Multiple Myeloma

MM-2
MM-3
MM-4
DSMM_XVII

MM-2

A randomized Phase II, 2-armed study in transplant ineligible patients with newly diagnosed multiple myeloma (NDMM) comparing Carfilzomib + Thalidomide + dexamethasone (KTd) versus Carfilzomib + Lenalidomide + dexamethasone (KRd) induction therapy with respect to response rates and investigating a Carfilzomib (K) monotherapy maintenance strategy

Synopsis

Short title: AGMT_MM-2

Title: A randomized Phase II, 2-armed study in transplant ineligible patients with newly diagnosed multiple myeloma (NDMM) comparing Carfilzomib + Thalidomide + dexamethasone (KTd) versus Carfilzomib + Lenalidomide + dexamethasone (KRd) induction therapy with respect to response rates and investigating a Carfilzomib (K) monotherapy maintenance strategy

Status: active, not recruiting

Start: April 2017 (in Austria)

Coordinating Investigator: Univ. Prof. Dr. Heinz Ludwig

EudraCT Number: 2016-000475-24

ClinicalTrialsID: NCT02891811

Number of patients: 146 (international)

Sponsor: AGMT gemeinnützige GmbH

Design

This is a randomized, 2-arm phase II, multi-center study to evaluate the ORR in newly diagnosed, transplant ineligible MM patients receiving 9 cycles induction therapy with either KTd or KRd followed by randomization to either carfilzomib maintenance treatment for 12 months or to observation only.

Maintenance is given for 12 cycles or progression of disease, whatever occurs first. The patient population (n=146) will consist of adult male and female patients with NDMM (newly diagnosed multiple myeloma) who are not eligible for or not willing to undergo autologous stem cell transplantation.

After 4 cycles stem cells can be harvested (optional) in those patients who may undergo autologous stem cell transplantation as salvage therapy.

Treatment will be discontinued in case of progressive disease (PD) or due to intolerance. An end of treatment visit (EOT) will be performed 30 days (± 7 days) after the last dose of the last treatment cycle in the maintenance arm or after 12 months in the observation only group.

A second randomization will be performed after 9 cycles of induction therapy, and patients will be randomized 1:1 stratified by induction therapy either into a maintenance arm with carfilzomib monotherapy or into an observation only arm. Maintenance treatment with carfilzomib (last tolerated dose on day 1 and 15 (± 7 days) of each cycle) will be administered for a maximum period of 12 months. Follow-up visits after completion of maintenance period will be performed in 3-monthly intervals until progression of disease or death.

Primary objective:

To show non-inferiority with respect to response rates between KTd and KRd: to determine ORR in patients after receiving 9 cycles induction therapy with either carfilzomib in combination with thalidomide and dexamethasone or carfilzomib in combination with lenalidomide and dexamethasone

Secondary objectives:
  • Feasibility, safety and efficacy of a K monotherapy maintenance
  • PR, VGPR, CR, sCR, MDR according to IMWG
  • PFS of induction arm with or without maintenance
  • OS of patients receiving either KTd vs. KRd induction therapy
  • Quality of Life
  • Safety and tolerability of KTd and KRd

Inclusion/Exclusion criteria

Inclusion criteria (selected):
  • Male or female patients ≥ 18 years
  • Newly diagnosed multiple myeloma (MM), who are not eligible for or not willing to undergo autologous stem cell transplantation.
  • Measurable disease, as defined by one or more of the following (assessed within 21 days prior to randomization):
    • Serum M-protein ≥0.5 g/dL, or
    • Urine M-protein ≥200 mg/24 hours, or
    • In subjects without detectable serum or urine M-protein, serum-free light chain (SFLC) > 100 mg/L (involved light chain) and an abnormal ĸ/λ ratio
  • No prior treatment for multiple myeloma
Exclusion criteria (selected):
  • ECOG ≥ 2
  • Waldenström macroglobulinemia
  • POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
  • Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard differential)
  • Myelodysplastic syndrome
  • Smoldering Myelom and MGUS
  • Second malignancy within the past 5 years
  • History of, or current amyloidosis
  • Immunotherapy within the 21 days prior to randomization

MM-3

Denosumab for high risk SMM and SLiM CRAB positive, early myeloma patients- a randomized, placebo controlled, phase II trial
“DEFENCE” (DEnosumab For the rEductioN of the smoldering myeloma transformatioN inCidence ratE)

