Clinical trial NCT03948035: Elotuzumab in Combination With Carfilzomib, Lenalidomide and Dexamethasone (E-KRd) Versus KRd in MM
Official title: Elotuzumab in Combination With Carfilzomib, Lenalidomide and Dexamethasone (E-KRd) Versus KRd Prior to and Following Auto-SCT in Newly Diagnosed Multipe Myeloma and Subsequent Maintenance With Elotuzumab and Lenalidomide Versus Single-Agent Lenalidomide- A Phase III Study by DSMM
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Newly Diagnosed Multiple Myeloma
Keywords: multiple myeloma
autologous stem cell transplant
Elotuzumab
Carfilzomib
Lenalidomide
Lead sponsor: Wuerzburg University Hospital
Sponsor class: OTHER
Collaborators: name: ClinAssess GmbH
name: Arbeitsgemeinschaft medikamentoese Tumortherapie
First posted: 2019-05-13
Enrollment: 576
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: Multiple myeloma (MM) is a cancer originating from the antibody-secreting plasma cell and characterized by abnormal accumulation of clonal plasma cells in bone marrow. In Europe, 3.8 new cases of MM and 2.2 deaths per 100,000 individuals (age-standardized rate) due to MM were estimated in 2012.

Treatment options for myeloma patients have markedly improved during the last decades.

For frontline treatment, high-dose myeloablative chemotherapy followed by reinfusion of autologous peripheral blood stem cells has been a standard of care since 1996. Introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide led to improvement in remission rates and survival in newly diagnosed patients. However, high-dose chemotherapy remains essential for achievement of long-lasting remissions even in the era of novel agents.

While high-dose melphalan chemotherapy (HDT) plus autologous stem cell transplant (ASCT) remains a standard in eligible, medically fit subjects, defining an optimal pre- and post HDT approach is subject to rapidly evolving novel-compound based options. In 2010, a group from the U.S. presented results on the combination of lenalidomide, bortezomib, and dexamethasone (VRd) in newly diagnosed patients with an overall response rate of 98%, however without systematic consolidation by HDT. The next-generation proteasome inhibitor carfilzomib is more active and very well tolerated in terms of peripheral neuropathy and gastrointestinal adverse effects. A randomized phase III trial in pretreated myeloma patients found the triple regimen of carfilzomib and lenalidomide/dexamethasone (Rd) to be superior to standard-Rd in terms of depth of response; progression-free survival (PFS) and, most importantly, overall survival (OS). At the 2015 annual meetings of the American Society of Clinical Oncology as well as the European Society of Hematology, this regimen (KRd) was found to be exceptionally effective in a phase 2 trial when given in newly diagnosed patients in a prolonged fashion: patients received four KRd induction cycles prior to HDT. The latter was followed by an additional 4 consolidation and 8 maintenance cycles with KRd, followed by lenalidomide maintenance thereafter. The most appealing effect was the high rate of deep remissions: stringent complete response (sCR) rate increased from 22% following 4 x KRd and HDT to more than 80% following all 18 cycles. Notably, the vast majority of patients in sCR also were negative for minimal residual disease (MRD) as assessed by 10-color flow cytometry. MRD negativity probably has a major impact on long-term disease control as was recently shown in a French prospective trial investigating in the combination of VRd prior and post HDT followed by lenalidomide maintenance.

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.

Eligibility criteria: Inclusion Criteria:

* 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
* For patients with no detectable M-component: Serum FLC Assay: Involved FLC level ≥ 10 mg/dL (≥ 100 mg/L) provided serum FLC ratio is abnormal
* ECOG Performance Status ≤ 2
* Laboratory test results within these ranges:
* White blood cell count ≥ 2 x 109/L
* Absolute neutrophil (ANC) count ≥ 1.0 x 109/L
* Platelet count ≥ 75 x 109/L
* Haemoglobin \> 8 g/dL
* Calculated creatinine clearance (according to MDRD) ≥ 30 mL/minute
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
* AST and ALT ≤ 2.5 x ULN
* Corrected serum calcium level \< 3.5 mmol/L (\< 14 mg/dL)
* Patient's legal capacity to consent to study participation
* Patients capable to understand the purposes and risks of the study, who are willing and able to participate in the study and from whom written and dated informed consent to participate in the study has been obtained.
* All females

  * must acknowledge to have understood the hazards lenalidomide can cause to an unborn fetus and the necessary precautions associated with the use of lenalidomide.
  * must use adequate contraception and agree to use two reliable forms of contraception simultaneously or to practice complete abstinence
  * must agree to have medically supervised pregnancy tests on a regular basis
  * must agree to abstain from breastfeeding while taking lenalidomide, carfilzomib and elotuzumab and for at least 28 days after the last dose of lenalidomide, carfilzomib, and elotuzumab.
* Male subjects must

  * practice complete abstinence or use a condom during sexual contact with a pregnant female or a female with child bearing potential while taking lenalidomide, carfilzomib, and elotuzumab.
  * not donate semen or sperm
* All subjects must

  * agree to abstain from donating blood while taking lenalidomide, during dose interruptions and for at least 28 days after the last dose of lenalidomide.
  * agree never to give lenalidomide to another person.
  * agree to return all unused lenalidomide capsules to the investigator (with exception of prescribed lenalidomide capsules)
  * be aware that no more than a 28-day lenalidomide supply may be dispensed with each cycle of lenalidomide during induction and consolidation therapy and be prescribed during maintenance therapy.

Exclusion Criteria:

* 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.
* Known hypersensitivity to carfilzomib, lenalidomide, and elotuzumab or to any of the excipients of carfilzomib, lenalidomide, and elotuzumab or to any other component of any study drug formulation
* Participation in any other clinical trial or treatment with any experimental drug or other experimental therapy within 28 days before enrolment to the study or during study participation until the end of treatment visit

Primary outcomes:
measure: Induction phase
timeFrame: At the end of Cycle 6 (168 days for all cycles plus up to 36 days)
measure: Maintenance phase
timeFrame: 3 years from randomisation
Secondary outcomes:
measure: Measurement of long-term efficacy (1)
timeFrame: 10 years
measure: Measurement of long-term efficacy (2)
timeFrame: 10 years
measure: Measurement of long-term efficacy (3)
timeFrame: 10 years
Other outcomes:
Locations:
city: Krems
country: Austria
facility: Univ. Klinikum Krems
state: Lower Austria
city: St. Polten
country: Austria
facility: Universitätklinikum St. Pölten
state: Lower Austria
city: Graz
country: Austria
facility: LKH-Universitätsklinikum Graz
state: Styria
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
state: Tirol
city: Linz
country: Austria
facility: Kepler Universitätsklinikum
state: Upper Austria
city: Wels
country: Austria
facility: Klinikum Wels-Grieskirchen
state: Upper Austria
city: Rankweil
country: Austria
facility: LKH Rankweil-Feldkirch
state: Vorarlberg
city: Salzburg
country: Austria
facility: Landeskrankenhaus Salzburg
city: Vienna
country: Austria
facility: AKH Meduni Wien
city: Vienna
country: Austria
facility: Klinik Ottakring
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
state: Baden-Wuerttemberg
city: Mutlangen
country: Germany
facility: Kliniken Ostalb
state: Baden-Wuerttemberg
city: Ravensburg
country: Germany
facility: Studienzentrum Onkologie Ravensburg
state: Baden-Wuerttemberg
city: Stuttgart
country: Germany
facility: Diakonieklinikum Stuttgart
state: Baden-Wuerttemberg
city: Stuttgart
country: Germany
facility: Robert-Bosch Krankenhaus
state: Baden-Wuerttemberg
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
state: Baden-Wuerttemberg
city: Villingen-Schwenningen
country: Germany
facility: Onkologie Schwarzwald-Alb
state: Baden-Wuerttemberg
city: Amberg
country: Germany
facility: Gesundgheitszentrum St. Marien
state: Bavaria
city: Augsburg
country: Germany
facility: Klinikum Augsburg
state: Bavaria
city: Bamberg
country: Germany
facility: Sozialstiftung Bamberg
state: Bavaria
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth
state: Bavaria
city: Kempten
country: Germany
facility: Klinikum Kempten-Oberallgäu
state: Bavaria
city: Munich
country: Germany
facility: Rotkreuzklinikum München
state: Bavaria
city: Munich
country: Germany
facility: Ludwig-Maximilians-Universität München
state: Bavaria
city: Munich
country: Germany
facility: Klinikum rechts der Isar der TU München
state: Bavaria
city: Nuremberg
country: Germany
facility: Klinikum Nürnberg Nord
state: Bavaria
city: Regensburg
country: Germany
facility: Uniklinikum Regensburg
state: Bavaria
city: Traunstein
country: Germany
facility: Klinikum Traunstein
state: Bavaria
city: Wuerzburg
country: Germany
facility: Universitätsklinikum Würzburg, Medizinische Klinik II
state: Bavaria
city: Frankfurt
country: Germany
facility: Klinikum der Johann Wolfgang Goethe-Universität Frankfurt am Main
state: Hesse
city: Göttingen
country: Germany
facility: Universitätsklinikum Göttingen
state: Lower Saxony
city: Hannover
country: Germany
facility: Med. Hochschule Hannover
state: Lower Saxony
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
state: Lower Saxony
city: Greifswald
country: Germany
facility: Universitätmedizin Greifswald
state: Mecklenburg-Pomerania
city: Rostock
country: Germany
facility: Universitätsmedizin Rostock
state: Mecklenburg-Pomerania
city: Schwerin
country: Germany
facility: Helios Kliniken
state: Mecklenburg-Pomerania
city: Bielefeld
country: Germany
facility: Evangelisches Klinikum Bethel
state: North Rhine-Westphalia
city: Dortmund
country: Germany
facility: St. Johannes Hospital
state: North Rhine-Westphalia
city: Hamm
country: Germany
facility: St. Barbara-Klinik Hamm
state: North Rhine-Westphalia
city: Münster
country: Germany
facility: Universitätsklinikum Münster
state: North Rhine-Westphalia
city: Siegen
country: Germany
facility: St. Marien-Krankenhaus
state: North Rhine-Westphalia
city: Koblenz
country: Germany
facility: Gemeinschaftsklinikum Mittelrhein
state: Rhineland-Palatinate
city: Halle (Saale)
country: Germany
facility: Universitätsklinikum Halle
state: Saxony-Anhalt
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg
state: Saxony-Anhalt
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus
state: Saxony
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
state: Saxony
city: Flensburg
country: Germany
facility: Malteser Krankenhaus
state: Schleswig-Holstein
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
state: Schleswig-Holstein
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
state: Schleswig-Holstein
city: Bad Berka
country: Germany
facility: Zentralklinik Bad Berka
state: Thuringia
city: Jena
country: Germany
facility: Klinikum der Friedrich-Schiller-Universität Jena
state: Thuringia
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Berlin
country: Germany
facility: Helios Kliniken
city: Berlin
country: Germany
facility: Vivantes Klinikum Spandau
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte
city: Hamburg
country: Germany
facility: Asklepios Klinik Altona
Study officials:
affiliation: Wuezburg University Hospital
name: Hermann Einsele, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.