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Trial on the Effect of Isatuximab to Lenalidomide/Bortezomib/Dexamethasone (RVd) Induction and Lenalidomide Maintenance in Patients With Newly Diagnosed Myeloma (GMMG HD7)

Primary Purpose

Multiple Myeloma

Status
Active
Phase
Phase 3
Locations
Germany
Study Type
Interventional
Intervention
Lenalidomide
Bortezomib
Dexamethasone
Isatuximab
Sponsored by
University of Heidelberg Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multiple Myeloma

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Confirmed diagnosis of untreated multiple myeloma requiring systemic therapy (diagnostic criteria (IMWG updated criteria (2014)1) see appendix IA. For some patients systemic therapy may be required though these diagnostic criteria are not fulfilled. In this case the GMMG study office has to be consulted prior to inclusion.)
  2. Patient is eligible for high dose therapy and autologous stem cell transplantation.

  3. Measurable disease, defined as any quantifiable monoclonal protein value, defined by at least one of the following three measurements:2

    • Serum M-protein ≥ 10g/l (for IgA ≥ 5g/l)
    • Urine light-chain (M-protein) of ≥ 200 mg/24 hours
    • Serum FLC assay: involved FLC level ≥ 10 mg/dl provided sFLC ratio is abnormal
  4. Age 18 - 70 years inclusive
  5. WHO performance status 0-2
  6. Negative pregnancy test at inclusion (females of childbearing potential)
  7. All patients must agree on the requirements regarding the lenalidomide pregnancy prevention plan described in section 6. For all men and females of childbearing potential: patients must be willing and capable to use adequate contraception during the complete therapy.

  8. All patients must

    • agree to abstain from donating blood while taking lenalidomide and for 28 days following discontinuation of lenalidomide therapy
    • agree not to share study drug lenalidomide with another person and to return all unused study drug to the investigator or pharmacist
  9. Ability of patient to understand character and individual consequences of the clinical trial
  10. Provide written informed consent (must be available before enrolment in the trial)

Exclusion Criteria

  1. Patient has known hypersensitivity (or contraindication) to dexamethasone, sucrose histidine (as base and hydrochloride salt), boron, mannitol, and polysorbate 80 or any of the components of study therapy that are not amenable to premedication with steroids or H2 blockers that would prohibit further treatment with these agents.
  2. Systemic AL amyloidosis (except for AL amyloidosis of the skin or the bone marrow)
  3. Plasma cell leukemia
  4. Previous chemotherapy or radiotherapy during the past 5 years except local radiotherapy in case of local myeloma progression. (Note: patients may have received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency therapy.) Previous therapy due to smouldering myeloma may be acceptable. In this case the GMMG study office has to be consulted prior to inclusion
  5. Severe cardiac dysfunction (NYHA classification III-IV), ejection fraction < 40%
  6. 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 myeloma.
  7. Patients with active or history of hepatitis B or C
  8. HIV positivity
  9. Patients with active, uncontrolled infections
  10. Patients with severe renal insufficiency (Creatinine Clearance < 30ml/min)
  11. Patients with peripheral neuropathy or neuropathic pain, CTC grade 2 or higher (as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0)
  12. Patients with a history of 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
  13. Patients with acute diffuse infiltrative pulmonary and/or pericardial disease
  14. Autoimmune hemolytic anemia with positive Coombs test or immune thrombocytopenia
  15. Platelet count < 75 x 109/l
  16. Haemoglobin < 8.0 g/dl, unless related to myeloma
  17. Absolute neutrophil count (ANC) < 1.0 x 109/l (the use of colony stimulating factors within 14 days before the test is not allowed)
  18. Corrected serum calcium > 14 mg/dl (> 3.5 mmol/l)
  19. Unable or unwilling to undergo thromboprophylaxis
  20. Pregnancy and lactation
  21. Participation in other clinical trials. This does not include long-term follow-up periods without active drug treatment of previous studies during the last 6 months.
  22. Prisoners or subjects who are legally institutionalized, or those unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.

No patients will be allowed to enrol in this trial more than once.

