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

Sponsor

University of Heidelberg Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT05804032

Collaborator

Deutsche Studiengruppe Multiples Myelom (DSMM) (Other), KKS Netzwerk (Other), Sanofi (Industry)

514

Enrollment

Locations

Arms

39.6

Anticipated Duration (Months)

17.1

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Isatuximab Drug: Isatuximab Drug: Lenalidomide Drug: Bortezomib Drug: Dexamethasone	Phase 3

Detailed 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:

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).
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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

514 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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.

Anticipated Study Start Date :

Apr 6, 2023

Anticipated Primary Completion Date :

Jul 24, 2025

Anticipated Study Completion Date :

Jul 24, 2026

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A - Intravenous isatuximab Patients in arm A are treated with 3 cycles RVd + i.v. isatuximab, followed by a standard intensification and autologous stem cell transplantation.	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. Other Names: Sarclisa Drug: Lenalidomide Both arms: 25 mg per os on day 1-14 and d22-35 in induction cycle 1-3 Drug: Bortezomib Both arms: 1.3 mg/m^2 subcutaneous on day 1, 4, 8, 11, 22, 25, 29 32 in 3 induction cycles Other Names: Velcade Drug: 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.
Experimental: Arm B - Subcutaneous isatuximab Patients in arm B are treated with 3 cycles RVd + s.c. isatuximab, followed by a standard intensification and autologous stem cell transplantation.	Drug: 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 Other Names: Sarclisa Drug: Lenalidomide Both arms: 25 mg per os on day 1-14 and d22-35 in induction cycle 1-3 Drug: Bortezomib Both arms: 1.3 mg/m^2 subcutaneous on day 1, 4, 8, 11, 22, 25, 29 32 in 3 induction cycles Other Names: Velcade Drug: 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.

Arm

Intervention/Treatment

Active Comparator: Arm A - Intravenous isatuximab

Patients in arm A are treated with 3 cycles RVd + i.v. isatuximab, followed by a standard intensification and autologous stem cell transplantation.

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.

Other Names:

Sarclisa

Drug: Lenalidomide

Both arms: 25 mg per os on day 1-14 and d22-35 in induction cycle 1-3

Drug: Bortezomib

Both arms: 1.3 mg/m^2 subcutaneous on day 1, 4, 8, 11, 22, 25, 29 32 in 3 induction cycles

Other Names:

Velcade

Drug: 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.

Experimental: Arm B - Subcutaneous isatuximab

Patients in arm B are treated with 3 cycles RVd + s.c. isatuximab, followed by a standard intensification and autologous stem cell transplantation.

Drug: 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

Other Names:

Sarclisa

Drug: Lenalidomide

Both arms: 25 mg per os on day 1-14 and d22-35 in induction cycle 1-3

Drug: Bortezomib

Both arms: 1.3 mg/m^2 subcutaneous on day 1, 4, 8, 11, 22, 25, 29 32 in 3 induction cycles

Other Names:

Velcade

Drug: 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.

Outcome Measures

Primary Outcome Measures

Demonstration of non-inferiority of subcutaneous (SC) isatuximab compared to intravenous (IV) isatuximab, both in combination with RVd. [18 weeks after start of study treatment]
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).

Secondary Outcome Measures

Quality of life compared between Arm A and B. [18 weeks after start of study treatment]
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)
Non-inferiority of rates of MRD negativity in Arm B compared to Arm A [18 weeks after start of study treatment]
Rates of NGS-MRD negativity (sensitivity 10^-5, from bone marrow aspirate) after induction therapy
Rates of MRD negativity by NGS and NGF (sensitivity 10^-5, from BMA) independent of standard IMWG response after first HDM/ASCT [18 weeks (timepoint "after induction") or 35 weeks (timepoint "after first HDM/ASCT") after start of study treatment]
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)
Rates of best overall response to treatment (BOR) [Depending on the timepoint of best response out of all response assessments, up to 10 months from randomization]
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)
Progression-free survival (PFS) [Until EOS (28 months after start of study)]
Time from randomization (at study inclusion) to progression or death from any cause whichever occurs first

