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Four-Drug cocktail aims to crush myeloma before transplant

NCT ID NCT04483739

Disease control Sponsor: European Myeloma Network B.V. Source: ClinicalTrials.gov ↗

First seen Jul 16, 2026 · Last updated Jul 17, 2026 · Updated 1 time

Summary

This phase 3 trial tests whether adding the targeted antibody isatuximab to a standard three-drug regimen (carfilzomib, lenalidomide, dexamethasone) can achieve deeper remissions in people newly diagnosed with multiple myeloma who are eligible for a stem cell transplant. Participants receive either the four-drug combo (Isa-KRd) or the standard three-drug combo (KRd) before and after transplant. The main goal is to see if more patients become minimal residual disease (MRD) negative — meaning no cancer cells are detectable by a sensitive test — after consolidation therapy.

What this could mean

Our plain-language read of the trial. This is informational only, not medical advice or a prediction.

Active substance: a combination of isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd)
What this could lead to: If successful, this could establish a more effective upfront treatment for multiple myeloma, potentially leading to deeper remissions and longer disease control before and after stem cell transplant.
What could go wrong: This is a phase 3 trial, so results are not yet known. Adding a fourth drug may increase side effects, and the benefit in long-term outcomes like survival is still unproven.

This is an AI summary of the original study and may miss details. Read our disclaimer.

Study facts

What this study's own registry entry says, in plain language.

Phase

Phase 3

Large-scale testing in a bigger group. Usually the last step before a treatment can be approved.

Participants

302 people

The number who actually took part.

Started

Sep 2020

Expected to finish

Dec 2032

An estimate. End dates often move.

Lead sponsor

A research network

The lead sponsor is a research network or cooperative group.

Who can take part

This study's own entry requirements. Only the study team can say for certain whether you qualify.

Ages

18 to 70 years

Sex

Anyone

Healthy volunteers

Not accepted

This study is not open to healthy volunteers. The entry requirements below say who it is open to.

Show the full entry requirements

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

Inclusion Criteria: * Patient with newly diagnosed multiple myeloma and eligible to ASCT. * Patient is, in the investigator's opinion, willing and able to comply with the study visits and procedures required per protocol. * Patient has provided written informed consent in accordance with federal, local, and institutional guidelines prior to initiation of any study-specific activities or procedures. Subject does not have kind of condition that, in the opinion of the Investigator, may compromise the ability of the subject to give written informed consent and patient is, in the investigator(s) opinion, willing and able to comply with the protocol requirements. * Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma and documented multiple myeloma satisfying at least one of the calcium, renal, anemia, bone (CRAB) criteria or biomarkers of malignancy criteria: * CRAB criteria: * Hypercalcemia: serum calcium \>0.25 mmol/L (\>1 mg/dL) higher than upper limit of normal (ULN) or \>2.75 mmol/L (\>11 mg/dL) * Renal insufficiency: creatinine clearance \<40mL/min or serum creatinine \>177 μmol/L (\>2 mg/dL) * Anemia: hemoglobin \>2 g/dL below the lower limit of normal or hemoglobin \<10 g/dL * Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT * Biomarkers of Malignancy: * Clonal bone marrow plasma cell percentage ≥60% * Involved: uninvolved serum FLC ratio ≥100 * \>1 focal lesion on magnetic resonance imaging (MRI) studies * Patient is 18 - 70 years old and is eligible for autologous stem cell transplantation * Patient has measurable disease as defined by any one of the following: * Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or * Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin FLC ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio. * Life expectancy ≥ 3 months * ECOG status ≤2 * Clinical laboratory values meeting the following criteria during the Screening Phase: * Adequate hepatic function, with serum (alanine aminotransferase) ALT ≤ 2.5 times the upper limit of normal (ULN), AST (aspartate transaminase) ≤ 2.5 x the ULN * Serum direct bilirubin ≤ 1.5 ULN) (except in subjects with congenital bilirubinemia, such as Gilbert syndrome, direct bilirubinemia ≤ 1.5 ULN) * Absolute neutrophil count (ANC) ≥ 1.0 × 109/L * Platelet count ≥ 75× 109/L (≥ 50× 109/L if myeloma involvement in the bone marrow is \> 50%) and no platelet infusion in the 1 week prior to screening platelet count * Creatinine clearance (CrCl) ≥ 30 mL/minute. Creatinine clearance should be calculated using eGFR (Modified Diet in Renal Disese \[MDRD\]) * Corrected serum calcium ≤ 13.5 mg/dL (3.4 mmol/L) * LVEF ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available. * Females of childbearing potential (FCBP)\* complies with the conditions of the Pregnancy Prevention Plan, including confirmation that she has an adequate level of understanding and must agree to ongoing pregnancy testing and to practice contraception or true abstinence. FCBP must use a highly effective and an additional barrier contraception method simultaneously for 4 weeks before starting therapy, during treatment and dose interruptions and for 5 months after the last dose of study drugs. * Male subjects must agree to practice contraception if sexually active with FCBP during the treatment and for 5 months after the last dose of study drugs. Males must agree to refrain from donating sperm for at least 90 days after the last dose of carfilzomib and for at least 5 months after the last dose of isatuximab. * \*Note 1: a FCBP is a woman who: * has achieved menarche at some time point, * has not undergone a hysterectomy or bilateral oophorectomy or, * has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). * Note 2: true abstinence is acceptable when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Exclusion Criteria: * Previous treatment with anti-myeloma therapy (does not include radiotherapy, biphosphonates, or a single short course of steroid ≤ to the equivalent of dexamethasone 40 mg/day for 4 days). * Patients with non-secretory MM unless serum free light chains are present and the ratio is abnormal or a plasmacytoma with minimum largest diameters of \> 2 cm. * Patients with plasma cell leukemia, amyloidosis, Waldenstrom Disease, POEMS syndrome * Meningeal involvement of multiple myeloma * Patient ineligible for autologous transplantation * Pregnant or lactating females * Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomization * Known human immunodeficiency virus infection (HIV) * Active hepatitis A, B or C infection. Hepatitis C infection (subjects with hepatitis C that achieve a sustained virologic response after antiviral therapy are allowed), or hepatitis B infection (subjects with hepatitis B surface antigen or core antibody that achieve sustained virologic response with antiviral therapy are allowed). Tests to be performed if required per local country regulations. In fact it is not possible to avoid the risk of virological reactivation with the study treatments. * Unstable angina or myocardial infarction within 4 months prior to randomization, NYHA Class III or IV heart failure, uncontrolled angina, uncontrolled hypertension, (Uncontrolled hypertension, defined as an average systolic blood pressure ≥ 160 mmHg or diastolic ≥ 100 mmHg despite optimal treatment (measured following European Society of Hypertension/European Society of Cardiology 2013 guidelines), pulmonary embolia, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker * Non-hematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas * Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to randomization as defined by National Cancer Institute Common Toxicity Criteria (NCI CTCAE) 5.0 * Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib) and to PS80; prior hypersensitivity to sucrose, histidine (as base and hydrochloride salt), or any of the components (active substance or excipients) of study treatments that are not amenable to premedication with steroids, or H2 blockers, that would prohibit further treatment with these agents. * Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment * Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent * Pregnant or breastfeeding woman or woman who intends to become pregnant during the participation in the study. FCBP unwilling to prevent pregnancy by the use of 2 reliable methods of contraception for ≥4 weeks before the start of study treatment, during treatment (including dose interruptions), and for at least 28 days following discontinuation of study lenalidomide, or 30 days following discontinuation of carfilzomib or for 5 months after discontinuation of isatuximab treatment, whichever occurs last, * Male participants who disagree to practice true abstinence or disagree to use a condom during sexual contact with a pregnant woman or a FCBP while participating in the study, during dose interruptions, and for at least 28 days following discontinuation of study lenalidomide, or 30 days following discontinuation of carfilzomib, or for 5 months after discontinuation of isatuximab treatment, whichever occurs last, even if he has undergone a successful vasectomy.

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Conditions

The condition(s) this trial relates to.

plasma cell myeloma

As listed by the trial registrant

The condition terms exactly as the trial's registrant entered them.

Multiple myeloma

Contacts and locations

Locations

A.O.U. Città della Salute e della Scienza di Torino-U.O. Ematologia

Torino, Italy
Albert Schweitzerplaats 25

Dordrecht, Netherlands
Alexandra Hospital - Department of Clinical Therapeutics National & Kapodistrian University of Athens School of Medicine

Athens, Greece
Amphia Hospital-Internal Medicine - Hematology

Breda, Netherlands
Amsterdam-Vrije Universiteit Medical Center (VUMC)

Amsterdam, Netherlands
Azienda Ospedaliera Santa Croce E Carle - S.C. Ematologia

Cuneo, Italy
Azienda Ospedaliero Universitaria Ospedali Riuniti Umberto I G M Lancisi G Salesi-SOD Clinica Ematologica

Ancona, Italy
Azienda Ospedaliero-Universitaria Di Bologna IRCCS Istituto Di Ricerca E Di Cura A Carattere Scientifico - U.O. di Ematologia

Bologna, Italy
Azienda Ospedaliero-Universitaria Maggiore Della Carita - SDCU Ematologia

Novara, Italy
Azienda Sanitaria Locale Di Pescara - U.O. Ematologia

Pescara, Italy
Azienda Sanitaria Universitaria Giuliano Isontina-SC U.O.C Ematologia

Trieste, Italy
Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia - UOC Ematologia

Brescia, Italy
Careggi University Hospital - SOD Ematologia

Florence, Italy
Clinica Universidad De Navarra - Central Clinical Trials Unit

Pamplona, Spain
ErasmusMC, Rotterdam-Department of Hematology

Rotterdam, Netherlands
Fakultni Nemocnice Brno - Internal Hematology and Oncology Clinic

Brno, Czechia
Fakultni Nemocnice Hradec Kralove - 4th Department of Internal Medicine

Nový Hradec Králové, Czechia
Fakultni Nemocnice Ostrava - Department of Haematooncology

Ostrava, Czechia
Fondazione IRCCS Policlinico San Matteo-UOC Ematologia 1

Pavia, Italy
Haga Hospital - Internal Medicine - Hematology

s-Gravenweg, Netherlands
Het Ziekenhuisnetwerk Antwerpen - Department of Hematology

Antwerp, Belgium
Hospital Clinic De Barcelona - Myeloma and Amyloidosis Unit

Barcelona, Spain
Hospital Germans Trias I Pujol - Hematology Service ICO Badalona Clinic

Badalona, Spain
Hospital Universitario 12 De Octubre - Hematology

Madrid, Spain
Hospital Universitario 12 De Octubre -Hematology and Hemotherapy Service

Madrid, Spain
Hospital Universitario De Salamanca-Department of Hematology of the Salamanca University Care Complex

Salamanca, Spain
Hospital Universitario Marques De Valdecilla -Hematology and Hemotherapy Service

Santander, Spain
Klinikum rechts der Isar der TU Muenchen AöR - Innere Medizin III-Haematologie/Onkologie

München, Germany
Meander Medisch Centrum -Internal Medicine - Hematology

Amersfoort, Netherlands
Medical Center - University Of Freiburg - Department Innere Medizin Klinik für Innere Medizin I

Freiburg im Breisgau, Germany
Medisch Centrum Leeuwarden B.V. - Oncologisch Centrum Leeuwarden (OCL) and Internal Medicine - Hematology

Leeuwarden, Netherlands
Noordwest Ziekenhuisgroep Stichting - Internal Medicine - Hematology

Alkmaar, Netherlands
Oslo University Hospital HF - Oslo myelomatosesenter

Oslo, Norway
Sint Antonius Ziekenhuis Stichting-Internal Medicine - Hematology

Nieuwegein, Netherlands
St. Olavs Hospital HF - Department of Hematology

Trondheim, Norway
Theageneio General Hospital - Department of Hematology Oncology

Thessaloniki, Greece
Universitair Medisch Centrum Groningen-Department of Haematology

Groningen, Netherlands
University Hospital Consorziale Policlinico-U.O. di Ematologia con Trapianto

Bari, Italy
University Medical Center Hamburg-Eppendorf - Medizinische Klinik und Polikllinik Onkologie und Knochenmarktransplantation, Haematologie

Hamburg, Germany
Vseobecna Fakultni Nemocnice V Praze - Internal Medicine, Hematology Clinic

Prague, Czechia
Zuyderland Medisch Centrum Stichting - Internal Medicine - Hematology

Geleen, Netherlands

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