Clinical trial NCT06216158: Iberdomide Vs. Iberdomide Plus Isatuximab Maintenance Therapy Post ASCT in Newly Diagnosed Multiple Myeloma
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Multiple Myeloma
Lead sponsor: University of Heidelberg Medical Center
Sponsor class: OTHER
Collaborators: name: KKS Netzwerk
name: Wuerzburg University Hospital
name: Sanofi
name: Bristol-Myers Squibb
First posted: 2024-01-22
Enrollment: 411
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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?

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Demonstration of superiority of iberdomide plus isatuximab compared to iberdomide with respect to bone marrow minimal residual disease (MRD).
timeFrame: 24 months after start of maintenance therapy
Secondary outcomes:
measure: Progression-free survival (PFS) from date of randomization.
timeFrame: 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
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen, Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltransplantation
city: Bad Saarow
country: Germany
facility: Helios Klinikum Bad Saarow
city: Berlin
country: Germany
facility: Charité, III. Medizinische Abteilung
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukölln, Klinik für Hämatologie und Onkologie
city: Berlin
country: Germany
facility: Helios Klinikum Berlin-Buch
city: Berlin
country: Germany
facility: Vivantes Klinikum Spandau
city: Bielefeld
country: Germany
facility: Evangelisches Klinikum Bethel
city: Bonn
country: Germany
facility: Johanniter Krankenhaus
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz
city: Cottbus
country: Germany
facility: Carl-Thiem-Klinikum Cottbus gGmbH, 2. Medizinische Klinik
city: Darmstadt
country: Germany
facility: Klinikum Darmstadt GmbH, Medizinische Klinik V
city: Dortmund
country: Germany
facility: St. Johannes Hospital Dortmund
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus Dresden
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Düsseldorf
country: Germany
facility: Marien Hospital Düsseldorf GmbH, Klinik für Onkologie, Hämatalogie und Palliativmedizin
city: Essen
country: Germany
facility: KEM I Evang. Kliniken Essen-Mitte gGmbH, Evangelisches Krankenhaus Essen-Werden gGmbH, Klinik für Hämatologie, Onkologie und Stammzelltransplantation
city: Flensburg
country: Germany
facility: Malteser Krankenhaus
city: Frankfurt am Main
country: Germany
facility: Centrum für Hämatologie und Onkologie Bethanien
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald
city: Hagen
country: Germany
facility: Katholisches Krankenhaus Hagen
city: Halle
country: Germany
facility: Universitätsmedizin Halle
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf, Zentrum für Onkologie
city: Heidelberg
country: Germany
facility: Onkologische Schwerpunktpraxis Heidelberg
city: Heidelberg
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg, Medizinische Klinik V
city: Heilbronn
country: Germany
facility: SLK Kliniken Heilbronn, Medizinische Klinik III
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes, Klinik für Innere Medizin 1
city: Jena
country: Germany
facility: Klinikum der Friedrich-Schiller-Universität Jena, Klinik für Innere Medizin II, Abteilung Hämatologie und internistische Onkologie
city: Kaiserslautern
country: Germany
facility: Westpfalz-Klinikum
city: Kempten
country: Germany
facility: Klinikverbund Allgäu, Klinikum Kempten, Hämatologie / Onkologie
city: Koblenz
country: Germany
facility: Gemeinschaftsklinikum Mittelrhein Koblenz
city: Lebach
country: Germany
facility: Oncocare, Gemeinschaftspraxis für Hämatologie und Onkologie
city: Ludwigshafen
country: Germany
facility: Klinikum der Stadt Ludwigshafen
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg
city: Mannheim
country: Germany
facility: Universitätsklinikum Mannheim, III. Medizinische Klinik
city: Marburg
country: Germany
facility: Philipps-Universität Marburg Hämatologie/Onkologie
city: Meschede
country: Germany
facility: Klinikum Hochsauerland
city: Mutlangen
country: Germany
facility: Kliniken Ostalb
city: Mönchengladbach
country: Germany
facility: Kliniken Maria Hilf
city: München
country: Germany
facility: Rotkreuzklinikum
city: München
country: Germany
facility: Klinikum rechts der Isar der TU München
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Paderborn
country: Germany
facility: Brüderkrankenhaus St. Josef
city: Regensburg
country: Germany
facility: Krankenhaus Barmherzige Brüder Regensburg, Klinik für Onkologie und Hämatologie
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Speyer
country: Germany
facility: Onkologische Schwerpunktpraxis Speyer
city: Stuttgart
country: Germany
facility: Klinikum der Landeshauptstadt Stuttgart - Katharinenhospital
city: Stuttgart
country: Germany
facility: Robert-Bosch-Krankenhaus
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Villingen-Schwenningen
country: Germany
facility: Schwarzwald Baar Klinikum
city: Würzburg
country: Germany
facility: University of Würzburg, Med. Klinik und Poliklinik II
Study officials:
affiliation: University Hospital Heidelberg
name: Hartmut Goldschmidt, Prof.
role: PRINCIPAL_INVESTIGATOR
References: