloma (NDMMTE) shall undergo several cycles of induction, followed by one or two cycles high-dose melphalan followed by autologous stem cell transfusion (ASCT). Currently, induction therapy schemes usually consist of an immunomodulator (thalidomide or lenalidomide), a transmembrane glycoprotein CD38 targeting antibody, a proteasome inhibitor, and dexamethasone. The induction therapy is then followed by stem cell mobilization and subsequently one or two cycles of high-dose melphalan-chemotherapy based on the initial cytogenetic findings of the malignant plasma cells and the initial stage of the disease. Essentially, all NDMMTE patients undergo at least one cycle of high-dose chemotherapy, which is associated with high morbidity including acute toxicities like cytopenia, infection, and long-term effects such as myelodysplastic disease (MDS) and secondary malignancies and rarely death. Based on preliminary data and published reports, exposure to high-doses of the genotoxic agent melphalan might render the residual malignant myeloma cells into more aggressive clones, accelerating relapse by potentially altering stroma. Finally, exposure to melphalan is well known to increase the possibility of secondary malignant disease development. In MM patients, high-dose melphalan therapy improves OS and PFS if patients from all risk groups are taken in consideration. Yet, it remains to be answered, whether also low risk patients have an additional benefit from high-dose melphalan therapy or whether for these patients, a less toxic regime would be similarly sufficient with regard to PFS and OS. The challenging question will be whether the effect of melphalan on initial disease control might be outpaced by the negative effects as described above. Hence, the sponsor will explore whether treatment with high-dose melphalan might represent an overtreatment for certain subpopulation myeloma patients. These patients might be adequately treated without need of high-dose melphalan as part of the first line treatment. The sponsor, therefore, proposes to use a personalized approach to evaluate whether patients with a low-risk profile and with a gene expression profile indicating a standard risk of relapse might be sufficiently treated with an intensified induction course without subsequent upfront high-dose melphalan chemotherapy.

Conditions

Newly Diagnosed Multiple Myeloma

Outcome Measures

Primary Outcomes (1)

• Rate of minimal residual negativity combined with complete remission rate according to IMWG and EuroFlow criteria

  Minimal Residual Disease (MRD) (less than 1 malignant plasma cell per 1 Mio bone marrow cells based on EuroFLow criteria) and complete remission rate (no paraprotein detectable, Immunfixation negative urine and serum) according to international myeloma working group (IMWG) criteria after high dose chemotherapy or 6 courses of IVRD (Isatuximab, Bortezomib, lenalidomide, Dexamethasone) (week 40)

  Week 40 after start of induction therapy (18 weeks after randomization).

Secondary Outcomes (6)

• PFS

  from inclusion till end of overall study

• OS

  From start to end of overall study

• Toxicity

  From start to end of overall study

• Response criteria

  week 20, week 40, year 1, year 2

• Response criteria MRD

  week 20, week 40, year 1, year 2

Study Arms (2)

Arm A (Control)

ACTIVE COMPARATOR

Three cycles of induction (isatuximab, bortezomib, lenalidomide, dexamethasone, I-VRD), followed by standard of care therapy (e.g. stem cell mobilization, and apheresis with a subsequent high-dose melphalan and autologous stem cell transfusion). Both groups will receive subsequently an isatuximab- and lenalidomide-based maintenance therapy.

Drug: Isatuximab; Drug: Lenalidomide; Drug: Bortezomib; Drug: Dexamethasone; Other: autologous stem cell transplant

Arm B (Experimental)

EXPERIMENTAL

Three cycles of induction (I-VRD), stem cell mobilization, and apheresis followed by three cycles of consolidation (I-VRD). Both groups will receive subsequently an isatuximab- and lenalidomide-based maintenance therapy.

Drug: Isatuximab; Drug: Lenalidomide; Drug: Bortezomib; Drug: Dexamethasone

Interventions

Isatuximab DRUG

i.v. Induction Phase (Arm A and B): Induction Cycle 1 10 mg/kg D 1, 8, 15, 22, 29. Induction Cycle 2-3 10 mg/kg D 1, 15, 29 Consolidation Phase (Arm B): Consolidation Cycle 1-3 10 mg/kg D 1, 15, 29 Maintenance Phase (Arm A and B): Maintenance Cycle 1 and subsequent cycles 10 mg/kg D 1, 15, 29

Also known as: Sarclisa®

Arm A (Control); Arm B (Experimental)

Lenalidomide DRUG

hard capsule for oral use. Induction Phase (Arm A and B): Induction Cycle 1-3 25 mg D1-14, 20-35. Consolidation Phase (Arm B): Consolidation Cycle 1-3 25 mg D1-14, 20-35. Maintenance Phase (Arm A and B): Maintenance Cycle 1-2 10 mg D1-28. Maintenance Cycle 3 and subsequent cycles 15 mg D1-28 if tolerable

Also known as: Lenalidomid®

Arm A (Control); Arm B (Experimental)

Bortezomib DRUG

s.c. injection. Induction Phase (Arm A and B): Induction Cycle 1-3 1,3 mg/m² D1, 4, 8, 11, 22, 25, 29, 32. Consolidation Phase (Arm B): Consolidation Cycle 1-3 1,3 mg/m² D1, 4, 8, 11, 22, 25, 29, 32

Also known as: Velcade®

Arm A (Control); Arm B (Experimental)

Dexamethasone DRUG

orally and i.v. Induction Phase (Arm A and B): Induction Cycle 1 20 mg p.o. D 1-2, 4-5, 8-9, 11-12, 15; 22-23, 25-26, 29-30, 32-33; 20 mg i.v. D1, 8, 15, 22 and 29. Induction Cycles 2 and 3 20 mg p.o. D 1-2, 4-5, 8-9, 11-12, 15; 22-23, 25-26, 29-30, 32-33; 20 mg i.v. D1, 15 and 29. Consolidation Phase (Arm B): Consolidation Cycle 1-3 20 mg p.o. on D 1-2, 4-5, 8-9, 11-12, 15; 22-23, 25-26, 29-30, 32-33; 20 mg i.v. on D1, 15 and 29

Arm A (Control); Arm B (Experimental)

autologous stem cell transplant OTHER

autologous stem cell transplant

Arm A (Control)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• newly diagnosed, untreated, symptomatic, documented myeloma (according to the revised Hypercalcaemia, renal dysfunction, anaemia and bone lesions (CRAB) criteria 2014, see Appendix 1) 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 (positron emission tomography) V. Clonal BM plasma cell percentage ≥60% VI. Involved: uninvolved serum free light chain ratio ≥100 VII. \>1 focal lesion 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 (free light chain) level ≥ 10 mg/dl, provided sFLC (free light chain) ratio is abnormal.
• R-ISS stage I33 (see appendix 2)
• 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 (see Appendix 3) 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
• Male or Female
• Male participants:
• 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.

You may not qualify if:

• 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).
• Patients with any of the following laboratory abnormalities:
• 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 hepatitis A, B, or C active infection.
• Uncontrolled or active hepatitis B virus (HBV) infection: Patients with positive HBsAg and/or HBV DNA
• Of note:
• Patient can be eligible if anti-HBc immunoglobulin G (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.

Sponsors & Collaborators

• University Hopsital Schleswig Holstein Campus Lübeck: lead

Study Sites (6)

Heloisklinikum Berlin Buch GmbH

Berlin, 12200, Germany

RECRUITING

Klinikum Bielefeld - Onkologie, Hämatologie, Paliativmedizin

Bielefeld, 33604, Germany

RECRUITING

Universitätsklinikum Hamburg Eppendorf (UKE)

Hamburg, 20246, Germany

RECRUITING

Universitätsklinikum Schleswig-Holstein, Campus Lübeck

Lübeck, 23538, Germany

RECRUITING

Universitätsklinikum Münster

Münster, 48149, Germany

RECRUITING

Universitätsklinikum Würzburg

Würzburg, 97080, Germany

NOT YET RECRUITING

MeSH Terms

Interventions

isatuximab; Lenalidomide; Bortezomib; Dexamethasone

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Pyrazines; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Cyrus Khandanpour, Prof. Dr.

  University Hospital Schleswig-Holstein, Campus Lübeck

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Cyrus Khandanpour, Prof. Dr.

CONTACT

+49 451 500; Cyrus.Khandanpour@uksh.de

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor and Deputy Director of Department of Haematology and Oncoloy

Study Record Dates

• First Submitted: November 28, 2022
• First Posted: December 27, 2022
• Study Start: February 3, 2023
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): October 1, 2028
• Last Updated: December 11, 2024

Record last verified: 2024-12

Locations

DE (6)