Multiples Myelom

MM-4
DSMM_XVII
GMMG-HD8
GMMG-HD9

MM-4

Isatuximab in combination with Lenalidomide-Dexamethasone compared to Lenalidomide-Dexamethasone in elderly patients (aged ≥70 years) with newly diagnosed myeloma: a randomized phase II study (SGZ-2019-12650)

Synopsis

Short title: AGMT_MM-4

Title: Isatuximab in combination with Lenalidomide-Dexamethasone compared to Lenalidomide-Dexamethasone in elderly patients (aged ≥70 years) with newly diagnosed myeloma: a randomized phase II study (SGZ-2019-12650)

Status: active, not recruiting

Start: Oct. 2021

Coordinating Investigator: Univ. Prof. Dr. Heinz Ludwig

EudraCT Nummer: 2020-004972-17

ClinicalTrialsID: NCT04891809

Number of patients: 139

Sponsor: AGMT gemeinnützige GmbH

Design

This is a prospective, multicenter, multinational, randomized, open-label, parallel group, 2-arm study evaluating the clinical benefit of isatuximab in combination with lenalidomide and low-dose dexamethasone followed by isatuximab and lenalidomide maintenance therapy as compared to lenalidomide and low-dose dexamethasone followed by lenalidomide maintenance therapy for the treatment of patients with newly diagnosed multiple myeloma 70 years of age or older.

Randomization/treatment arms
After confirmation of eligibility criteria, patients will be randomly assigned in a 1:1 ratio to one of the two arms:

  • Isatuximab in combination with lenalidomide and low-dose dexamethasone (8 cycles) followed by isatuximab and lenalidomide maintenance therapy (IRd/Id), experimental arm
  • Lenalidomide and low-dose dexamethasone (8 cycles) followed by lenalidomide maintenance therapy (Rd/R), control arm
Primary objective:

To demonstrate the benefit of isatuximab in combination with lenalidomide and low-dose dexamethasone followed by isatuximab and lenalidomide maintenance therapy in increasing the proportion of patients with MRD negativity as compared to lenalidomide and low-dose dexamethasone followed by lenalidomide maintenance treatment in patients with newly diagnosed multiple myeloma (NDMM).

Secondary objectives:
  • To evaluate the Overall Response Rate (ORR), Partial Response (PR), Very Good Partial Response (VGPR) and Complete Response (CR) as per International Myeloma Working Group (IMWG) criteria in each arm.
  • To compare the Progression-free (PFS) and Overall Survival (OS) between the two arms.
  • To evaluate the proportion of patients with MRD negativity (defined by NGF [next generation flow] at 10-5) after 12 months (13 cycles) of maintenance treatment.
  • To evaluate the Time to Progression (TTP) in each arm.
  • To evaluate the PFS in high risk cytogenetic population defined as patients carrying a) del(17p), t(4;14), t(14;16) in each arm and b) the same aberrations plus amp1q21.
  • To evaluate the Duration of Response in each arm.
  • To evaluate safety in both treatment arms.
  • To assess disease-specific and a generic health-related quality of life (HRQL), disease and treatment-related symptoms, health state utility and health status.
  • To evaluate PFS of potential second line therapy.

Inclusion/Exclusion criteria

Inclusion criteria (selected):
  • Age ≥ 70 years
  • Able to provide written informed consent in accordance with federal, local, and institutional guidelines
  • Patients must have newly diagnosed, symptomatic multiple myeloma with evidence of measurable disease (assessed within 21 days prior to randomization)
  • No prior treatment for multiple myeloma
  • ECOG (PS) of 0-2
  • Patients at cardiac risk (NYHA >ll) or pre-existing coronary heart disease, or any other clinically relevant cardiac complication) should be scheduled for a baseline ECHO and can only be included if the LVEF is >40%
Exclusion criteria (selected):
  • ECOG status >2
  • Patients unlikely to tolerate Rd
  • Waldenström macroglobulinemia
  • POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
  • Plasma cell leukemia (> 2.0 x 109/L circulating plasma cells by standard differential)
  • Myelodysplastic syndrome
  • Smoldering Myeloma and MGUS
  • History of or current amyloidosis
  • Significant neuropathy (Grade 2 with pain or Grade 3 or higher) within the 14 days prior to randomization

DSMM_XVII

Elotuzumab (E) in Combination with Carfilzomib, Lenalidomide and Dexamethasone (E-KRd) versus KRd prior to and following Autologous Stem Cell Transplant in Newly Diagnosed Multiple Myeloma and Subsequent Maintenance with Elotuzumab and Lenalidomide versus Single-Agent Lenalidomide

Synopsis

Short title: DSMM_XVII

Title: Elotuzumab (E) in Combination with Carfilzomib, Lenalidomide and Dexamethasone (E-KRd) versus KRd prior to and following Autologous Stem Cell Transplant in Newly Diagnosed Multiple Myeloma and Subsequent Maintenance with Elotuzumab and Lenalidomide versus Single-Agent Lenalidomide

Status: active, not recruiting

Start: Q3 2019 (in Austria)

Coordinating Investigator: Assoc. Prof. Dr. Wolfgang Willenbacher (Austria)

EudraCT Nummer: 2017-001616-11

ClinicalTrialsID: NCT03948035

Number of patients: 576 (international)

Sponsor: University Hospital Würzburg in cooperation with DSMM (Deutsche Studiengruppe Multiples Myelom) and AGMT gemeinnützige GmbH (Sponsor representative in Austria)

Design

This is an interventional, multicentre, open-label, randomized phase III trial with two parallel arms to compare two different regimens. Quadruple elotuzumab in combination with carfilzomib, lenalidomide, and dexamethasone [E-KRd] versus triple carfilzomib, lenalidomide, and dexamethasone [KRd]) is given during induction treatment prior to ASCT and as consolidation treatment after ASCT in patients suffering from newly diagnosed multiple myeloma according to the updated IMWG criteria.

Consolidation treatment is followed by maintenance treatment (elotuzumab in combination with lenalidomide versus lenalidomide monotherapy).

Patients are randomized in a 1:1 ratio to be administered 6 cycles induction treatment, either E-KRd (Arm A) or KRd (Arm B).

After three cycles of induction therapy cyclophosphamide (4.5 g/m2 BSA) is given for stem cell mobilisation (Arm A and Arm B) followed by stem cell harvest. In case of failure, a second attempt of stem mobilization therapy is at discretion of the local investigator.

All patients who obtain at least stable disease (SD) at the restaging following six cycles of induction treatment will proceed to high-dose melphalan chemotherapy followed by ASCT.

The patients are given four cycles of consolidation treatment, patients in Arm A receive E-KRd and patients in Arm B receive KRd. Another restaging is performed within two weeks after Cycle 4 Day 28 of consolidation treatment and before the start of maintenance treatment.

As maintenance treatment the combination of elotuzumab and lenalidomide continuously is administered in Arm A and continuous lenalidomide monotherapy in Arm B until progression or occurrence of unacceptable toxicity whichever period is shorter.

Primary endpoints:

For the induction phase:

  • Rate of patients who have VGPR or better response according to IMWG criteria and are MRD-negative as assessed by flow cytometry following six cycles of induction treatment

For the maintenance phase:

  • 3-year PFS rate calculated from randomization
Secondary endpoints:

Efficacy variables:

  • Objective response rate (ORR) following induction and consolidation treatment with E-KRd versus KRd
  • ORR at the end of the study
  • PFS and OS

Safety variables:

  • Type, incidence, relatedness, and severity of adverse events
  • Occurence of laboratory abnormalities

Inclusion/Exclusion criteria

Inclusion criteria (selected):
  • Adult patients of age ≥ 18 and ≤ 70 years at the time of signing the informed  consent form
  • Eligible for autologous stem cell transplantation (ASCT)
  • Patient must not have been previously treated with any prior systemic therapy for the treatment of multiple myeloma
  • Newly diagnosed multiple myeloma according to the IMWG updated criteria
  • ECOG Performance Status ≤ 2
  • FCBPs and males who are willing to comply with the lenalidomide Pregnancy Prevention Risk Management Plan
Exclusion criteria (selected):
  • POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
  • Waldenström’s macroglobulinemia or IgM myeloma
  • Plasma cell leukemia (> 2.0 x 109/L circulating plasma cells)
  • Prior cerebral vascular accident (CVA) with persistent neurological deficit
  • Active infection
  • > Grade 2 peripheral neuropathy
  • Any systemic anti-myeloma therapy except a cumulative dose of 320 mg of dexamethasone

GMMG-HD8 / DSMM XIX

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

Synopsis

Short title: GMMG-HD8 / DSMM XIX

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

Status: active, not recruiting

Start: Q4 2023 (in Austria)

Coordinating Investigator: Univ. Prof. Dr. Richard Greil (Austria)

EudraCT Nummer: 2022-000996-38

ClinicalTrialsID: NCT05804032

Number of patients: 514 (international)

Sponsor: Ruprecht-Karls-Universität Heidelberg in cooperation with GMMG (German-Speaking Myeloma Multicenter Group) and DSMM (Deutsche Studiengruppe Multiples Myelom) and AGMT gemeinnützige GmbH (Sponsor representative in Austria)

Design

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.

Primary endpoints:

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 endpoints:
  • 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.

Inclusion/Exclusion criteria

Inclusion criteria (selected):
  • 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 (selected):
  • 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
  • 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)

GMMG-HD9 / DSMM XVIII

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

Synopsis

Short title: GMMG-HD9 / DSMM XVIII

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

Status: recruiting

Start: Q3 2024 (in Austria)

Coordinating Investigator: Univ. Prof. Dr. Richard Greil (Austria)

EU CT Nummer: 2023-507402-13-00

ClinicalTrialsID: NCT06216158

Number of patients: 411 (international)

Sponsor: Ruprecht-Karls-Universität Heidelberg in cooperation with GMMG (German-Speaking Myeloma Multicenter Group) and DSMM (Deutsche Studiengruppe Multiples Myelom) and AGMT gemeinnützige GmbH (Sponsor representative in Austria)

Design

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.

Primary endpoints:

Demonstration of superiority of iberdomide plus isatuximab compared to iberdomide with respect to bone marrow minimal residual disease (MRD) negativity rates (sensitivity 2×10^-6 via next-generation flow cytometry [NGF]) after two years of maintenance therapy.

Key Secondary endpoints:

PFS, defined as time from randomization to disease progression or death from any cause, whichever occurs first.

Inclusion/Exclusion criteria

Inclusion criteria (selected):
  • 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
Exclusion criteria (selected):
  • 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
  • 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.
  • 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)
  • Autoimmune haemolytic anaemia with positive indirect Coombs test or immune thrombocytopenia

Studien