Synopsis

Short title: AGMT_MM-3

Title: Denosumab for high risk SMM and SLiM CRAB positive, early myeloma patients- a randomized, placebo controlled, phase II trial
“DEFENCE” (DEnosumab For the rEductioN of the smoldering myeloma transformatioN inCidence ratE)

Status: closed

Start: June 2019 (in Austria)

Coordinating Investigator: Univ. Prof. Dr. Heinz Ludwig

EudraCT Number: 2018-000924-32

ClinicalTrialsID: NCT03792763

Number of patients: 164 (international)

Sponsor: AGMT gemeinnützige GmbH

Design

This is a randomized, placebo controlled, multicenter study of denosumab in patients with high risk SMM (Smoldering Multiple Myeloma) and “ultra-high risk” SMM (=now defined as “SLiM” CRAB positive early MM without symptoms).

Eligible patients will be randomized 1:1 in each of the two groups (stratification according to high risk SMM and “SLiM” CRAB positive early MM without symptoms, and time since intial diagnosis ≤/> 3 years):

  • Arm A: treatment with denosumab 120 mg SC every 4 weeks (Q4W) for 6 months, then every 3 months (Q3M) for a total of 3 years or until progression to active, symptomatic MM
  • Arm B: treatment with placebo SC every 4 weeks (Q4W) for 6 months, then every 3 months (Q3M) for a total of 3 years or until progression to active, symptomatic MM
Primary objective:

Time from randomization to transformation to symptomatic, active MM (defined as progression to active multiple myeloma according to IMWG diagnosis criteria 2014) or progression of disease according to IMWG response criteria 2016

Secondary objectives:
  • Percentage of patients with high-risk SMM and early ‘slim CRAB’ positive MM transforming to CRAB positive multiple myeloma and/or developing serological progression (as defined by IMWG criteria 2016 for MM) within 3 years
  • Percentage of high risk SMM patients progressed to active, symptomatic MM within 3 years
  • Percentage of ultra-high risk SMM (asymptomatic, early MM, defined by “SLiM CRAB”) patients progressed to active, symptomatic MM within 3 years  
  • Incidence of bone lesions as MM defining events
  • Time to first skeletal-related event
  • Time to symptomatic skeletal-related event
  • Time to first anti-myeloma treatment
  • Overall survival

Exploratory endpoints: Correlation of therapy with genetic modification and with bone remodeling markers, investigation of the composition and influence of the environment of myeloma cells in the bone marrow.

Inclusion/Exclusion criteria

Inclusion criteria (selected):
  • Age ≥ 18 years
  • Able to provide written informed consent in accordance with federal, local, and institutional guidelines
  • Must meet criteria of high risk smoldering MM or early “SLiM CRAB” MM based on the criteria described below:
    • High-risk SMM is defined here according to the Mayo Clinical algorithm :
      • Bone marrow clonal plasma cells ≥10% +
      • Serum M protein ≥3.0g/dL +
      • Serum free light chain ratio < 0.125 (but > 0.01) or  ≥8 (but < 100), measured with “Binding site Kit”
    • Early ‘SLiM CRAB’ multiple myeloma. Patients must present with one or more of the following features:
      • Bone marrow clonal plasma cells ≥ 60%, or
      • Serum FLC ratio ≥ 100 (κ-LC leading) or ≤ 0.01 (λ-LC leading), measured with “Binding site Kit”, or
      • >1 Focal bone lesion of ≥5mm (not associated with osteolysis, detected by PET-CT or whole-body low-dose CT (WBLDCT))
      • Time from diagnosis of high risk SMM or SLIM CRAB positive, early MM to study enrollment: <5 years
Exclusion criteria (selected):
  • ECOG >3
  • Active, symptomatic MM (fulfilling CRAB-criteria)
  • Non secretory MM
  • MGUS
  • Hypocalcemia (can be corrected by drug intervention before start of treatment)
  • Second malignancy within the past 5 years
  • Active infection within the 14 days prior to randomization requiring systemic antibiotics and/or antiviral therapy
  • Known human immunodeficiency virus (HIV) seropositivity or active hepatitis C or hepatitis B infection
  • Prior administration of denosumab
  • Use of oral bisphosphonates with a cumulative exposure of more than 1 year (wash out period for allowed bisphosphonate exposure 1 month)
  • More than 1 previous dose of IV bisphosphonate administration (wash out period for allowed bisphosphonate exposure 1 month)
  • Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw

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: Recruiting

Start: October 2021

Coordinating Investigator: Univ. Prof. Dr. Heinz Ludwig

EudraCT Number: 2020-004972-17

ClinicalTrialsID: NCT04891809

Number of patients: 198

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 Number: 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

Trials