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Uniklinik RWTH Aachen, Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltransplantation	Aachen	Germany	52074
2	Klinikum Augsburg, II. Medizinische Klinik Hämatologie/Onkologie	Augsburg	Germany	86156
3	Helios Klinikum Bad Saarow, Klinik für Hämatologie, Onkologie und Palliativmedizin	Bad Saarow	Germany	15526
4	Charité, III. Medizinische Abteilung (Hämatologie/Onkologie)	Berlin	Germany	12200
5	Vivantes Klinikum Neukölln, Klinik für Hämatologie und Onkologie	Berlin	Germany	12351
6	Universitätsklinikum Bonn, Medizinische Klinik III	Bonn	Germany	53127
7	Klinikum Chemnitz gGmbH	Chemnitz	Germany	09116
8	Carl-Thiem-Klinikum Cottbus gGmbH, 2. Medizinische Klinik	Cottbus	Germany	03048
9	Klinikum Darmstadt, Medizinische Klinik V Hämatologie/Onkologie	Darmstadt	Germany	64283
10	Universitätsklinikum Carl Gustav Carus an der TU Dresden, Medizinische Klinik und Poliklinik I	Dresden	Germany	01307
11	Helios St. Johannes Klinik Duisburg, Medizinische Klinik 2	Duisburg	Germany	47166
12	Universitätsklinikum Düsseldorf, Klinik für Hämatologie, Onkologie und Klinische Immunologie	Düsseldorf	Germany	40225
13	Marien Hospital Düsseldorf GmbH, Klinik für Onkologie, Hämatalogie und Palliativmedizin	Düsseldorf	Germany	40479
14	St. Antonius-Hospital Eschweiler, Klinik für Hämatologie / Onkologie	Eschweiler	Germany	52249
15	KEM I Evang. Kliniken Essen-Mitte gGmbH, Evangelisches Krankenhaus Essen-Werden gGmbH, Klinik für Hämatologie, Onkologie und Stammzelltransplantation	Essen	Germany	45239
16	Universitätsklinikum Frankfurt, Medizinische Klinik 2, Hämatologie/Onkologie	Frankfurt am Main	Germany	60590
17	Universitätsklinikum Hamburg-Eppendorf, Zentrum für Onkologie	Hamburg	Germany	20246
18	Onkologische Schwerpunktpraxis Heidelberg	Heidelberg	Germany	69115
19	Universitätsklinikum Heidelberg, Medizinische Klinik V	Heidelberg	Germany	69120
20	SLK Kliniken Heilbronn, Medizinische Klinik III	Heilbronn	Germany	74078
21	Universitätsklinikum des Saarlandes, Klinik für Innere Medizin 1	Homburg	Germany	66421
22	Klinikum der Friedrich-Schiller-Universität Jena, Klinik für Innere Medizin II, Abteilung Hämatologie und internistische Onkologie	Jena	Germany	07740
23	InVo Institut für Versorgungsforschung in der Onkologie	Koblenz	Germany	56068
24	Mannheimer Onkologie Praxis	Mannheim	Germany	68161
25	Kliniken Maria Hilf GmbH, Medizinische Klinik I	Mönchengladbach	Germany	41063
26	Diakonie-Klinikum Schwäbisch Hall gGmbH, Innere Medizin III (Tumorerkrankungen, Palliativmedizin)	Schwäbisch Hall	Germany	74523
27	ZAHO-Zentrum für ambulante Hämatologie und Onkologie	Siegburg	Germany	53721
28	Onkologische Schwerpunktpraxis Speyer	Speyer	Germany	67346
29	Universität Tübingen, Medizinische Universitätsklinik, Innere Medizin II: Onkologie, Hämatologie, Klinische Immunologie und Rheumatologie	Tübingen	Germany	72076
30	University of Würzburg, Med. Klinik und Poliklinik II	Würzburg	Germany	97080