Iberdomide vs. Iberdomide Plus Isatuximab Maintenance Therapy Post ASCT in Newly Diagnosed Multiple Myeloma

Multiple Myeloma Clinical Trial

Official title:

A Randomized Phase III Trial Assessing Iberdomide Versus Iberdomide Plus Isatuximab Maintenance Therapy Post Autologous Hematopoietic Stem-Cell Transplantation in Patients With Newly Diagnosed Multiple Myeloma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06216158
• Other study ID #: GMMG-HD9/DSMM XVIII
• Status: Recruiting
• Phase: Phase 3
• Start date: April 5, 2024
• Est. completion date: June 2029

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 goal of this clinical trial is to compare a maintenance therapy consisting of iberdomide and isatuximab with an iberdomide-only regimen. The trial is the subsequent maintenance therapy to GMMG-HD8/DSMM XIX trial for patients with newly-diagnosed multiple myeloma. The main question it aims to answer is: • Will the addition of isatuximab lead to decreased amounts of measurable myeloma cells in the bone marrow after two years?

Description:

Prospective, multicentre, randomised, parallel group, open, phase III clinical trial for a maintenance therapy, for patients who underwent an induction therapy and autologous stem cell transplantation in the GMMG-HD8/DSMM XIX trial. Investigational Medicinal Product: Iberdomid (oral), isatuximab (subcutaneous administration via a wearable injector system). Randomisation will be performed centrally by GMMG/DSMM offices after verification of the eligibility of the patient. At the time of study inclusion, randomization will be performed into arm A (iberdomide) or arm B (iberdomide + isatuximab). Randomization will be stratified by centrally assessed MRD negativity status (yes vs. no vs. unknown); assessed by NGF from BMA; sensitivity of 10^-5; independent of standard IMWG response) and number of HDM/ASCT (single vs. tandem). Patients randomized in arm A will receive 39 cycles of the drug iberdomide, a Cereblon E3 Ubiquitin Ligase Modulating Drug (CELMoD®) that shares structural similarities to the immunomodulatory compounds (IMiDs) such as thalidomide and lenalidomide. Each cycle will last for 29 days. Patients in arm B will receive the same the 39 cycles of iberdomide plus monoclonal anti-CD38 antibody isatuximab subcutaneously. In both arms, patients will receive 20 mg dexamethasone in cycle 1, on the same days as the isatuximab administration in Arm B. End of study will be after 36 months of the maintenance therapy. There is one primary objective: - Demonstration of superiority of iberdomide plus isatuximab compared to iberdomide with respect to bone marrow minimal residual disease (MRD) negativity rates (sensitivity 2x10^-6 via next-generation flow cytometry [NGF]) after two years of maintenance therapy. There is one key secondary objective: - PFS, defined as time from randomization to disease progression or death from any cause, whichever occurs first. Further secondary objectives are: - Rates of sustained MRD negativity (at sensitivity levels of 10-5 and 2x10^-6 via NGF from BMA) after 1, 2 and 3 years of maintenance therapy. - Conversion from MRD positive to negative (at sensitivity levels of 10^-5 and 2x10^-6 via NGF from BMA). - Rates of best overall response to treatment (BOR). - Rates of partial response (PR), very good partial response (VGPR), complete response (CR) and stringent complete response (sCR). - Time-to-next-treatment (TTNT). - PFS on subsequent line of therapy. - Overall survival (OS). - Improvement of IMWG response categories (PR, VGPR, CR, sCR). - Proportions of patients in both treatment arms maintaining BOR and CR from baseline. - Assessment of quality-of-life (QoL) via the EORTC-QLQC30, EORTC-QLQMY20, and EQ-5D-5L questionnaires.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 411
• Est. completion date: June 2029
• Est. primary completion date: December 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Prior inclusion and treatment within the GMMG-HD8 / DSMM XIX trial
• Received at least one cycle high dose melphalan therapy (HDM) and autologous stem cell transplantation (ASCT)
• At least Partial Response (PR) according to IMWG criteria at inclusion in the trial
• Age of at least 18 years at trial inclusion
• WHO performance status of 0, 1, or 2
• Negative pregnancy test at inclusion (women of childbearing potential)
• For all men and women of childbearing potential: patients must be willing and capable to use adequate contraception during the complete therapy
• Ability of patient to understand character and individual consequences of the clinical trial
• Written informed consent (must be available before enrolment in the trial)

Exclusion Criteria:

• Subjects with gastrointestinal disease that may significantly alter the absorption of iberdomide
• Patient has known hypersensitivity (or contraindication) to any of the components of study therapy that are not amenable to premedication with steroids or H1 blockers and that would prohibit further treatment with these agents (e.g. known intolerance or hypersensitivity to infused proteins products, sucrose, histidine, and polysorbate 80 as well as intolerance to arginine and Poloxamer 188)
• Patients with a history of serious allergic reaction to another immunomodulatory agent (thalidomide, lenalidomide, or pomalidomide)", as angioedema and severe dermatologic reactions, including Grade 4 rash and exfoliative or bullous rash
• Patients currently being treated with strong inhibitors or inducers of CYP3A4/5
• Systemic AL amyloidosis (except for localized AL amyloidosis limited to the skin or the bone marrow), plasma cell leukemia or polyneuropathy, organomegaly, endocrinopathy, monoclonal-protein and skin abnormalities or Waldenström macroglobulinemia.
• Previous systemic anti-myeloma treatment other than administered within the GMMG-HD8 / DSMM XIX trial (including up to two cycles cycle high dose melphalan therapy (HDM) and autologous stem cell transplantation (ASCT). Local, consolidative radiotherapy for myeloma disease is permitted unless performed in case of progressive disease according to IMWG criteria
• Severe cardiac dysfunction (NYHA classification III-IV)
• Significant hepatic dysfunction (ASAT and/or ALAT = 3 times normal level and/or serum bilirubin = 1.5 times normal level if not due to hereditary abnormalities as Gilbert's disease), unless related to MM or HDM/ASCT.
• Patients with active or uncontrolled hepatitis B or C or detectable liver disease due to hepatitis B or C. In case of history of hepatitis B or C, it must be clarified whether it has been overcome and negative circulating HBV-DNA or HCV-RNA must be provided. Positive hepatitis B status may only be acceptable in absence of circulating HBV-DNA or signs of chronic or acute infection and if an adequate prophylaxis is being implemented during the course of the study. Prophylaxis for patients with history of hepatitis B or C should be set on a patient individual basis.
• HIV positivity
• Patients with active, uncontrolled infections
• Patients with severe renal insufficiency (Creatinine Clearance < 30ml/min) 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 (NCI CTCAE, version 5.0)
• 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. A history of an early stage malignancy during the past 5 years may be acceptable, however, in this case the GMMG study office has to be consulted prior to study inclusion
• Patients with acute diffuse infiltrative pulmonary and/or pericardial disease
• Autoimmune haemolytic anaemia with positive indirect Coombs test or immune thrombocytopenia
• Platelet count < 75 x 109/l
• Haemoglobin = 8.0 g/dl, unless related to MM
• Absolute neutrophil count (ANC) < 1.0 x 109/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)
• Unable or unwilling to undergo thromboprophylaxis
• Pregnancy and lactation
• Participant has any concurrent severe and/or uncontrolled medical condition or psychiatric disease that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study or that confounds the ability to interpret data from the study
• Subjects, who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
• Participation in other interventional clinical trials. This does not include long-term follow-up periods without active drug treatment of previous studies during the last 6 months.

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Iberdomide
Iberdomide p.o. (1.0 mg, day 1-21 of each 29-days cycle)
• Isatuximab
Isatuximab s.c. (1400 mg, cycle 1: day 1, 8, 15, 22; cycles 2-3: day 1 and 15; from C4: day 1)
• Dexamethasone
Dexamethasone p.o. or i.v. (20 mg, cycle 1 only: day 1, 8, 15, 22)

Locations

Country	Name	City	State
Germany	Uniklinik RWTH Aachen, Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltransplantation	Aachen
Germany	Universitätsklinikum Augsburg	Augsburg
Germany	Helios Klinikum Bad Saarow	Bad Saarow
Germany	Charité Campus Benjamin Franklin	Berlin
Germany	Helios Klinikum Berlin-Buch	Berlin
Germany	Vivantes Klinikum Neukölln, Klinik für Hämatologie und Onkologie	Berlin
Germany	Vivantes Klinikum Spandau	Berlin
Germany	Evangelisches Klinikum Bethel	Bielefeld
Germany	Studiengesellschaft Onkologie Bielefeld	Bielefeld
Germany	Johanniter Krankenhaus	Bonn
Germany	Universitätsklinikum Bonn	Bonn
Germany	Universitätsklinikum Bonn, Medizinische Klinik III	Bonn
Germany	Klinikum Chemnitz	Chemnitz
Germany	Carl-Thiem-Klinikum Cottbus gGmbH, 2. Medizinische Klinik	Cottbus
Germany	Klinikum Darmstadt GmbH, Medizinische Klinik V	Darmstadt
Germany	St. Johannes Hospital Dortmund	Dortmund
Germany	Universitätsklinikum Carl Gustav Carus Dresden	Dresden
Germany	Helios St. Johannes Klinik Duisburg	Duisburg
Germany	Marien Hospital Düsseldorf GmbH, Klinik für Onkologie, Hämatalogie und Palliativmedizin	Düsseldorf
Germany	Universitätsklinikum Düsseldorf	Düsseldorf
Germany	KEM I Evang. Kliniken Essen-Mitte gGmbH, Evangelisches Krankenhaus Essen-Werden gGmbH, Klinik für Hämatologie, Onkologie und Stammzelltransplantation	Essen
Germany	Centrum für Hämatologie und Onkologie Bethanien	Frankfurt am Main
Germany	Universitätsmedizin Greifswald	Greifswald
Germany	Katholisches Krankenhaus Hagen	Hagen
Germany	Universitätsmedizin Halle	Halle
Germany	Universitätsklinikum Hamburg-Eppendorf, Zentrum für Onkologie	Hamburg
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	Klinikverbund Allgäu, Klinikum Kempten, Hämatologie / Onkologie	Kempten
Germany	Oncocare, Gemeinschaftspraxis für Hämatologie und Onkologie	Lebach
Germany	Universitätsklinikum Leipzig	Leipzig
Germany	Universitätsklinikum Schleswig-Holstein	Lübeck
Germany	Klinikum der Stadt Ludwigshafen	Ludwigshafen
Germany	Universitätsklinikum Magdeburg	Magdeburg
Germany	Universitätsklinikum Mannheim, III. Medizinische Klinik	Mannheim
Germany	Philipps-Universität Marburg Hämatologie/Onkologie	Marburg
Germany	Klinikum Hochsauerland	Meschede
Germany	Kliniken Maria Hilf	Mönchengladbach
Germany	Klinikum rechts der Isar der TU München	München
Germany	Universitätsklinikum Münster	Münster
Germany	Kliniken Ostalb	Mutlangen
Germany	Klinikum 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	Onkologische Schwerpunktpraxis Speyer	Speyer
Germany	Klinikum der Landeshauptstadt Stuttgart - Katharinenhospital	Stuttgart
Germany	Universitätsklinikum Tübingen	Tübingen
Germany	Universitätsklinikum Ulm	Ulm
Germany	Schwarzwald Baar Klinikum	Villingen-Schwenningen
Germany	University of Würzburg, Med. Klinik und Poliklinik II	Würzburg

Sponsors (5)

Lead Sponsor	Collaborator
University of Heidelberg Medical Center	Bristol-Myers Squibb, KKS Netzwerk, Sanofi, Wuerzburg University Hospital

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Demonstration of superiority of iberdomide plus isatuximab compared to iberdomide with respect to bone marrow minimal residual disease (MRD).	The primary objective of this trial is to compare the two-year MRD negativity rate (sensitivity 2x10^-6 via next-generation flow cytometry [NGF]; from bone marrow aspirate) when treated with iberdomide plus isatuximab, with the MRD negativity after treatment with iberdomide only.	24 months after start of maintenance therapy
Secondary	Progression-free survival (PFS) from date of randomization.	PFS, defined as time from randomization to disease progression or death from any cause, whichever occurs first.	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months