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Sites / Locations

  • Uniklinik RWTH Aachen, Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltransplantation
  • Studienzentrum Aschaffenburg
  • Helios Klinikum Bad Saarow, Klinik für Hämatologie, Onkologie und Palliativmedizin
  • Charité, Campus Benjamin Franklin , III. Medizinische Abteilung (Hämatologie/Onkologie)
  • Vivantes Klinikum Neukölln, Klinik für Hämatologie und Onkologie
  • HELIOS Klinikum, Klinik für Hämatologie, Onkologie und Immunologie
  • Studiengesellschaft Onkologie Bielefeld GbR
  • Klinikum Bielefeld, Klinik für Hämatologie, Onkologie und Palliativmedizin
  • Medizinische Universitätsklinik, Knappschaftskrankenhaus
  • Universitätsklinikum Bonn, Medizinische Klinik und Poliklinik III, Schwerpunkt Onkologie, Hämatologie und Rheumatologie
  • Johanniter Krankenhaus Bonn
  • Zentrum für ambulante Hämatologie und Onkologie (ZAHO)
  • Städtisches Klinikum Braunschweig, Med. Klinik III, Hämatologie und Onkologie
  • Klinikum Chemnitz GmbH, Innere Medizin III
  • Carl-Thiem-Klinikum Cottbus gGmbH, II. Medizinische Klinik
  • Onkologisches Studienzentrum Darmstadt
  • Klinikum Darmstadt, Med. Klinik V, Hämatologie/Onkologie
  • Universitätsklinikum Carl Gustav Carus Dresden, an der Technischen Universität Dresden, Medizinische Klinik und Poliklinik I
  • HELIOS St. Johannes Klinik, Akademisches Krankenhaus der Heinrich-Heine-Universität Düsseldorf
  • Marien Hospital Düsseldorf GmbH, Klinik für Onkologie, Hämatologie und Palliativmedizin
  • Universitätsklinikum Düsseldorf, Klinik für Hämatologie,Onkologie und Klin. Immunologie
  • Universitätsklinik Erlangen
  • St. Antonius-Hospital Eschweiler, Klinik für Hämatologie / Onkologie
  • Universitätsklinikum Essen, Klinik für Hämatologie
  • Ev. Krankenhaus Essen-Werden gGmbH, Zentrum für Innere Medizin, Klinik für Hämatologie, Onkologie und Stammzelltransplantation
  • Gemeinschaftspraxis Prof. Dr. Michael Kiehl und Dipl. Med. Wolfgang Stein
  • Klinikum Frankfurt (Oder) GmbH
  • Centrum für Hämatologie und Onkologie Bethanien
  • Agaplesion Markus Krankenhaus, Med. Klinik I
  • Krankenhaus Nordwest, Institut für Klinisch-Onkologische Forschung
  • Universitätsklinikum Frankfurt, Goethe-Universität Medizinische Klinik II
  • Klinikum Fulda, Klinisches Studienzentrum GmbH
  • Universitätsklinik der Justus-Liebig-Universität, Medizinische Klinik IV
  • Katholisches Karl-Leisner-Klinikum gGmbH, Wilhelm-Anton-Hospital Goch, Klinik für Hämatologie - Onkologie
  • Kath. Krankenhaus Hagen gGmbH, Abt. Hämatologie/Onkologie
  • Asklepios Klinik Hamburg St. Georg
  • Universitätsklinikum Hamburg Eppendorf, Zentrum für Onkologie, Studienzentrale der II. Medizinischen Klinik
  • Asklepios Klinik Hamburg Altona, II. Med. Klinik
  • Immunologisch-onkologisches MVZ am Siloah Krankenhaus
  • KRH Klinikum Siloah, Klinik für Hämatologie und Onkologie
  • Onkologische Schwerpunktpraxis Heidelberg
  • Krankenhaus St. Vincentius der evangelischen Stadtmission Heidelberg, Abt. Hämatologie, Onkologie, Rheumatologie
  • University Hospital Heidelberg, Med. Klinik V
  • SLK Kliniken Heilbronn, Med. Klinik III
  • Marien Hospital Herne
  • Universitätsklinikum des Saarlandes, Innere Medizin I
  • Westpfalz-Klinikum GmbH, Klinik für Innere Medizin I
  • Städtisches Klinikum Karlsruhe
  • Praxisklinik für Hämatologie und Onkologie
  • Uniklinik Köln, Klinik I für Innere Medizin
  • Gemeinschaftspraxis für Hämatologie und Onkologie am Caritas Krankenhaus
  • Universitätsklinikum Leipzig AöR, Medizinische Klinik und Poliklinik I-Hämatologie und Zelltherapie, Internistische Onkologie, Hämostaseologie
  • Med. Klinik A, Klinikum der Stadt Ludwigshafen am Rhein gGmbH
  • Universitätsmedizin der Johannes Gutenberg-Universität Mainz, III. Med. Klinik
  • III. Medizinische Klinik Hämatologie und Internistische Onkologie
  • Mannheimer Onkologie Praxis
  • Philipps-Universität Marburg, Hämatologie/Onkologie/Immunologie
  • Mühlenkreiskliniken (AöR) Johannes Wesling Klinikum Minden, Hämatologie/Onkologie, Hämostaseologie und Palliativmedizin
  • Krankenhaus Maria Hilf GmbH, Franziskuskrankenhaus, Med. Klinik I
  • Universitätsklinikum Münster, Med. Klinik A
  • Klinikum Osnabrück GmbH
  • Brüderkrankenhaus St. Josef Paderborn, Klinik für Hämatologie und Onkologie
  • Krankenhaus Barmherzige Brüder, Klinik für Onkologie und Hämatologie
  • Gemeinschaftspraxis für Hämatologie und Onkologie, Onkologisches Zentrum
  • Diakonie-Klinikum Schwäbisch Hall gGmbH, Innere Medizin III
  • ZAHO-Zentrum für ambulante Hämatologie und Onkologie, Standort Siegburg
  • Onkologische Schwerpunktpraxis Speyer
  • Klinikum Stuttgart, Stuttgart Cancer Center, Tumorzentrum Eva Mayr-Stihl
  • Klinikum Mutterhaus der Borromäerinnen gGmbH
  • University Hospital Tübingen, Med. Klinik und Poliklinik, Abt. II
  • Bundeswehrkrankenhaus Ulm, Abteilung Innere Medizin - Hämatologie und internistische Onkologie
  • Schwarzwald-Baar Klinikum, Innere Medizin II
  • Rems-Murr-Kliniken gGmbH

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Experimental

Active Comparator

Experimental

Arm Label

IA

IB

IIA

IIB

Arm Description

Patients in arm IA are treated with 3 cycles RVd (lenalidomide 25 mg/d p.o. d1 - 14 and d22 - 35; bortezomib 1.3 mg/m2 s.c. d1, 4, 8, 11, 22, 25, 29, 32; dexamethasone p.o. 20 mg/d d1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, 32-33).Treatment repeats every 42 days (d43 = cycle 2 d1). Standard intensification: For all patients, stem cells are mobilized by GMMG Standard protocols (CAD: cyclophosphamide, doxorubicin, dexamethasone) and G-CSF. At least 7.5x106 CD34+ cells/kg body weight are harvested. High dose treatment (melphalan 200mg/m², HDT) followed by autologous stem cell transplantation (ASCT) is started 4 - 6 weeks after CAD. For patients not in CR after HDT1, a second HDT is performed within 3 months.

Patients in arm IB are treated with 3 cycles RVd + Isatuximab (lenalidomide 25 mg/d p.o. d1 - 14 and d22 - 35; bortezomib 1.3 mg/m2 s.c. d1, 4, 8, 11, 22, 25, 29, 32;dexamethasone p.o. 20 mg/d d1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, 32-33).Isatuximab (10 mg/kg i.v. C1: d 1, 8, 15, 22, 29; C2-3: d 1, 15, 29).Treatment repeats every 42 days (d43 = cycle 2 d1). Standard intensification: For all patients, stem cells are mobilized by GMMG Standard protocols (CAD: cyclophosphamide, doxorubicin, dexamethasone) and G-CSF. At least 7.5x106 CD34+ cells/kg body weight are harvested. High dose treatment (melphalan 200mg/m², HDT) followed by autologous stem cell transplantation (ASCT) is started 4 - 6 weeks after CAD. For patients not in CR after HDT1, a second HDT is performed within 3 months.

maintenance treatment with Lenalidomide 10mg/d (increased to 15mg/d after 3 months) repeated every 28d. Maintenance treatment is planned for up to 36 months or until progression if progression occurs first.

maintenance treatment with Lenalidomide 10mg/d (increased to 15mg/d after 3 months) + Isatuximab (10 mg/kg; C1: d1, 8, 15, 22; C2-C3: d1 + 15; C4-39:d1, repeated every 28d). Within the trial, maintenance treatment is planned for up to 36 months or until progression if progression occurs first.

Outcomes

Primary Outcome Measures

MRD negativity after induction Treatment (comparison of arms IA and IB)
Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5)
Progression Free Survival (PFS) after second randomization (arms IIA and IIB)
Response Evaluation by IMWG criteria

Secondary Outcome Measures

to compare the four treatment arms (IA-IIA, IA-IIB, IB-IIA, IB-IIB) regarding Progression free survival (PFS)
Response evaluation by IMWG criteria
to compare all 4 treatment arms (IA-IIA, IA-IIB, IB-IIA, IB-IIB) regarding overall survival (OS) from time of 1.randomization
survival status
Overall survival from second randomization
survival status
Complete Response (CR) rates after induction therapy
Response Evaluation by IMWG criteria
Complete Response (CR) after high dose therapy
Response Evaluation by IMWG criteria
Complete Response (CR) during/after maintenance therapy
Response Evaluation by IMWG criteria
MRD negativity after high dose therapy
Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5)
MRD negativity during and after maintenance therapy
Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5)
Best response to treatment during the trial
Response evaluation by IMWG criteria
PFS 2 (PFS after next line of therapy) from 2. randomization
Response evaluation by IMWG criteria
Toxicity during induction and maintenance with respect to adverse events of CTC grade >3 (and specific adverse events of CTC grade > 2 as defined in the protocol and serious adverse events
toxicity according CTCAE Version v5.0
Quality of Life Assessment
EORTC (European Organization of Research and Treatment of Cancer) -QLQC30 Questionnaire to assess the quality of life of cancer patients. Impairment of daily life is asked in 4 scales from "not at all" (best) to "very much" (worst scale), EORTC-QLQMY20 questionnaire to assess health-related quality of life in patients with multiple myeloma with 4 scales from "not at all (best scale) to "very much" (worst scale); EQ(EuroQol Group)-5D-5L Health questionnaire comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. Additionally a visual analogue scale from 100 (best) to 0 (worst scale) is used to assess the quality of health questionnaires.
Pharmakokinetic analyses of Isatuximab in induction treatment of patients in Arm IB (selected sites only)
Determination of serum concentration of isatuximab at different timepoints before, during and after isatuximab infusion
Pharmakokinetic analyses of Isatuximab in maintenance treatment of patients in Arm IIB (selected sites only)
Determination of serum concentration of isatuximab at different timepoints

Full Information

First Posted
July 24, 2018
Last Updated
May 11, 2023
Sponsor
University of Heidelberg Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT03617731
Brief Title
Trial on the Effect of Isatuximab to Lenalidomide/Bortezomib/Dexamethasone (RVd) Induction and Lenalidomide Maintenance in Patients With Newly Diagnosed Myeloma (GMMG HD7)
Official Title
A Randomized Phase III Trial Assessing the Benefit of the Addition of Isatuximab to Lenalidomide / Bortezomib / Dexamethasone (RVd) Induction and Lenalidomide Maintenance in Patients With Newly Diagnosed Multiple Myeloma
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 18, 2018 (Actual)
Primary Completion Date
May 2025 (Anticipated)
Study Completion Date
December 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Heidelberg Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Trial in patients with newly diagnosed myeloma to evaluate the effect of isatuximab in induction therapy with lenalidomide/bortezomib/dexamethasone (RVd) and in lenalidomide maintenance treatment
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 Products: Isatuximab, Lenalidomide Randomization: Patients are randomized in one of 2 study arms (IA or IB) before induction therapy. Patients randomized in arm IA will receive 3 cycles RVd (Bortezomib (Velcade®), Lenalidomide (Revlimid®, each cycle is 42 days), Dexamethasone). Patients in arm IB will additionally receive the monoclonal antibody Isatuximab in the 3 cycles RVd. After induction therapy patients undergo intensifying therapy according to GMMG standard (usually mobilization therapy followed by stem cell collection and autologous stem cell transplantation). Randomization: Before maintenance treatment patients are randomized in one of 2 study arms (IIA and IIB): Patients in arm IIA receive Lenalidomide maintenance therapy for three years, patients in arm IIB receive additional Isatuximab. There are two primary objectives: to compare the induction regimen (IA vs IB) regarding minimal residual disease (MRD) negativity after induction (assessed by flow cytometry; sensitivity at least 1e-5) to compare the maintenance strategies (arms IIA vs IIB) regarding progression-free survival (PFS), defined as time from 2nd randomization (prior to maintenance therapy) to progression or death from any cause whichever occurs first. The duration of the trial for each patients is expected to be 45-48 months (induction and intensification treatment: 6-9 months, 3 months rest between intensification and start of maintenance phase 36 months).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
2 x 2 arms, 1. randomization before induction therapy (arm IA and IB), 2. randomization before maintenance therapy (arm IIA and IIB)
Masking
None (Open Label)
Allocation
Randomized
Enrollment
662 (Actual)

8. Arms, Groups, and Interventions

Arm Title
IA
Arm Type
Active Comparator
Arm Description
Patients in arm IA are treated with 3 cycles RVd (lenalidomide 25 mg/d p.o. d1 - 14 and d22 - 35; bortezomib 1.3 mg/m2 s.c. d1, 4, 8, 11, 22, 25, 29, 32; dexamethasone p.o. 20 mg/d d1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, 32-33).Treatment repeats every 42 days (d43 = cycle 2 d1). Standard intensification: For all patients, stem cells are mobilized by GMMG Standard protocols (CAD: cyclophosphamide, doxorubicin, dexamethasone) and G-CSF. At least 7.5x106 CD34+ cells/kg body weight are harvested. High dose treatment (melphalan 200mg/m², HDT) followed by autologous stem cell transplantation (ASCT) is started 4 - 6 weeks after CAD. For patients not in CR after HDT1, a second HDT is performed within 3 months.
Arm Title
IB
Arm Type
Experimental
Arm Description
Patients in arm IB are treated with 3 cycles RVd + Isatuximab (lenalidomide 25 mg/d p.o. d1 - 14 and d22 - 35; bortezomib 1.3 mg/m2 s.c. d1, 4, 8, 11, 22, 25, 29, 32;dexamethasone p.o. 20 mg/d d1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, 32-33).Isatuximab (10 mg/kg i.v. C1: d 1, 8, 15, 22, 29; C2-3: d 1, 15, 29).Treatment repeats every 42 days (d43 = cycle 2 d1). Standard intensification: For all patients, stem cells are mobilized by GMMG Standard protocols (CAD: cyclophosphamide, doxorubicin, dexamethasone) and G-CSF. At least 7.5x106 CD34+ cells/kg body weight are harvested. High dose treatment (melphalan 200mg/m², HDT) followed by autologous stem cell transplantation (ASCT) is started 4 - 6 weeks after CAD. For patients not in CR after HDT1, a second HDT is performed within 3 months.
Arm Title
IIA
Arm Type
Active Comparator
Arm Description
maintenance treatment with Lenalidomide 10mg/d (increased to 15mg/d after 3 months) repeated every 28d. Maintenance treatment is planned for up to 36 months or until progression if progression occurs first.
Arm Title
IIB
Arm Type
Experimental
Arm Description
maintenance treatment with Lenalidomide 10mg/d (increased to 15mg/d after 3 months) + Isatuximab (10 mg/kg; C1: d1, 8, 15, 22; C2-C3: d1 + 15; C4-39:d1, repeated every 28d). Within the trial, maintenance treatment is planned for up to 36 months or until progression if progression occurs first.
Intervention Type
Drug
Intervention Name(s)
Lenalidomide
Other Intervention Name(s)
Revlimid
Intervention Description
25 mg per os on day 1-14 and d22-35 in induction cycle 1-3 (Arms IA and IB) 10 mg p.o. on day 1-28 in maintenance cycle 1-3, 15 mg p.o. on day 1-28 in maintenance cycle 4-39 (Arms IIA and IIB)
Intervention Type
Drug
Intervention Name(s)
Bortezomib
Other Intervention Name(s)
Velcade
Intervention Description
all arms: 1,3 mg/m^2 subcutaneous on day 1, 4, 8, 11, 22, 25, 29 32 in 3 induction cycles
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Intervention Description
20 mg per os on day 1,2 and 4,5 and 8,9 and 11,12 and 15 and 22,23 and 25,26 and 29,30 and 32,33 in induction cycles 1-3 (Arms IA and IB). Maintenance cycle 1 on day 1, 8, 15, 22 Dexamethasone 20 mg/d per os (Arm IIA). In Arm IIB Dexamethasone 20 mg i.v. on days of Isatuximab infusion in the first maintenance cycle (d 1, 8, 15, 22), dexamethasone will be administered intravenously as part of the premedication. If an isatuximab dose is skipped or discontinued dexamethasone should be administered orally.
Intervention Type
Drug
Intervention Name(s)
Isatuximab
Intervention Description
10 mg/kg in the vein( i.v) on day 1,8,15, 22, 29 in induction cycle 1 on day 1, 15 and 29 in induction cycle 2 and 3 (Arm IB). 10 mg/kg i.v. on day 1,8, 15 and 22 in maintenance cycle 1, 10 mg/kg i.v. on day 1 and 15 in maintenance cycle 2 and 3, 10 mg/kg i.v. on day 1 in maintenance cycle 4 - 39 (Arm IIB)
Primary Outcome Measure Information:
Title
MRD negativity after induction Treatment (comparison of arms IA and IB)
Description
Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5)
Time Frame
18 weeks after start of study treatment
Title
Progression Free Survival (PFS) after second randomization (arms IIA and IIB)
Description
Response Evaluation by IMWG criteria
Time Frame
time from 2. randomization to progression or death from any cause whichever comes first, censored after three years of maintenance therapy
Secondary Outcome Measure Information:
Title
to compare the four treatment arms (IA-IIA, IA-IIB, IB-IIA, IB-IIB) regarding Progression free survival (PFS)
Description
Response evaluation by IMWG criteria
Time Frame
time from 1. randomization (study inclusion) to progression or death whichever comes first (assessed up to 79 months)
Title
to compare all 4 treatment arms (IA-IIA, IA-IIB, IB-IIA, IB-IIB) regarding overall survival (OS) from time of 1.randomization
Description
survival status
Time Frame
time from randomisation to time of death from any cause (assessed up to 79 months)
Title
Overall survival from second randomization
Description
survival status
Time Frame
time from 2. randomization to time of death from any cause (assessed up to 75 months)
Title
Complete Response (CR) rates after induction therapy
Description
Response Evaluation by IMWG criteria
Time Frame
After induction treatment (18 weeks after start of treatment)
Title
Complete Response (CR) after high dose therapy
Description
Response Evaluation by IMWG criteria
Time Frame
After high dose therapy (9 or 12 months after start of therapy)
Title
Complete Response (CR) during/after maintenance therapy
Description
Response Evaluation by IMWG criteria
Time Frame
During/after maintenance therapy (6 months after start of therapy up to 36 months of maintenance therapy)
Title
MRD negativity after high dose therapy
Description
Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5)
Time Frame
After high dose therapy (9 or 12 months after start of therapy)
Title
MRD negativity during and after maintenance therapy
Description
Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5)
Time Frame
up to 36 months after start of maintenance therapy
Title
Best response to treatment during the trial
Description
Response evaluation by IMWG criteria
Time Frame
response assessment after 3 months, 4,5 months, 5,5 months, 9 months (if applicable: 3 months later after 2. high dose therapy) subsequently every 3 months during maintenance treatment, up to 48 months after start of study treatment
Title
PFS 2 (PFS after next line of therapy) from 2. randomization
Description
Response evaluation by IMWG criteria
Time Frame
time from 2. randomization to time of overall end of trial (up to 75 months)
Title
Toxicity during induction and maintenance with respect to adverse events of CTC grade >3 (and specific adverse events of CTC grade > 2 as defined in the protocol and serious adverse events
Description
toxicity according CTCAE Version v5.0
Time Frame
: from first administration of study drug until 30 days after last administration of study drug or any drug of the study treatment or upon start of a new subsequent chemotherapy, whichever occurs first
Title
Quality of Life Assessment
Description
EORTC (European Organization of Research and Treatment of Cancer) -QLQC30 Questionnaire to assess the quality of life of cancer patients. Impairment of daily life is asked in 4 scales from "not at all" (best) to "very much" (worst scale), EORTC-QLQMY20 questionnaire to assess health-related quality of life in patients with multiple myeloma with 4 scales from "not at all (best scale) to "very much" (worst scale); EQ(EuroQol Group)-5D-5L Health questionnaire comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. Additionally a visual analogue scale from 100 (best) to 0 (worst scale) is used to assess the quality of health questionnaires.
Time Frame
assessed at baseline, after ca. 4.5 months, 9 months, (additionally after 12 months,if a second high dose therapy is administered) after 12 months of maintenance and at end of study (up to 50 months)
Title
Pharmakokinetic analyses of Isatuximab in induction treatment of patients in Arm IB (selected sites only)
Description
Determination of serum concentration of isatuximab at different timepoints before, during and after isatuximab infusion
Time Frame
Up to 18 weeks in induction treatment (C1: D1, before infusion, at end of infusion, 1 h after infusion, C1 D8,15,22,29 before infusion; C2 and 3:D1 before infusion
Title
Pharmakokinetic analyses of Isatuximab in maintenance treatment of patients in Arm IIB (selected sites only)
Description
Determination of serum concentration of isatuximab at different timepoints
Time Frame
Up to 9 months (C1: D1, before infusion, at end of infusion, 1 h after infusion, C1 D8,15,22 before infusion, C2 -9, D1: before infusion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Confirmed diagnosis of untreated multiple myeloma requiring systemic therapy (diagnostic criteria (IMWG updated criteria (2014)1) see appendix IA. For some patients systemic therapy may be required though these diagnostic criteria are not fulfilled. In this case the GMMG study office has to be consulted prior to inclusion.) Patient is eligible for high dose therapy and autologous stem cell transplantation. Measurable disease, defined as any quantifiable monoclonal protein value, defined by at least one of the following three measurements:2 Serum M-protein ≥ 10g/l (for IgA ≥ 5g/l) Urine light-chain (M-protein) of ≥ 200 mg/24 hours Serum FLC assay: involved FLC level ≥ 10 mg/dl provided sFLC ratio is abnormal Age 18 - 70 years inclusive WHO performance status 0-2 Negative pregnancy test at inclusion (females of childbearing potential) All patients must agree on the requirements regarding the lenalidomide pregnancy prevention plan described in section 6. For all men and females of childbearing potential: patients must be willing and capable to use adequate contraception during the complete therapy. All patients must agree to abstain from donating blood while taking lenalidomide and for 28 days following discontinuation of lenalidomide therapy agree not to share study drug lenalidomide with another person and to return all unused study drug to the investigator or pharmacist Ability of patient to understand character and individual consequences of the clinical trial Provide written informed consent (must be available before enrolment in the trial) Exclusion Criteria Patient has known hypersensitivity (or contraindication) to dexamethasone, sucrose histidine (as base and hydrochloride salt), boron, mannitol, and polysorbate 80 or any of the components of study therapy that are not amenable to premedication with steroids or H2 blockers that would prohibit further treatment with these agents. Systemic AL amyloidosis (except for AL amyloidosis of 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 myeloma progression. (Note: patients may have received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency therapy.) Previous therapy due to smouldering myeloma may be acceptable. In this case the GMMG study office has to be consulted prior to inclusion Severe cardiac dysfunction (NYHA classification III-IV), ejection fraction < 40% 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 myeloma. Patients with active or history of hepatitis B or C HIV positivity Patients with active, uncontrolled infections Patients with severe renal insufficiency (Creatinine Clearance < 30ml/min) Patients with peripheral neuropathy or neuropathic pain, CTC 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 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 Patients with acute diffuse infiltrative pulmonary and/or pericardial disease Autoimmune hemolytic anemia with positive Coombs test or immune thrombocytopenia Platelet count < 75 x 109/l Haemoglobin < 8.0 g/dl, unless related to myeloma 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 Participation in other clinical trials. This does not include long-term follow-up periods without active drug treatment of previous studies during the last 6 months. Prisoners or subjects who are legally institutionalized, or those unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions. No patients will be allowed to enrol in this trial more than once. -
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hartmut Goldschmidt, Prof. Dr.
Organizational Affiliation
Med. Klinik V, University Hospital Heidelberg
Official's Role
Principal Investigator
Facility Information:
Facility Name
Uniklinik RWTH Aachen, Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltransplantation
City
Aachen
ZIP/Postal Code
52074
Country
Germany
Facility Name
Studienzentrum Aschaffenburg
City
Aschaffenburg
ZIP/Postal Code
63739
Country
Germany
Facility Name
Helios Klinikum Bad Saarow, Klinik für Hämatologie, Onkologie und Palliativmedizin
City
Bad Saarow
ZIP/Postal Code
15526
Country
Germany
Facility Name
Charité, Campus Benjamin Franklin , III. Medizinische Abteilung (Hämatologie/Onkologie)
City
Berlin
ZIP/Postal Code
12200
Country
Germany
Facility Name
Vivantes Klinikum Neukölln, Klinik für Hämatologie und Onkologie
City
Berlin
ZIP/Postal Code
12351
Country
Germany
Facility Name
HELIOS Klinikum, Klinik für Hämatologie, Onkologie und Immunologie
City
Berlin
ZIP/Postal Code
13125
Country
Germany
Facility Name
Studiengesellschaft Onkologie Bielefeld GbR
City
Bielefeld
ZIP/Postal Code
33604
Country
Germany
Facility Name
Klinikum Bielefeld, Klinik für Hämatologie, Onkologie und Palliativmedizin
City
Bielefeld
ZIP/Postal Code
D-33604
Country
Germany
Facility Name
Medizinische Universitätsklinik, Knappschaftskrankenhaus
City
Bochum
ZIP/Postal Code
D-44892
Country
Germany
Facility Name
Universitätsklinikum Bonn, Medizinische Klinik und Poliklinik III, Schwerpunkt Onkologie, Hämatologie und Rheumatologie
City
Bonn
ZIP/Postal Code
53105
Country
Germany
Facility Name
Johanniter Krankenhaus Bonn
City
Bonn
ZIP/Postal Code
53113
Country
Germany
Facility Name
Zentrum für ambulante Hämatologie und Onkologie (ZAHO)
City
Bonn
ZIP/Postal Code
53113
Country
Germany
Facility Name
Städtisches Klinikum Braunschweig, Med. Klinik III, Hämatologie und Onkologie
City
Braunschweig
ZIP/Postal Code
38114
Country
Germany
Facility Name
Klinikum Chemnitz GmbH, Innere Medizin III
City
Chemnitz
ZIP/Postal Code
D-09116
Country
Germany
Facility Name
Carl-Thiem-Klinikum Cottbus gGmbH, II. Medizinische Klinik
City
Cottbus
ZIP/Postal Code
03048
Country
Germany
Facility Name
Onkologisches Studienzentrum Darmstadt
City
Darmstadt
ZIP/Postal Code
64283
Country
Germany
Facility Name
Klinikum Darmstadt, Med. Klinik V, Hämatologie/Onkologie
City
Darmstadt
ZIP/Postal Code
D-64283
Country
Germany
Facility Name
