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

NCT04096066 | Active Not Recruiting Phase 3 DMC

• 1 other identifier: EMN20
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 40

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.

Conditions

Multiple Myeloma; New Diagnosis Tumor

Keywords

Multiple Myeloma; AUTOLOGOUS STEM CELL TRANSPLANTATION INELIGIBLE; Proteasome inhibitor; Immunomodulating agents

Outcome Measures

Primary Outcomes (2)

• Minimal residual disease (MRD)

  1\. Minimal residual disease (MRD): unit of measure is not applicable, MRD is expressed as a pure number

  5 years

• Progression-free survival (PFS)

  2\. Progression-free survival (PFS): unit of measure is not applicable, PFS is expressed as a pure number

  5 years

Secondary Outcomes (11)

• Rate of drug reduction or drug discontinuation

  5 years

• Cardiovascular assessment

  5 years

• Rate of dose reduction, drug discontinuation and toxicities

  5 years

• Response rate

  5 years

• Progression-free survival 2 (PFS2)

  5 years

Study Arms (2)

KRd (Experimental Arm)

EXPERIMENTAL

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.

Drug: Carfilzomib; Drug: Lenalidomide; Drug: Dexamethasone

Rd (Control Arm)

ACTIVE COMPARATOR

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.

Drug: Lenalidomide; Drug: Dexamethasone

Interventions

Carfilzomib 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.

Also known as: Kyprolis

KRd (Experimental Arm)

Lenalidomide DRUG

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

Also known as: Revlimid

KRd (Experimental Arm); Rd (Control Arm)

Dexamethasone 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.

KRd (Experimental Arm); Rd (Control Arm)

Eligibility Criteria

• Age: 65 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• 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:
• % 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)

You may not qualify if:

• 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.

Sponsors & Collaborators

• Fondazione EMN Italy Onlus: lead

Study Sites (40)

AO "SS. Antonio e Biagio"

Alessandria, Italy

Location

AOU Ospedali Riuniti Umberto I

Ancona, Italy

Location

Ospedale Mazzoni

Ascoli Piceno, Italy

Location

Policlinico di Bari

Bari, Italy

Location

Ospedali Riuniti

Bergamo, Italy

Location

Azienda Sanitaria di Bolzano - Ospedale Lorenz B:Ohler

Bolzano, Italy

Location

A.O. Spedali Civili di Brescia

Brescia, Italy

Location

Ospedale "A. Businco"

Cagliari, Italy

Location

Istituto per la Cura e la RIcerca del Cancro di Candiolo

Candiolo, Italy

Location

Ospedale Civico S. Croce e Carle

Cuneo, Italy

Location

AOU Careggi

Florence, Italy

Location

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

Meldola, Italy

Location

Azienda Ospedaliera Papardo

Messina, Italy

Location

Policlinico Universitario di Messina

Messina, Italy

Location

ASST Grande Ospedale Metropolitano Niguarda

Milan, Italy

Location

Istituto Europeo Oncologico

Milan, Italy

Location

Istituto Nazionale Tumori

Milan, Italy

Location

Ospedale Maggiore Policlinico di Milano

Milan, Italy

Location

Università Federico II-Policlinico

Napoli, Italy

Location

Ospedale Maggiore

Novara, Italy

Location

AO San Luigi Gonzaga

Orbassano, Italy

Location

AO di Padova

Padua, Italy

Location

AO Cervello

Palermo, Italy

Location

Ospedale S. Maria della Misericordia

Perugia, Italy

Location

Ospedale Santa Maria delle Croci

Ravenna, Italy

Location

AO Bianchi Melacrino Morelli

Reggio Calabria, Italy

Location

Ausl-Irccs

Reggio Emilia, Italy

Location

Ospedale Infermi

Rimini, Italy

Location

Ospedale Oncologico Regionale

Rionero in Vulture, Italy

Location

ASL Roma 1

Roma, Italy

Location

Azienda Ospedaliera Universitaria Policlinico Tor Vergata

Roma, Italy

Location

Ospedale S. Eugenio - Università Tor Vergata

Roma, Italy

Location

Ospedale San Camillo Forlanini

Roma, Italy

Location

Policlinico Umberto I - Università La Sapienza

Roma, Italy

Location

Istituto Clinico Humanitas

Rozzano, Italy

Location

IRCCS Ospedale Casa Sollievo della Sofferenza

San Giovanni Rotondo, Italy

Location

AO S. Maria

Terni, Italy

Location

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

Torino, Italy

Location

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

Torino, Italy

Location

Policlinico Universitario di Udine

Udine, Italy

Location

Related Publications (1)

• 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.

  PMID: 40769686 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

carfilzomib; Lenalidomide; Dexamethasone

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

• Sara Bringhen

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

  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: July 2, 2019
• First Posted: September 19, 2019
• Study Start: July 1, 2019
• Primary Completion: January 1, 2026
• Study Completion: January 1, 2026
• Last Updated: January 15, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (40)