Lenalidomide, Adriamycin, Dexamethasone (RAD) Versus Lenalidomide, Bortezomib, Dexamethasone (VRD) for Induction in Newly Diagnosed Multiple Myeloma Followed by Response-adapted Consolidation and Lenalidomide Maintenance

Phase 3

Active, not recruiting

• Conditions: Previously Untreated Symptomatic Multiple Myeloma
• Interventions: Drug: Lenalidomide, Bortezomib; Biological: autologous stem cell transplant; Biological: allogeneic stem cell transplant

• Registration Number: NCT01685814
• Lead Sponsor: Wuerzburg University Hospital

Brief Summary

The investigators propose this study utilizing Lenalidomide, Adriamycin, Dexamethasone (RAD) as comparator arm for Lenalidomide, Bortezomib, Dexamethasone (VRD) with the latter being considered a novel "standard" as an induction protocol, since response in general occurs early after starting treatment we decided to choose three cycles of either induction regimen.

Together with the "novel compounds", tandem high-dose melphalan is still the standard of care; it seems desirable to re-address the question of the number of transplant (single vs. double high-dose melphalan) procedures required in the context of triplet-induction protocols utilizing at least one of the novel compounds.

Thus, the question to be asked in the current protocol is whether immediate lenalidomide maintenance (i.e. following one cycle of high-dose therapy) as an investigational agent will result in identical progression free survival (PFS) when compared to tandem high-dose melphalan with deferred maintenance therapy.

Despite induction with novel compounds, approximately 25 - 40% of patients will be in less than very good partial response. Very recently, achievement of less than VGPR was confirmed to negatively impact on both PFS as well as overall survival (OS). Therefore, allogeneic stem cell transplantation is considered the standard of care in patients with suboptimal response to a first autograft.

In the current protocol, the standard for favourable responders (tandem-autologous transplant) is combined with 3 years of lenalidomide maintenance. This approach will be investigated for patients with less than VGPR following a first autotransplant and compared to the current standard of intensification in poor responders (allogeneic transplantation).

Detailed Description

Not available

Study Timeline

• Study Start: 2012-05
• Study First Submitted: 2012-06-27
• Study First Submitted QC: 2012-09-11
• Study First Posted: 2012-09-14
• Primary Completion: 2016-09
• Status Verified: 2023-04
• Last Update Submitted: 2023-04-26
• Last Update Posted: 2023-04-27
• Study Completion: 2023-12

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 406

Inclusion Criteria

• Understand and voluntarily sign an informed consent form
• Patients willing and able to undergo autologous and allogeneic transplantation
• no previous systemic therapy for the treatment of multiple myeloma (dexamethasone at a cumulative dose of 320 mg; plasmapheresis/dialysis without concomitant chemotherapy, local irradiation of bone lesions; and surgical intervention is accepted as pretreatment)
• Newly diagnosed multiple myeloma according to common diagnostic criteria including presence of CRAB and measurable disease parameters
• Cardiac ejection fraction (LVEF) of at least 50%
• Corrected DLCO of at least 50% ; alternatively pO2 [art.] of at least 70mmHg
• Karnofsky performance status of greater or equal to 50%
• adequate bone marrow function
• adequate serum chemistry values
• Use of adequate contraception for female subjects with childbearing potential and male subjects
• Bone marrow sample available for analysis of molecular cytogenetics
• Able to administer low molecular-weight heparin as a prophylactic anticoagulation therapy for the first three months(applicable for subjects randomized to RAD) and able to administer ASS 100 mg/d (applicable for subjects randomized to VRD)

Exclusion Criteria

• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form
• Pregnant or lactating females
• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk
• History of myocardial infarction; NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias; concomitant pericarditis or peri-/myocarditis
• Use of any other experimental drug or therapy within 28 days of baseline
• Greater or equal to Grade 2 peripheral neuropathy on clinical examination within 14 days before enrollment
• Known intolerance of boron
• Hypersensitivity to acyclovir or similar anti-viral drug
• Prior malignancy except adequately treated basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer
• HIV positive, active hepatitis B, C or D viral infection, known CMV reactivation/active infection, EBV reactivation/active infection or treponema pallidum infection
• Uncontrolled diabetes mellitus
• Non-secretory MM
• Clinically relevant active infection or serious co-morbid medical conditions

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
tandem autologous transplant	autologous stem cell transplant	Arm D
single stem cell transplant, 3-year lenalidomide maintenance	Lenalidomide, Bortezomib	Arm A
single stem cell transplant, 3-year lenalidomide maintenance	autologous stem cell transplant	Arm A
tandem autologous transplant, lenalidomide maintenance	Lenalidomide, Bortezomib	Arm B
tandem autologous transplant, lenalidomide maintenance	autologous stem cell transplant	Arm B
allogeneic stem cell transplant, lenalidomide maintenance	Lenalidomide, Bortezomib	Arm C
allogeneic stem cell transplant, lenalidomide maintenance	allogeneic stem cell transplant	Arm C
allogeneic stem cell transplant, lenalidomide maintenance	autologous stem cell transplant	Arm C
tandem autologous transplant	Lenalidomide, Bortezomib	Arm D

Primary Outcome Measures

Name	Time	Method
The primary efficacy endpoint for the induction phase is the rate of patients with CR at first restaging	within 8 days after end of last induction cycle ((Day 92(RAD); Day 71(VRD))
In the consolidation phase the primary efficacy endpoint for comparison II (response <VGPR after first ASCT) is the PFS rate	3 years after the first ASCT, calculated from day 1 of ASCT.

Secondary Outcome Measures

Name	Time	Method
Overall survival (OS)	8 years from study entry
ORR following 3 cycles of induction treatment (VRD vs RAD)	within 8 days after end of last induction cycle
Numbers of hospital stays and hospitalization days	within two years from second restaging
CR and ORR at the end of the whole treatment programme	at the end of the whole treatment programme (approx. 8 years)
Incidence, severity and relationship of SAEs	30 days post last dosing of study drug

Trial Locations

Locations (32)

St. Marien-Hospital gem. GmbHKna; 🇩🇪 Hamm, Germany

Klinikum der Johann Woflgang Goethe Universität, Frankfurt am Mai; 🇩🇪 Frankfurt am Main, Germany

Universitätsklinikum Aachen, Med. Klinik IV, Hämatologie u. Onkologie; 🇩🇪 Aachen, Germany

Universitätsklinikum Erlangen, Medizinische Klinik 5; 🇩🇪 Erlangen, Germany

Schön Klinik Starnberger See, Hämatologie und Onkologie; 🇩🇪 Berg, Germany

Charité Campus Virchow-Klinikum, Hämatologie, Onkologie u. Tumorimmunologie; 🇩🇪 Berlin, Germany

Klinikum Bremen-Mitte gGmbH, Klinik für Innere Medizin I; 🇩🇪 Bremen, Germany

Universitätsklinikum Carl Gustav Carus an der TU Dresden, Medizinische Klinik und Poliklinik I; 🇩🇪 Dresden, Germany

Malteser Krankenhaus St. Franziskus-Hospital, medizinische Klinik I; 🇩🇪 Flensburg, Germany

Universitätsklinikum Freiburg, Abteilung für Innere Medizin I; 🇩🇪 Freiburg, Germany

Klinikum Frankfurt (Oder) GmbH Medizinische Klinik I; 🇩🇪 Frankfurt/Oder, Germany

Universitätmedizin Greifswald, Klinik und Poliklinik für Innere Medizin C; 🇩🇪 Greifswald, Germany

Universitätsklinikum Schleswig-Holstein Campus Kiel, II. Med. Poliklinik; 🇩🇪 Kiel, Germany

Universitätsklinikum des Saarlandes Innere Medizin I; 🇩🇪 Homburg/Saar, Germany

Städtisches Klinikum Karlsruhe Medizinische Klinik III, Abt. Hämatologie u. Onkologie; 🇩🇪 Karlsruhe, Germany

Klinikum der Friedrich-Schiller-Universität Jena, Klinikum für Innrere Medizin II; 🇩🇪 Jena, Germany

Universitätsklinikum Schleswig-Holstein, Medizinische Klinik und Poliklinik II im städtischen Krankenhaus Kiel; 🇩🇪 Kiel, Germany

Stiftungsklinikum Mittelrhein GmbH, Klinik für Innere Medizin; 🇩🇪 Koblenz, Germany

Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Medizinische Klinik I; 🇩🇪 Lübeck, Germany

Universitätsmedizin Mannheim medizinische Klinik III; 🇩🇪 Mannheim, Germany

Klinikum Schwabing; 🇩🇪 München, Germany

Klinikum der Universität München-Großhadern; 🇩🇪 München, Germany

Klinikum Nürnberg Nord, 5. Medizinische LKinik, Onkologie/Hämatologie; 🇩🇪 Nürnberg, Germany

Klinikum Oldenburg GmbH, Klinik für Innere Medizin II; 🇩🇪 Oldenburg, Germany

III. Med. Klinik und Poliklinik, Klinikum rechts der Isar der TU München; 🇩🇪 München, Germany

Universitätsklinikum Münster, Medizinische Klinik u. Poliklinik A; 🇩🇪 Münster, Germany

Robert-Bosch-Krankenhaus, Abt. Hämatologie, Onkologie u. Palliativmedizin; 🇩🇪 Stuttgart, Germany

Schwarzwald-Baar Klinkum Villingen-Schwennigen GmbH; 🇩🇪 Villingen-Schwenningen, Germany

Dr. Horst Schmidt Kliniken, Klinik Innere Medizin III; 🇩🇪 Wiesbaden, Germany

Universitätsklinikum Wuerzburg, Medizinische Klinik II; 🇩🇪 Wuerzburg, Germany

Universitätsklinikum Ulm,Klinik für Innere Medizin III; 🇩🇪 Ulm, Germany

Uniklinikum Regensburg, Abteilung für Hämatologie und internistische Onkologie; 🇩🇪 Regensburg, Germany