A Trial That Compare Two Treatments in Newly Diagnosed Myeloma Patients Not Eligible for Transplant

NCT ID: NCT04096066

Last Updated: 2025-01-15

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 84 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-07-01
• Study Completion Date: 2026-01-01

Brief Summary

The combination of lenalidomide plus low-dose dexamethasone (Rd) is considered the new standard for elderly newly diagnosed multiple myeloma (NDMM) patients. The combination carfilzomib plus lenalidomide-dexamethasone (KRd) in relapsed-refractory MM patients improved the progression-free survival (PFS) of approximately 1 year compared to standard Rd treatment. In a small phase 2 trial (23 pts) the KRd combination in elderly NDMM pts showed a complete response (CR) rate of 79% and a PFS at 3 years of 80%. Cardiovascular adverse events are the most limiting toxicities, especially in elderly patients.

Detailed Description

This protocol is a randomized, multicenter study designed to determine the MRD negativity and the PFS of KRd treatment regimen.

Patients will be randomized in a 1:1 ratio to receive carfilzomib-lenalidomide-dexamethasone (KRd - Arm A) or lenalidomide-dexamethasone (Rd - Arm B).

Patients will be stratified basing on international staging system (ISS) and fitness status using a web-based procedure completely concealed to study participants.

All consecutive patients ≥ 65 years with newly diagnosed MM will be enrolled in a large randomized study during a period of 24 months.

Patients will be treated until disease progression or intolerance to the therapy. The only exception is for patients enrolled in KRd arm who achieve at least a VGPR during the first year of treatment and in sustained MRD negativity (MRD negative at least at 10-5 after one and two years of therapy): these patients will stop carfilzomib administration after 2 years, whereas treatment with lenalidomide and dexamethasone will be continued.

Conditions

Multiple Myeloma; New Diagnosis Tumor

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

KRd (Experimental Arm)

Carfilzomib (K):

• 20 mg/m2 IV on day 1 of cycle 1;
• 56 mg/m2 IV on days 8 and 15 in cycle 1;
• 56 mg/m2 IV on days 1, 8 and 15 in cycles 2-12;
• 56 mg/m2 on days 1 and 15 from cycle 13 and onwards.

Lenalidomide (R):

• 25 mg orally on days 1-21 of each cycle.

Dexamethasone (d):

• 40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is a 28-day cycle.

Until PD or intolerance. Only patients that achieve at least a VGPR within the first year of treatment and in sustained MRD negativity (MRD negative at least at 10-5 after 1 and 2 years of therapy) will stop carfilzomib after 2 years of treatment, and will continue with lenalidomide and dexamethasone administration.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

• 20 mg/m2 IV on day 1 of cycle 1 enhanced to 56 mg/m2 on days 8, and 15 of cycle 1;
• 56 mg/m2 IV on days 1, 8 and 15 in cycles 2-12;
• 56 mg/m2 IV on days 1 and 15 from cycle 13 and onwards.

Lenalidomide

Intervention Type: DRUG

\- 25 mg orally on days 1-21 of each cycle.

Dexamethasone

Intervention Type: DRUG

• 40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is to be repeated every 28 days. Patients that achieve at least a VGPR within the first year of study treatment and in sustained MRD negativity (MRD negative at least at 10-5 after 1 and 2 years of therapy) will stop carfilzomib administration after 2 years and will continue with lenalidomide and dexamethasone treatment until disease progression or intolerance to the therapy. Other patients will continue carfilzomib administration until disease progression or intolerance.

For patients >75 years of age, the dose of dexamethasone is 20 mg/day on Days 1, 8, 15 and 22 of each treatment cycle.

Rd (Control Arm)

Lenalidomide (R):

-25 mg orally on days 1-21 of each cycle.

Dexamethasone (d):

-40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is a 28-day cycles.

Until PD or intolerance.

Group Type: ACTIVE_COMPARATOR

Lenalidomide

Intervention Type: DRUG

\- 25 mg orally on days 1-21 of each cycle.

Dexamethasone

Intervention Type: DRUG

• 40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is to be repeated every 28 days. Patients that achieve at least a VGPR within the first year of study treatment and in sustained MRD negativity (MRD negative at least at 10-5 after 1 and 2 years of therapy) will stop carfilzomib administration after 2 years and will continue with lenalidomide and dexamethasone treatment until disease progression or intolerance to the therapy. Other patients will continue carfilzomib administration until disease progression or intolerance.

For patients >75 years of age, the dose of dexamethasone is 20 mg/day on Days 1, 8, 15 and 22 of each treatment cycle.

Interventions

Carfilzomib

• 20 mg/m2 IV on day 1 of cycle 1 enhanced to 56 mg/m2 on days 8, and 15 of cycle 1;
• 56 mg/m2 IV on days 1, 8 and 15 in cycles 2-12;
• 56 mg/m2 IV on days 1 and 15 from cycle 13 and onwards.

Intervention Type: DRUG

Lenalidomide

\- 25 mg orally on days 1-21 of each cycle.

Intervention Type: DRUG

Dexamethasone

• 40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is to be repeated every 28 days. Patients that achieve at least a VGPR within the first year of study treatment and in sustained MRD negativity (MRD negative at least at 10-5 after 1 and 2 years of therapy) will stop carfilzomib administration after 2 years and will continue with lenalidomide and dexamethasone treatment until disease progression or intolerance to the therapy. Other patients will continue carfilzomib administration until disease progression or intolerance.

For patients >75 years of age, the dose of dexamethasone is 20 mg/day on Days 1, 8, 15 and 22 of each treatment cycle.

Intervention Type: DRUG

Other Intervention Names

Kyprolis; Revlimid

Eligibility Criteria

Inclusion Criteria

• Newly diagnosed symptomatic MM based on either standard CRAB criteria (at least 10% of clonal bone marrow plasma cells plus CRAB defined as the onset of any of the following clinical symptoms: hypercalcemia, renal failure, anemia and bone lesions) or at least 10% of bone marrow plasma cells plus the presence of at least one of the following biomarkers of malignancy:

• 60% or greater clonal plasma cells on bone marrow examination;
• Serum involved/uninvolved free light chain (FLC) ratio of 100 or greater;
• More than one focal lesion on magnetic resonance imaging (MRI) that is at least 5 mm or greater in size.
• Patient not eligible for ASCT (age ≥ 65 years or abnormal cardiac, pulmonary and liver function).
• Patient defined as fit or intermediate according to the IMWG (International Myeloma Working Group) frailty score
• Patient has given voluntary written informed consent.
• Patient is able to be compliant with hospital visits and procedures required per protocol.
• Patient agrees to use acceptable methods for contraception.
• Patient has measurable disease according to IMWG criteria.
• Patient has ECOG (Eastern Cooperative Oncology Group) performance status < 3.
• Pre-treatment clinical laboratory values within 30 days before randomization:

• Platelet count ≥50 x 109/L (≥30 x 109 /L if myeloma involvement in the bone marrow is > 50%)
• Absolute neutrophil count (ANC) ≥ 1 x 109/L without the use of growth factors
• Corrected serum calcium ≤14 mg/dL (3.5 mmol/L)
• Alanine transaminase (ALT): ≤ 3 x the ULN
• Total bilirubin: ≤ 2 x the ULN
• Calculated or measured creatinine clearance: ≥ 30 mL/minute.
• LVEF≥ 40%: 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation; multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available
• Pre-treatment blood pressure value < 140/90 mmHg even with adequate therapy: 24 hours blood pressure monitoring is the preferred method of evaluation; blood pressure diary at home for 2 weeks is acceptable.
• Females of childbearing potential (FBCP) comply with the conditions of the Pregnancy Prevention Plan, including confirmation that she has an adequate level of understanding.
• FBCP must follow the Pregnancy Prevention Plan and use a highly effective and an additional barrier contraception method simultaneously for 4 weeks before starting therapy, during treatment and dose interruptions and for at least 30 days after the last dose of study drugs*
• Males must use an effective barrier method of contraception if sexually active with FCBP during the treatment and for at least 90 days after the last administration of study drug/s. Male subjects must agree to refrain from sperm donation for at least 90 days after the last dose of carfilzomib.

Exclusion Criteria

• Serious medical condition, laboratory abnormality or psychiatric illness that prevented the subject from the screening or place the subject at unacceptable risk.
• Patient defined as frail according to the IMWG frailty score.
• Previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid < to the equivalent of dexamethasone 40 mg/day for 4 days).
• Pregnant or lactating females.
• Presence of:

• Clinical active infectious hepatitis type A, B, C or HIV
• Acute active infection requiring antibiotics or infiltrative pulmonary disease
• Pulmonary hypertension and interstitial lung disease
• Uncontrolled arrhythmias or history of QT prolongation
• Myocardial infarction or unstable angina ≤ 6 months or other clinically significant heart disease
• Peripheral neuropathy or neuropathic pain grade 2 or higher, as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 5.0 (Appendix A)
• Uncontrolled hypertension defined as persistent hypertension (>140/90 mmHg) regardless treatment with 3 drugs, including a diuretic.
• Contraindication to any of the required drugs or supportive treatments and hypersensitivity to any excipient of the study drugs.
• Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib).
• Invasive malignancy within the past 3 years.
• Administration of any experimental drug within 4 weeks prior the baseline or within 5 drug half-lives.

• Minimum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fondazione EMN Italy Onlus

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sara Bringhen

Role: PRINCIPAL_INVESTIGATOR

A.O.U. Città della Salute e della Scienza

Locations

AO "SS. Antonio e Biagio"

Alessandria, , Italy

AOU Ospedali Riuniti Umberto I

Ancona, , Italy

Ospedale Mazzoni

Ascoli Piceno, , Italy

Policlinico di Bari

Bari, , Italy

Ospedali Riuniti

Bergamo, , Italy

Azienda Sanitaria di Bolzano - Ospedale Lorenz B:Ohler

Bolzano, , Italy

A.O. Spedali Civili di Brescia

Brescia, , Italy

Ospedale "A. Businco"

Cagliari, , Italy

Istituto per la Cura e la RIcerca del Cancro di Candiolo

Candiolo, , Italy

Ospedale Civico S. Croce e Carle

Cuneo, , Italy

AOU Careggi

Florence, , Italy

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.)

Meldola, , Italy

Azienda Ospedaliera Papardo

Messina, , Italy

Policlinico Universitario di Messina

Messina, , Italy

ASST Grande Ospedale Metropolitano Niguarda

Milan, , Italy

Istituto Europeo Oncologico

Milan, , Italy

Istituto Nazionale Tumori

Milan, , Italy

Ospedale Maggiore Policlinico di Milano

Milan, , Italy

Università Federico II-Policlinico

Napoli, , Italy

Ospedale Maggiore

Novara, , Italy

AO San Luigi Gonzaga

Orbassano, , Italy

AO di Padova

Padua, , Italy

AO Cervello

Palermo, , Italy

Ospedale S. Maria della Misericordia

Perugia, , Italy

Ospedale Santa Maria delle Croci

Ravenna, , Italy

AO Bianchi Melacrino Morelli

Reggio Calabria, , Italy

Ausl-Irccs

Reggio Emilia, , Italy

Ospedale Infermi

Rimini, , Italy

Ospedale Oncologico Regionale

Rionero in Vulture, , Italy

ASL Roma 1

Roma, , Italy

Azienda Ospedaliera Universitaria Policlinico Tor Vergata

Roma, , Italy

Ospedale S. Eugenio - Università Tor Vergata

Roma, , Italy

Ospedale San Camillo Forlanini

Roma, , Italy

Policlinico Umberto I - Università La Sapienza

Roma, , Italy

Istituto Clinico Humanitas

Rozzano, , Italy

IRCCS Ospedale Casa Sollievo della Sofferenza

San Giovanni Rotondo, , Italy

AO S. Maria

Terni, , Italy

AOU Città della Salute e della Scienza di Torino - PO Molinette - Ematologia U

Torino, , Italy

AOU Città della Salute e della Scienza di Torino - PO Molinette

Torino, , Italy

Policlinico Universitario di Udine

Udine, , Italy

Countries

Italy

References

Bringhen S, Cani L, Antonioli E, Derudas D, Fazio F, Larocca A, Ronconi S, Cellini C, Falcone AP, Accardi F, Liberati AM, Galieni P, Belotti A, Cafro AM, Ria R, Benevolo G, Vincelli ID, Mannina D, Lotti F, Bruno B, Marasco V, Mazza R, Tosi P, Rivolti E, Boccadoro M, D'Agostino M. Carfilzomib-lenalidomide-dexamethasone versus lenalidomide-dexamethasone in patients with newly diagnosed myeloma ineligible for autologous stem-cell transplantation (EMN20): a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2025 Aug;12(8):e621-e634. doi: 10.1016/S2352-3026(25)00162-0.

Reference Type: DERIVED

PMID: 40769686 (View on PubMed)

Other Identifiers

EMN20

Identifier Type: -

Identifier Source: org_study_id