Lenalidomide, Bortezomib and Dexamethasone Induction Therapy With Either Intravenous or Subcutaneous Isatuximab in Patients With Newly Diagnosed Multiple Myeloma

Multiple Myeloma Clinical Trial

Official title:

A Randomized Phase III Non-inferiority Trial Assessing Lenalidomide, Bortezomib and Dexamethasone Induction Therapy With Either Intravenous or Subcutaneous Isatuximab in Transplant-eligible Patients With Newly Diagnosed Multiple Myeloma.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05804032
• Other study ID #: GMMG-HD8/DSMM XIX
• Status: Recruiting
• Phase: Phase 3
• Start date: April 14, 2023
• Est. completion date: July 24, 2026

Study information

• Verified date: May 2024
• Source: University of Heidelberg Medical Center
• Contact: Hartmut Goldschmidt, Prof.
• Phone: +49 6221 568198
• Email: s.gmmg[@]med.uni-heidelberg.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The trial aims to demonstrate the non-inferiority of subcutaneous to intravenous isatuximab administration in transplant-eligible patients with newly diagnosed multiple myeloma.

Description:

Prospective, multicentre, randomised, parallel group, open, phase III clinical trial, for patients with confirmed diagnosis of untreated multiple myeloma requiring systemic therapy.

Investigational Medicinal Product: Isatuximab, subcutaneous administration via a wearable injector system.

Randomization: Patients are randomized in one of 2 study arms (A or B) before induction therapy. Patients randomized in arm A will receive 3 cycles of the monoclonal antibody isatuximab intravenously, combined with RVd regimen (Lenalidomide, Bortezomib, Dexamethasone). Each cycle will last for 42 days. Patients in arm B will receive 3 cycles RVd plus isatuximab subcutaneously. After induction therapy, patients will receive standard intensification (usually cyclophosphamide-based mobilization therapy, stem cell collection and high-dose melphalan followed by autologous stem cell transplantation (HDM/ASCT)). End of study will be after the first HDM/ASCT.

There is one primary objective:

Demonstration of non-inferiority of subcutaneous (SC) isatuximab compared to intravenous (IV) isatuximab, both in combination with RVd, with respect to rates of VGPR or better after induction therapy (according to standard International Myeloma Working Group (IMWG) response criteria).

Key secondary objectives are:

1. Comparison of patient-reported outcomes (PRO) regarding route of administration of isatuximab (SC vs. IV) on induction therapy as assessed by modified CTSQ (modified 9-item questionnaire).

2. Non-inferiority of rates of MRD negativity (assessed by NGS from BMA; sensitivity 10^-5) independent of standard IMWG response after induction therapy.

The duration of the trial for each patients is expected to be approximately 10 months (induction and intensification treatment).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 514
• Est. completion date: July 24, 2026
• Est. primary completion date: July 24, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Confirmed diagnosis of untreated MM requiring systemic therapy (diagnostic criteria according to IMWG)

• Patient is eligible for high-dose melphalan (200 mg/m^2 melphalan) and autologous stem cell transplantation

• Measurable MM disease according to IMWG criteria, defined as any quantifiable monoclonal protein value, defined by at least one of the following three measurements: serum M-protein = 10 g/L; urine light-chain (M-protein) of = 200 mg/24 hours; involved FLC level = 10 mg/dL provided sFLC ratio is abnormal

• Age 18-70 years at trial inclusion

Exclusion Criteria:

• Patient has known hypersensitivity (or contraindication) to any of the components of study therapy

• Systemic amyloid light-chain amyloidosis (except for localized AL amyloidosis limited to the skin or the bone marrow)

• Plasma cell leukemia

• Previous chemotherapy or radiotherapy during the past 5 years except local radiotherapy in case of local MM progression

• Severe cardiac dysfunction (NYHA classification III-IV)

• Patients with active or uncontrolled hepatitis B or C or detectable liver disease due to hepatitis B or C

• HIV positivity

• Patients with active, uncontrolled infections

• Patients with severe renal insufficiency or requiring hemodialysis

• Patients with peripheral neuropathy or neuropathic pain, grade 2 or higher (as defined by the NCI Common Terminology Criteria for Adverse Events)

• Patients with a history of any active malignancy during the past 5 years with the exception of following malignancies after curative therapy: basal cell carcinoma of the skin, squamous cell skin carcinoma, stage 0 cervical carcinoma or any in situ malignancy

• Platelet count < 75 x 10^9/L

• Haemoglobin = 8.0 g/dL, unless related to MM

• Absolute neutrophil count (ANC) < 1.0 x 10^9/L (the use of colony stimulating factors within 14 days before the test is not allowed)

• Corrected serum calcium > 14 mg/dL (> 3.5 mmol/L)

• Pregnancy and lactation

For further details on inclusion/exclusion criteria please refer to the study protocol.

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Isatuximab
IV isatuximab will be administered weekly in the first cycle (Cycle 1) on days 1, 8, 15, 22, 29, and biweekly on the 2 subsequent cycles at days 1, 15 and 29, at the dose of 10 mg/kg.
• Isatuximab
SC isatuximab will be administered on days 1, 8, 15, 22, 29 of cycle 1, and on days 1, 15 and 29 of cycles 2-3, at the dose of 1400 mg
• Lenalidomide
Both arms: 25 mg per os on day 1-14 and d22-35 in induction cycle 1-3
• Bortezomib
Both arms: 1.3 mg/m^2 subcutaneous on day 1, 4, 8, 11, 22, 25, 29 32 in 3 induction cycles
• Dexamethasone
20 mg per os on day 1-2, 4-5, 8-9, 11-12, 15; and 22-23, 25-26, 29-30, 32-33 in induction cycles 1-3.

Locations

Country	Name	City	State
Austria	Universitätsklinikum Krems	Krems
Austria	Ordensklinikum Linz	Linz
Austria	Landeskrankenhaus Feldkirch-Rankweil	Rankweil
Austria	Universitätsklinikum der Paracelsus, 3. Med. Abteilung/Onkologie Ambulanz	Salzburg
Austria	Universitätsklinikum St. Pölten - Lilienfeld	St. Pölten
Austria	Phyrn-Eisenwurzen Klinikum Steyr	Steyr
Germany	Uniklinik RWTH Aachen, Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltransplantation	Aachen
Germany	Klinikum Augsburg, II. Medizinische Klinik Hämatologie/Onkologie	Augsburg
Germany	Helios Klinikum Bad Saarow, Klinik für Hämatologie, Onkologie und Palliativmedizin	Bad Saarow
Germany	MedZentrum Klinikum Bayreuth GmbH	Bayreuth
Germany	Charité, III. Medizinische Abteilung (Hämatologie/Onkologie)	Berlin
Germany	Klinik für Hämatologie und Stammzelltransplantation, Helios Klinikum Berlin-Buch	Berlin
Germany	Vivantes Klinikum Neukölln, Klinik für Hämatologie und Onkologie	Berlin
Germany	Vivantes Klinikum Spandau	Berlin
Germany	Bielefeld Praxis, Studiengesellschaft Onkologie	Bielefeld
Germany	Evangelisches Klinikum Bethel	Bielefeld
Germany	Johanniter-Krankenhaus Bonn	Bonn
Germany	Universitätsklinikum Bonn, Medizinische Klinik III	Bonn
Germany	Städtisches Klinikum Braunschweig	Braunschweig
Germany	Klinikum Bremen-Mitte	Bremen
Germany	Klinikum Chemnitz gGmbH	Chemnitz
Germany	Carl-Thiem-Klinikum Cottbus gGmbH, 2. Medizinische Klinik	Cottbus
Germany	Klinikum Darmstadt, Medizinische Klinik V Hämatologie/Onkologie	Darmstadt
Germany	St.-Johannes-Hospital	Dortmund
Germany	Universitätsklinikum Carl Gustav Carus an der TU Dresden, Medizinische Klinik und Poliklinik I	Dresden
Germany	Helios St. Johannes Klinik Duisburg, Medizinische Klinik 2	Duisburg
Germany	Marien Hospital Düsseldorf GmbH, Klinik für Onkologie, Hämatalogie und Palliativmedizin	Düsseldorf
Germany	Universitätsklinikum Düsseldorf, Klinik für Hämatologie, Onkologie und Klinische Immunologie	Düsseldorf
Germany	St. Antonius-Hospital Eschweiler, Klinik für Hämatologie / Onkologie	Eschweiler
Germany	KEM I Evang. Kliniken Essen-Mitte gGmbH, Evangelisches Krankenhaus Essen-Werden gGmbH, Klinik für Hämatologie, Onkologie und Stammzelltransplantation	Essen
Germany	Universitätsklinikum Essen	Essen
Germany	Malteser Krankenhaus, St. Franziskus Hospital, Hämatologie/Onkologie	Flensburg
Germany	Centrum für Hämatologie und Onkologie Bethanien	Frankfurt am Main
Germany	Universitätsklinikum Frankfurt, Medizinische Klinik 2, Hämatologie/Onkologie	Frankfurt am Main
Germany	Universitätsklinikum Freiburg	Freiburg
Germany	Universitätsklinikum Göttingen	Göttingen
Germany	Universitätsmedizin Greifswald, Klinik und Poliklinik für Innere Medizin C	Greifswald
Germany	Katholisches Krankenhaus Hagen gGmbH, Klinik für Hämatologie und Onkologie	Hagen
Germany	Universitätsklinikum Halle	Halle
Germany	Universitätsklinikum Hamburg-Eppendorf, Zentrum für Onkologie	Hamburg
Germany	Asklepios Kliniken Hamburg GmbH	Hamburg-Altona
Germany	Onkologische Schwerpunktpraxis Heidelberg	Heidelberg
Germany	Universitätsklinikum Heidelberg, Medizinische Klinik V	Heidelberg
Germany	SLK Kliniken Heilbronn, Medizinische Klinik III	Heilbronn
Germany	Universitätsklinikum des Saarlandes, Klinik für Innere Medizin 1	Homburg
Germany	Klinikum der Friedrich-Schiller-Universität Jena, Klinik für Innere Medizin II, Abteilung Hämatologie und internistische Onkologie	Jena
Germany	Westpfalz-Klinikum	Kaiserslautern
Germany	Städtisches Klinikum Karlsruhe	Karlsruhe
Germany	Klinikverbund Allgäu, Klinikum Kempten, Hämatologie / Onkologie	Kempten
Germany	Universitätsklinikum Schleswig-Holstein, Campus Kiel	Kiel
Germany	Gemeinschaftsklinikum Mittelrhein	Koblenz
Germany	Universitätsklinikum Köln	Köln
Germany	Gemeinschaftspraxis für Hämatologie und Onkologie	Lebach
Germany	Universitätsklinikum Leipzig	Leipzig
Germany	Universitätsklinikum Schleswig-Holstein, Campus Lübeck	Lübeck
Germany	Klinikum der Stadt Ludwigshafen	Ludwigshafen
Germany	Universitätsklinikum Magdeburg	Magdeburg
Germany	Universitätsmedizin der Johannes Gutenberg-Universität Mainz, III. Medizinische Klinik und Poliklinik	Mainz
Germany	Mannheimer Onkologie Praxis	Mannheim
Germany	Universitätsklinikum Mannheim, III. Medizinische Klinik	Mannheim
Germany	Philipps-Universität Marburg, Abteilung Hämatologie, Onkologie und Immunologie am Universitätsklinikum Gießen und Marburg GmbH	Marburg
Germany	Klinikum Hochsauerland	Meschede
Germany	Kliniken Maria Hilf GmbH, Medizinische Klinik I	Mönchengladbach
Germany	Klinikum rechts der Isar der Technischen Universität München, Klinik und Poliklinik für Innere Medizin III, Hämatologie und Onkologie	München
Germany	Rotkreuzklinikum	München
Germany	Universitätsklinikum Münster, 1. Medizinische Klinik A	Münster
Germany	Kliniken Ostalb - Standort Stauferklinikum, Hämatologie und Onkologie	Mutlangen
Germany	Klinik Oldenburg	Oldenburg
Germany	Klinikum Osnabrück	Osnabrück
Germany	Brüderkrankenhaus St. Josef	Paderborn
Germany	Krankenhaus Barmherzige Brüder Regensburg, Klinik für Onkologie und Hämatologie	Regensburg
Germany	Universitätsklinikum Regensburg	Regensburg
Germany	Diakonie-Klinikum Schwäbisch Hall gGmbH, Innere Medizin III (Tumorerkrankungen, Palliativmedizin)	Schwäbisch Hall
Germany	ZAHO-Zentrum für ambulante Hämatologie und Onkologie	Siegburg
Germany	Zentrum für ambulante Hämatologie und Onkologie (ZAHO)	Siegburg
Germany	Onkologische Schwerpunktpraxis Speyer	Speyer
Germany	Klinikum der Landeshauptstadt Stuttgart - Katharinenhospital	Stuttgart
Germany	Robert-Bosch-Krankenhaus	Stuttgart
Germany	Universität Tübingen, Medizinische Universitätsklinik, Innere Medizin II: Onkologie, Hämatologie, Klinische Immunologie und Rheumatologie	Tübingen
Germany	Universitätsklinikum Ulm	Ulm
Germany	University of Würzburg, Med. Klinik und Poliklinik II	Würzburg

Sponsors (4)

Lead Sponsor	Collaborator
University of Heidelberg Medical Center	Deutsche Studiengruppe Multiples Myelom (DSMM), KKS Netzwerk, Sanofi

Countries where clinical trial is conducted

Austria,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Demonstration of non-inferiority of subcutaneous (SC) isatuximab compared to intravenous (IV) isatuximab, both in combination with RVd.	Rates of VGPR or better (according to standard IMWG response criteria), defined as proportion of patients with at least VGPR after induction therapy (according to standard International Myeloma Working Group (IMWG) response criteria).	18 weeks after start of study treatment
Secondary	Quality of life compared between Arm A and B.	Comparison of PRO (patient-reported outcome) regarding route of administration of isatuximab (SC vs. IV) on induction therapy as assessed by modified CTSQ (modified 9-item questionnaire)	18 weeks after start of study treatment
Secondary	Non-inferiority of rates of MRD negativity in Arm B compared to Arm A	Rates of NGS-MRD negativity (sensitivity 10^-5, from bone marrow aspirate) after induction therapy	18 weeks after start of study treatment
Secondary	Rates of MRD negativity by NGS and NGF (sensitivity 10^-5, from BMA) independent of standard IMWG response after first HDM/ASCT	defined as proportion of negative patients with the corresponding MRD method (NGS or NGF) at the defined timepoint (after induction therapy or first HDM/ASCT)	18 weeks (timepoint "after induction") or 35 weeks (timepoint "after first HDM/ASCT") after start of study treatment
Secondary	Rates of best overall response to treatment (BOR)	proportion of patients with BOR (at least PR or better) to treatment until end of study (based on timepoints post induction cycle 2 and 3, prior to HDM/ASCT and post first HDM/ASCT)	Depending on the timepoint of best response out of all response assessments, up to 10 months from randomization
Secondary	Progression-free survival (PFS)	Time from randomization (at study inclusion) to progression or death from any cause whichever occurs first	Until EOS (28 months after start of study)