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 - A phase III study by DSMM (Deutsche Studiengruppe Multiples Myelom)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Wuerzburg AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

24 Aug 2018 → ongoing

Decision date (initial)

2024-11-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Celgene International II Sàrl, Switzerland · Bristol Myers Squibb, United States · Amgen Limited, United Kingdom

External identifiers

EU CT number

2024-515783-31-00

EudraCT number

2017-001616-11

ClinicalTrials.gov

NCT03948035

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To compare the rate of patients who have VGPR or better response according to IMWG criteria and are MRD negative as assessed by flow cytometry
following two different induction regimens (quadruple [E-KRd] vs. triple [KRd]) in newly diagnosed multiple myeloma patients and to determine progression-free survival (PFS) following maintenance treatment.

Secondary objectives 2

1. To assess long-term efficacy, quality of life (QoL) and safety of the treatment regimens
2. To assess the impact of MRD negativity regardless of IMWG response on disease-free survival (DFS) and OS

Conditions and MedDRA coding

Newly Diagnosed Multiple Myeloma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 1. Adult patients of age ≥ 18 and ≤ 70 years at the time of signing the informed consent form
2. 2. Eligible for autologous stem cell transplantation (ASCT)
3. 3. 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)
4. 4. Newly diagnosed multiple myeloma according to the IMWG updated criteria42: Clonal bone marrow plasma cells ≥ 10% or extramedullary plasmacytoma 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
5. 5. Measurable disease parameters as follows:  Serum monoclonal paraprotein (M-component) level ≥ 1 g/dL and/or urine Mprotein 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
6. 6. ECOG Performance Status ≤ 2
7. 7. Echocardiography with left ventricular ejection fraction (LVEF) ≥ 50%
8. 8. Laboratory test results within these ranges:  White blood cell count (WBC)  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 (estimation of the glomerular filtration rate [GFR]; according to MDRD, see Appendix 19.5) ≥ 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)
9. 9. Patient’s legal capacity to consent to study participation
10. 10. 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.
11. 11. 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.  The investigator must ensure that a FCBP: - Complies with the conditions of the pregnancy prevention plan, including confirmation that she has an adequate level of understanding. - Acknowledges the aforementioned requirements.
12. 12. Male subjects must ▪ Understand the potential teratogenic risk if engaged in sexual activity with a pregnant female or a FCBP.  Understand the potential teratogenic risk if the subject donates semen or sperm.  Practice complete abstinence (true abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence [e.g. calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal are not acceptable methods of contraception.) or agree to use a condom during sexual contact with a pregnant female or a FCBP while taking lenalidomide, carfilzomib and elotuzumab, during any dose interruptions and for 28 days after the last dose of lenalidomide and for 90 days after last dose of carfilzomib if allocated in Arm B without administration of elotuzumab, or for a total of 180 days after last application of elotuzumab, if allocated in Arm A with application of elotuzumab, even if he has undergone a successful vasectomy.  Notify the investigator immediately, if pregnancy or a positive pregnancy test does occur in the partner of a male subject while taking lenalidomide, carfilzomib, and/or elotuzumab.  Not donate semen or sperm while receiving lenalidomide, during dose interruptions and for at least 28 days after the last dose of lenalidomide and for at least 90 days after the last dose of carfilzomib.  Receive counseling about pregnancy precautions and the potential risks of fetal exposure to lenalidomide at a minimum of every 28 days during induction and consolidation phase. In maintenance phase counseling must be conducted with each lenalidomide prescription issued by the investigator.
13. 13. All subjects must  Not donate 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)  During induction and consolidation phase, be aware that no more than a 28-day lenalidomide supply may be dispensed with each cycle of lenalidomide.  During maintenance therapy, be aware that for females of childbearing potential no more than a 28-day lenalidomide supply may be prescribed with each cycle of lenalidomide, for all others no more than a 12 week lenalidomide supply may be prescribed.

Exclusion criteria 15

1. 1. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
2. 2. Waldenström’s macroglobulinemia or IgM myeloma
3. 3. Plasma cell leukemia (> 2.0 x 109 /L circulating plasma cells by standard differential blood count)
4. 4. Pregnant, breast-feeding females, FCBPs and males who are unwilling to comply with the lenalidomide Pregnancy Prevention Risk Management Plan (see Appendix E).
5. 5. 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
6. 6. Prior cerebral vascular accident (CVA) with persistent neurological deficit
7. 7. Active infection
8. 8. 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) –serological testing for hepatitis A; B; C, D required. However, testing for hepatitis D only required in case of patients who tested positive for acute or chronic hepatitis B.
9. 9. 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.
10. 10. Greater or equal to Grade 2 peripheral neuropathy on clinical examination within 14 days before enrolment
11. 11. Major surgery within 4 weeks prior to randomization
12. 12. Any systemic anti-myeloma therapy except a cumulative dose of 320 mg of dexamethasone
13. 13. 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
14. 14. 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
15. 15. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 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
2. For the maintenance phase: 3-year PFS rate calculated from randomization

Secondary endpoints 13

1. 1. Objective response rate (ORR) following induction and consolidation treatment with EKRd versus KRd (response evaluation according to IMWG criteria, refer to Appendix A)
2. 2. ORR at the end of study treatment programme following induction, ASCT, consolidation, and maintenance treatment (response evaluation according to IMWG criteria, refer to Appendix A; target population: Intent - to - Treat)
3. 3. PFS, defined as the time from randomization to the date of disease progression after firstline therapy (study treatment) or death from any cause
4. 4. PFS 2, defined as the time from randomization to the date of disease progression or death from any cause during/after second-line therapy in the Intent-to-Treat Population
5. 5. PFS and OS in correlation with cytogenetic abnormalities
6. 6. Improvement of MRD negativity rate as assessed by flow-cytometry following consolidation treatment
7. 7. Improvement of MRD negativity rate as assessed by flow-cytometry during maintenance treatment
8. 8. Disease-free survival (DFS) for patients who obtain MRD negativity as assessed by flowcytometry (at any time point)
9. 9. OS
10. 10. OS for patients who obtain MRD negativity as assessed by flow-cytometry (at any time point)
11. 11. QoL evaluated with EORTC-QLQ C30 and EORTC multiple myeloma module QLQ-MY20
12. 12. Type, incidence, relatedness, and severity of adverse events according to NCI CTCAE version 4.03
13. 13. Occurrence of laboratory abnormalities

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 13

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Wuerzburg AöR

Sponsor organisation

Universitaetsklinikum Wuerzburg AöR

Address

Josef-Schneider-Strasse 2, Grombuehl Grombuehl

City

Wuerzburg

Postcode

97080

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Wuerzburg AöR

Contact name

Study Coordinator

Public contact point

Organisation

Universitaetsklinikum Wuerzburg AöR

Contact name

Study Coordinator

Third parties 7

Locations

2 EU/EEA countries · 50 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 18 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications