Elotuzumab in Combination With Carfilzomib, Lenalidomide and Dexamethasone (E-KRd) Versus KRd in MM

NCT03948035 | Active Not Recruiting Phase 3

• 2 other identifiers: DSMM XVII2017-001616-11
• Study Type: interventional
• Target: 576
• Locations: 2 countries
• Sites: 56

Brief Summary

Of the next-generation compounds, the monoclonal antibodies (moAbs) have recently attracted a lot of interest in MM. The anti-SLAMF7 directed moAb elotuzumab has completed phase III trials in MM patients. One phase III trial in MM patients with one to three prior lines of therapy compared elotuzumab-Rd with standard Rd. The triple combination was shown to significantly prolong PFS in this patient cohort with a greater proportion of patients in at least very good partial response (VGPR) when compared to subjects on Rd. Notably, the rate of infusion-related reactions with this specific moAb was very low, with an overall rate of 10% in premedicated patients and only 1% of Grade 3 severity. Grades 4/5 infusion-related reactions were absent and only 1% of patients on elotuzumab discontinued for infusion-related reactions. Of particular interest is the observation in this trial, that response and PFS were independent of cytogenetic high-risk features, i.e., deletion of chromosome 17p and translocation t(4;14). This effect distinguishes elotuzumab from most, if not all, other drug-based approaches. The investigators assume that incorporating the moAb into the KRd triple induction regimen should result in an even higher rate of deep (negative for MRD in conjunction with at least very good partial response \[VGPR\] as defined by the International Myeloma Working Group \[IMWG\]) with these responses occurring independently of cytogenetic risk. Due to potential interference of elotuzumab with serum immune fixation, the investigators chose VGPR rather than complete response (CR) to exclude false-positive immunofixation results. Furthermore the investigators hypothesize that combining elotuzumab with lenalidomide should prolong PFS further.

Conditions

Newly Diagnosed Multiple Myeloma

Keywords

multiple myeloma; autologous stem cell transplant; Elotuzumab; Carfilzomib; Lenalidomide

Outcome Measures

Primary Outcomes (2)

• Induction phase

  MRD negativity rate (%) as assessed by flow-cytometry in patients with VGPR or better response according to IMWG criteria following six cycles of induction treatment.

  At the end of Cycle 6 (168 days for all cycles plus up to 36 days)

• Maintenance phase

  Determination of progression-free survival (PFS) following randomisation

  3 years from randomisation

Secondary Outcomes (3)

• Measurement of long-term efficacy (1)

  10 years

• Measurement of long-term efficacy (2)

  10 years

• Measurement of long-term efficacy (3)

  10 years

Study Arms (2)

E-KRd/ Arm A

EXPERIMENTAL

Induction/ Consolidation: Elotuzumab, Carfilzomib, Lenalidomide, Dexamethasone (E-KRd), autologous stem cell transplant, Maintenance: Elotuzumab, Lenalidomide

Drug: Elotuzumab; Drug: Carfilzomib; Drug: Lenalidomide; Drug: Dexamethasone; Other: autologous stem cell transplant

KRd/ Arm B

ACTIVE COMPARATOR

Induction/ Consolidation: Carfilzomib, Lenalidomide, Dexamethasone (KRd), autologous stem cell transplant, Maintenance: Lenalidomide

Drug: Carfilzomib; Drug: Lenalidomide; Drug: Dexamethasone; Other: autologous stem cell transplant

Interventions

Elotuzumab DRUG

i.v. infusion. Induction 6 cycles: 10mg/kg BW D1,8,15,22 of cycle 1 and 2, D1,15 of cycles 3-6. Consolidation 4 cycles: 10mg/kg BW D1,15 of cycle 1-4. Maintenance 28-day cycles: 20mg/kg BW D1 of each 28-day cycle.

Also known as: Empliciti®

E-KRd/ Arm A

Carfilzomib DRUG

i.v. infusion. Induction 6 cycles: 20 mg/m² on D1 and 2 of cycle 1, 36 mg/m² on D8, 9, 15, 16 of cycle 1, 36 mg/m² on D1,2,8,9,15,16 of cycle 2-6; Consolidation 4 cycles: 36 mg/m² on days 1, 2, 8, 9, 15, 16 of cycles 1-4.

Also known as: Kyprolis®

E-KRd/ Arm A; KRd/ Arm B

Lenalidomide DRUG

hard capsule for oral use. Induction 6 cycles: 25mg D1-21 of cycle 1-6. Consolidation 4 cycles: 15mg D1-21 of cycle 1, 25mg D1-21 ov cycle 2-4. Maintenance 28-day cycles: 10mg D1-28 of cycle 1,2,3, 15mg D1-28 of cycle 4 and all subsequent cycles.

Also known as: Revlimid®

E-KRd/ Arm A; KRd/ Arm B

Dexamethasone DRUG

orally and i.v. IN ARM A:Induction 6 cycles: 28mg p.o. and 8mg i.v. D1,8,15,22 of cycles 1-2 and D1,15 of cycles 3-6, 40mg p.o. D8,22 of cycle 3-6. Consolidation 4 cycles: 28mg p.o. and 8mg i.v. D1,15 of cycle 1-4 and 20mg p.o. D8,22 of cycle 1-4. IN ARM B: Induction 6 cycles: 40mg p.o. D1,8,15,22 of cycles 1-6. Consolidation 4 cycles: 20mg p.o. D1,8,15, 22 of cycle 1-4 .

Also known as: Fortecortin®

E-KRd/ Arm A; KRd/ Arm B

autologous stem cell transplant OTHER

autologous stem cell transplant

E-KRd/ Arm A; KRd/ Arm B

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 (only dexamethasone at a cumulative dose of 320 mg; plasmapheresis/dialysis without concomitant chemotherapy,local irradiation of bone lesions; and surgical intervention permitted as pretreatment)
• Newly diagnosed multiple myeloma according to the IMWG updated criteria42: Clonal bone marrow plasma cells ≥ 10% or biopsy proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events:
• Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
• Hypercalcaemia: serum calcium \> 0.25 mmol/L (\> 1 mg/dL) higher than the upper limit of normal or \> 2.75 mmol/L (\> 11 mg/dL)
• Renal insufficiency: creatinine clearance \< 40 mL per min or serum creatinine \> 177 μmol/L (\> 2 mg/dL)
• Anaemia: haemoglobin value of \> 2 g/dL below the lower limit of normal, or a haemoglobin value \< 10 g/dL
• Bone lesions: one or more osteolytic lesions on skeletal radiography,computed tomography (CT), or PET-CT
• Any one or more of the following markers of malignancy:
• Clonal bone marrow plasma cell percentage ≥ 60%
• Involved: uninvolved serum free light chain ratio ≥ 100, provided the absolute level of the involved light chain is at least 100 mg/L
• One or more focal lesions of at least 5mm or greater in size on MRI studies
• Measurable disease parameters as follows:
• Serum monoclonal paraprotein (M-component) level ≥ 1 g/dL and/or urine M-protein level ≥ 200 mg/24 hours or
• In case of IgA myeloma: Serum monoclonal paraprotein level ≥ 0.5 g/dL and/or urine M-protein level ≥ 200 mg/24 hours or

You may not qualify if:

• 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 by standard differential blood count)
• Pregnant, breast-feeding females, FCBPs and males who are unwilling to comply with the lenalidomide Pregnancy Prevention Risk Management Plan.
• Patients with high cardiovascular risk, including but not limited to history of myocardial infarction or coronary stenting in the past 6 months; NYHA Class III or IV heart failure, uncontrolled angina, uncontrolled hypertension, severe uncontrolled arrhythmias
• Prior cerebral vascular accident (CVA) with persistent neurological deficit
• Active infection
• Known HIV-seropositivity, active or chronic hepatitis A, B, C or D-infection (including patients who are tested anti-HBC positive and/or HBsAg positive).
• Any other severe concomitant disease or disorder, including the presence of laboratory abnormalities, which places the subject at unacceptable risk or which could influence patient's ability to participate in the study and his/her safety during the study or interfere with interpretation of study results.
• Greater or equal to Grade 2 peripheral neuropathy on clinical examination within 14 days before enrollment
• Major surgery within 4 weeks prior to randomization
• Any systemic anti-myeloma therapy within 4 weeks of randomization except a max. cumulative dose of 320 mg auf dexamethasone.
• Any prior or concurrent malignancy other than multiple myeloma.
• Exceptions include patients who have been disease-free for at least five years before study entry or patients with adequately treated and completely resected basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer.

Sponsors & Collaborators

• Wuerzburg University Hospital: lead
• ClinAssess GmbH: collaborator
• Arbeitsgemeinschaft medikamentoese Tumortherapie: collaborator

Study Sites (56)

Univ. Klinikum Krems

Krems, Lower Austria, A-3500, Austria

Location

Universitätklinikum St. Pölten

Sankt Pölten, Lower Austria, A-3100, Austria

Location

LKH-Universitätsklinikum Graz

Graz, Styria, A-8036, Austria

Location

Medizinische Universität Innsbruck

Innsbruck, Tyrol, A-6020, Austria

Location

Kepler Universitätsklinikum

Linz, Upper Austria, A-4021, Austria

Location

Klinikum Wels-Grieskirchen

Wels, Upper Austria, A-4600, Austria

Location

LKH Rankweil-Feldkirch

Rankweil, Vorarlberg, A-6830, Austria

Location

Landeskrankenhaus Salzburg

Salzburg, A-5020, Austria

Location

AKH Meduni Wien

Vienna, A-1090, Austria

Location

Klinik Ottakring

Vienna, A-1160, Austria

Location

Universitätsklinikum Freiburg

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

Location

Kliniken Ostalb

Mutlangen, Baden-Wurttemberg, 73557, Germany

Location

Studienzentrum Onkologie Ravensburg

Ravensburg, Baden-Wurttemberg, 88212, Germany

Location

Diakonieklinikum Stuttgart

Stuttgart, Baden-Wurttemberg, 70176, Germany

Location

Robert-Bosch Krankenhaus

Stuttgart, Baden-Wurttemberg, 70376, Germany

Location

Universitätsklinikum Ulm

Ulm, Baden-Wurttemberg, 89081, Germany

Location

Onkologie Schwarzwald-Alb

Villingen-Schwenningen, Baden-Wurttemberg, 78052, Germany

Location

Gesundgheitszentrum St. Marien

Amberg, Bavaria, 92224, Germany

Location

Klinikum Augsburg

Augsburg, Bavaria, 86156, Germany

Location

Sozialstiftung Bamberg

Bamberg, Bavaria, 96049, Germany

Location

Klinikum Bayreuth

Bayreuth, Bavaria, 95445, Germany

Location

Klinikum Kempten-Oberallgäu

Kempten (Allgäu), Bavaria, 87439, Germany

Location

Rotkreuzklinikum München

Munich, Bavaria, 80634, Germany

Location

Ludwig-Maximilians-Universität München

Munich, Bavaria, 81377, Germany

Location

Klinikum rechts der Isar der TU München

Munich, Bavaria, 81675, Germany

Location

Klinikum Nürnberg Nord

Nuremberg, Bavaria, 90419, Germany

Location

Uniklinikum Regensburg

Regensburg, Bavaria, 93053, Germany

Location

Klinikum Traunstein

Traunstein, Bavaria, 83278, Germany

Location

Universitätsklinikum Würzburg, Medizinische Klinik II

Würzburg, Bavaria, 97080, Germany

Location

Klinikum der Johann Wolfgang Goethe-Universität Frankfurt am Main

Frankfurt am Main, Hesse, 60590, Germany

Location

Universitätsklinikum Göttingen

Göttingen, Lower Saxony, 37075, Germany

Location

Med. Hochschule Hannover

Hanover, Lower Saxony, 30625, Germany

Location

Klinikum Oldenburg

Oldenburg, Lower Saxony, 26133, Germany

Location

Universitätmedizin Greifswald

Greifswald, Mecklenburg-Pomerania, 17475, Germany

Location

Universitätsmedizin Rostock

Rostock, Mecklenburg-Pomerania, 18057, Germany

Location

Helios Kliniken

Schwerin, Mecklenburg-Pomerania, 19049, Germany

Location

Evangelisches Klinikum Bethel

Bielefeld, North Rhine-Westphalia, 33611, Germany

Location

St. Johannes Hospital

Dortmund, North Rhine-Westphalia, 44137, Germany

Location

St. Barbara-Klinik Hamm

Hamm, North Rhine-Westphalia, 59075, Germany

Location

Universitätsklinikum Münster

Münster, North Rhine-Westphalia, 48149, Germany

Location

St. Marien-Krankenhaus

Siegen, North Rhine-Westphalia, 57072, Germany

Location

Gemeinschaftsklinikum Mittelrhein

Koblenz, Rhineland-Palatinate, 56068, Germany

Location

Universitätsklinikum Carl Gustav Carus

Dresden, Saxony, 01307, Germany

Location

Universitätsklinikum Leipzig

Leipzig, Saxony, 04103, Germany

Location

Universitätsklinikum Halle

Halle, Saxony-Anhalt, 06120, Germany

Location

Universitätsklinikum Magdeburg

Magdeburg, Saxony-Anhalt, 39120, Germany

Location

Malteser Krankenhaus

Flensburg, Schleswig-Holstein, 24939, Germany

Location

Universitätsklinikum Schleswig-Holstein

Kiel, Schleswig-Holstein, 24105, Germany

Location

Universitätsklinikum Schleswig-Holstein

Lübeck, Schleswig-Holstein, 23538, Germany

Location

Zentralklinik Bad Berka

Bad Berka, Thuringia, 99437, Germany

Location

Klinikum der Friedrich-Schiller-Universität Jena

Jena, Thuringia, 07740, Germany

Location

Charité Universitätsmedizin Berlin

Berlin, 12200, Germany

Location

Helios Kliniken

Berlin, 13125, Germany

Location

Vivantes Klinikum Spandau

Berlin, 13585, Germany

Location

Klinikum Bremen-Mitte

Bremen, 28177, Germany

Location

Asklepios Klinik Altona

Hamburg, 22763, Germany

Location

Related Publications (1)

• Rassner M, Baur R, Wasch R, Schiffer M, Schneider J, Mackensen A, Engelhardt M. Two cases of carfilzomib-induced thrombotic microangiopathy successfully treated with Eculizumab in multiple myeloma. BMC Nephrol. 2021 Jan 18;22(1):32. doi: 10.1186/s12882-020-02226-5.

  PMID: 33461512 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

elotuzumab; carfilzomib; Lenalidomide; Dexamethasone; dexamethasone acetate

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Hermann Einsele, MD

  Wuezburg University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 20, 2018
• First Posted: May 13, 2019
• Study Start: August 28, 2018
• Primary Completion (Estimated): August 1, 2029
• Study Completion (Estimated): August 1, 2029
• Last Updated: May 6, 2023

Record last verified: 2023-05

Locations

DE (46); AU (10)