Universitätsklinikum Carl Gustav Carus Dresden, an der Technischen Universität Dresden, Medizinische Klinik und Poliklinik I
City
Dresden
ZIP/Postal Code
01307
Country
Germany
Facility Name
HELIOS St. Johannes Klinik, Akademisches Krankenhaus der Heinrich-Heine-Universität Düsseldorf
City
Duisburg
ZIP/Postal Code
47166
Country
Germany
Facility Name
Marien Hospital Düsseldorf GmbH, Klinik für Onkologie, Hämatologie und Palliativmedizin
City
Düsseldorf
ZIP/Postal Code
40479
Country
Germany
Facility Name
Universitätsklinikum Düsseldorf, Klinik für Hämatologie,Onkologie und Klin. Immunologie
City
Düsseldorf
ZIP/Postal Code
D-40225
Country
Germany
Facility Name
Universitätsklinik Erlangen
City
Erlangen
ZIP/Postal Code
91054
Country
Germany
Facility Name
St. Antonius-Hospital Eschweiler, Klinik für Hämatologie / Onkologie
City
Eschweiler
ZIP/Postal Code
52249
Country
Germany
Facility Name
Universitätsklinikum Essen, Klinik für Hämatologie
City
Essen
ZIP/Postal Code
D-45147
Country
Germany
Facility Name
Ev. Krankenhaus Essen-Werden gGmbH, Zentrum für Innere Medizin, Klinik für Hämatologie, Onkologie und Stammzelltransplantation
City
Essen
ZIP/Postal Code
D-45239
Country
Germany
Facility Name
Gemeinschaftspraxis Prof. Dr. Michael Kiehl und Dipl. Med. Wolfgang Stein
City
Frankfurt (Oder)
ZIP/Postal Code
15236
Country
Germany
Facility Name
Klinikum Frankfurt (Oder) GmbH
City
Frankfurt (Oder)
ZIP/Postal Code
15236
Country
Germany
Facility Name
Centrum für Hämatologie und Onkologie Bethanien
City
Frankfurt am Main
ZIP/Postal Code
60389
Country
Germany
Facility Name
Agaplesion Markus Krankenhaus, Med. Klinik I
City
Frankfurt am Main
ZIP/Postal Code
60431
Country
Germany
Facility Name
Krankenhaus Nordwest, Institut für Klinisch-Onkologische Forschung
City
Frankfurt am Main
ZIP/Postal Code
60488
Country
Germany
Facility Name
Universitätsklinikum Frankfurt, Goethe-Universität Medizinische Klinik II
City
Frankfurt am Main
ZIP/Postal Code
60590
Country
Germany
Facility Name
Klinikum Fulda, Klinisches Studienzentrum GmbH
City
Fulda
ZIP/Postal Code
36043
Country
Germany
Facility Name
Universitätsklinik der Justus-Liebig-Universität, Medizinische Klinik IV
City
Gießen
ZIP/Postal Code
35385
Country
Germany
Facility Name
Katholisches Karl-Leisner-Klinikum gGmbH, Wilhelm-Anton-Hospital Goch, Klinik für Hämatologie - Onkologie
City
Goch
ZIP/Postal Code
47574
Country
Germany
Facility Name
Kath. Krankenhaus Hagen gGmbH, Abt. Hämatologie/Onkologie
City
Hagen
ZIP/Postal Code
D-58095
Country
Germany
Facility Name
Asklepios Klinik Hamburg St. Georg
City
Hamburg
ZIP/Postal Code
20099
Country
Germany
Facility Name
Universitätsklinikum Hamburg Eppendorf, Zentrum für Onkologie, Studienzentrale der II. Medizinischen Klinik
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Facility Name
Asklepios Klinik Hamburg Altona, II. Med. Klinik
City
Hamburg
ZIP/Postal Code
D-22763
Country
Germany
Facility Name
Immunologisch-onkologisches MVZ am Siloah Krankenhaus
City
Hannover
ZIP/Postal Code
30449
Country
Germany
Facility Name
KRH Klinikum Siloah, Klinik für Hämatologie und Onkologie
City
Hannover
ZIP/Postal Code
30459
Country
Germany
Facility Name
Onkologische Schwerpunktpraxis Heidelberg
City
Heidelberg
ZIP/Postal Code
69115
Country
Germany
Facility Name
Krankenhaus St. Vincentius der evangelischen Stadtmission Heidelberg, Abt. Hämatologie, Onkologie, Rheumatologie
City
Heidelberg
ZIP/Postal Code
69117
Country
Germany
Facility Name
University Hospital Heidelberg, Med. Klinik V
City
Heidelberg
ZIP/Postal Code
D-69120
Country
Germany
Facility Name
SLK Kliniken Heilbronn, Med. Klinik III
City
Heilbronn
ZIP/Postal Code
D-74078
Country
Germany
Facility Name
Marien Hospital Herne
City
Herne
ZIP/Postal Code
44625
Country
Germany
Facility Name
Universitätsklinikum des Saarlandes, Innere Medizin I
City
Homburg (Saar)
ZIP/Postal Code
66421
Country
Germany
Facility Name
Westpfalz-Klinikum GmbH, Klinik für Innere Medizin I
City
Kaiserslautern
ZIP/Postal Code
67655
Country
Germany
Facility Name
Städtisches Klinikum Karlsruhe
City
Karlsruhe
ZIP/Postal Code
76133
Country
Germany
Facility Name
Praxisklinik für Hämatologie und Onkologie
City
Koblenz
ZIP/Postal Code
D-56068
Country
Germany
Facility Name
Uniklinik Köln, Klinik I für Innere Medizin
City
Köln
ZIP/Postal Code
50937
Country
Germany
Facility Name
Gemeinschaftspraxis für Hämatologie und Onkologie am Caritas Krankenhaus
City
Lebach
ZIP/Postal Code
66822
Country
Germany
Facility Name
Universitätsklinikum Leipzig AöR, Medizinische Klinik und Poliklinik I-Hämatologie und Zelltherapie, Internistische Onkologie, Hämostaseologie
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
Facility Name
Med. Klinik A, Klinikum der Stadt Ludwigshafen am Rhein gGmbH
City
Ludwigshafen am Rhein
ZIP/Postal Code
67063
Country
Germany
Facility Name
Universitätsmedizin der Johannes Gutenberg-Universität Mainz, III. Med. Klinik
City
Mainz
ZIP/Postal Code
D-55131
Country
Germany
Facility Name
III. Medizinische Klinik Hämatologie und Internistische Onkologie
City
Mannheim
ZIP/Postal Code
68167
Country
Germany
Facility Name
Mannheimer Onkologie Praxis
City
Mannheim
ZIP/Postal Code
D-68161
Country
Germany
Facility Name
Philipps-Universität Marburg, Hämatologie/Onkologie/Immunologie
City
Marburg
ZIP/Postal Code
35032
Country
Germany
Facility Name
Mühlenkreiskliniken (AöR) Johannes Wesling Klinikum Minden, Hämatologie/Onkologie, Hämostaseologie und Palliativmedizin
City
Minden
ZIP/Postal Code
32429
Country
Germany
Facility Name
Krankenhaus Maria Hilf GmbH, Franziskuskrankenhaus, Med. Klinik I
City
Mönchengladbach
ZIP/Postal Code
D-41063
Country
Germany
Facility Name
Universitätsklinikum Münster, Med. Klinik A
City
Münster
ZIP/Postal Code
48149
Country
Germany
Facility Name
Klinikum Osnabrück GmbH
City
Osnabrück
ZIP/Postal Code
49076
Country
Germany
Facility Name
Brüderkrankenhaus St. Josef Paderborn, Klinik für Hämatologie und Onkologie
City
Paderborn
ZIP/Postal Code
33098
Country
Germany
Facility Name
Krankenhaus Barmherzige Brüder, Klinik für Onkologie und Hämatologie
City
Regensburg
ZIP/Postal Code
93049
Country
Germany
Facility Name
Gemeinschaftspraxis für Hämatologie und Onkologie, Onkologisches Zentrum
City
Saarlouis
ZIP/Postal Code
66740
Country
Germany
Facility Name
Diakonie-Klinikum Schwäbisch Hall gGmbH, Innere Medizin III
City
Schwäbisch Hall
ZIP/Postal Code
74523
Country
Germany
Facility Name
ZAHO-Zentrum für ambulante Hämatologie und Onkologie, Standort Siegburg
City
Siegburg
ZIP/Postal Code
D-53721
Country
Germany
Facility Name
Onkologische Schwerpunktpraxis Speyer
City
Speyer
ZIP/Postal Code
D-67346
Country
Germany
Facility Name
Klinikum Stuttgart, Stuttgart Cancer Center, Tumorzentrum Eva Mayr-Stihl
City
Stuttgart
ZIP/Postal Code
70174
Country
Germany
Facility Name
Klinikum Mutterhaus der Borromäerinnen gGmbH
City
Trier
ZIP/Postal Code
54290
Country
Germany
Facility Name
University Hospital Tübingen, Med. Klinik und Poliklinik, Abt. II
City
Tübingen
ZIP/Postal Code
D-72076
Country
Germany
Facility Name
Bundeswehrkrankenhaus Ulm, Abteilung Innere Medizin - Hämatologie und internistische Onkologie
City
Ulm
ZIP/Postal Code
89081
Country
Germany
Facility Name
Schwarzwald-Baar Klinikum, Innere Medizin II
City
Villingen-Schwenningen
ZIP/Postal Code
78052
Country
Germany
Facility Name
Rems-Murr-Kliniken gGmbH
City
Winnenden
ZIP/Postal Code
71364
Country
Germany

12. IPD Sharing Statement

Citations:
PubMed Identifier
36328040
Citation
Goldschmidt H, Mai EK, Bertsch U, Fenk R, Nievergall E, Tichy D, Besemer B, Durig J, Schroers R, von Metzler I, Hanel M, Mann C, Asemissen AM, Heilmeier B, Weinhold N, Huhn S, Kriegsmann K, Luntz SP, Holderried TAW, Trautmann-Grill K, Gezer D, Klaiber-Hakimi M, Muller M, Khandanpour C, Knauf W, Scheid C, Munder M, Geer T, Riesenberg H, Thomalla J, Hoffmann M, Raab MS, Salwender HJ, Weisel KC; German-Speaking Myeloma Multicenter Group (GMMG) HD7 investigators. Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone as induction therapy for newly diagnosed, transplantation-eligible patients with multiple myeloma (GMMG-HD7): part 1 of an open-label, multicentre, randomised, active-controlled, phase 3 trial. Lancet Haematol. 2022 Nov;9(11):e810-e821. doi: 10.1016/S2352-3026(22)00263-0.
Results Reference
derived

Learn more about this trial

Trial on the Effect of Isatuximab to Lenalidomide/Bortezomib/Dexamethasone (RVd) Induction and Lenalidomide Maintenance in Patients With Newly Diagnosed Myeloma (GMMG HD7)

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