KRDI in Transplant-Eligible MM

NCT04430894 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 1 other identifier: 19-568
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 3

Brief Summary

This research study is testing the efficacy of an experimental drug combination for people with newly diagnosed multiple myeloma that are eligible for a stem cell transplant. The names of the study drugs involved in this study are:

• Carfilzomib
• Isatuximab
• Lenalidomide
• Dexamethasone

Conditions

Multiple Myeloma

Keywords

Multiple Myeloma

Outcome Measures

Primary Outcomes (1)

• Complete Response (CR + Stringent CR) Rate

  Percentage of patients who achieved a complete response (CR) or stringent CR (sCR) per International Myeloma Working Group (IMWG) Uniform Response criteria after 4 cycles of of Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (KRDI). IMWG criteria define a CR as "Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow" and an sCR as "CR plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence."

  112 Days

Secondary Outcomes (8)

• Overall Response Rate After 4 Cycles Induction Therapy

  112 days (4 cycles)

• Minimal Residual Disease (MRD) Rate After 4 Cycles Induction Therapy

  112 Days (4 Cycles)

• Minimal Residual Disease (MRD) Rate at 10^(-5) in Patients Receiving Upfront Stem Cell Transplant

  168 Days (6 cycles, upfront transplant)

• Minimal Residual Disease (MRD) Rate at 10^(-5) in Patients Deferring Stem Cell Transplant

  224 Days (8 cycles transplant-deferred)

• Progression Free Survival at 12 Months

  12 months

Study Arms (3)

Induction

EXPERIMENTAL

All participants will receive 4 cycles of induction therapy. Based on the recommendation of investigators, participants may or may not proceed to an autologous stem cell transplant (SCT) after cycles 1-4. Each cycle is 28 days in length (see dosing details below.) For patient undergoing upfront stem cell transplant (SCT): 4 cycles followed by stem cell collection, high-dose chemotherapy, and autologous SCT followed by 2 cycles (called consolidation). For patients deferring SCT following collection: 4 cycles followed by stem cell collection followed by 4 additional cycles. Carfilzomib: 56 mg/m2 IV on days 1, 8,15 Lenalidomide 25 mg orally (PO) on Days 1-21 Isatuximab: 10 mg/kg IV weekly for cycles 1-2 (days 1, 8, 15, 22), then every 2 weeks for cycles 3-6 (days 1 and 15), and monthly (day 1) thereafter Dexamethasone: 20 mg orally (PO) administered day of and day after carfilzomib and isatuximab (days 1, 2, 8, 9, 15, and 16; days 22 and 23 during cycles 1-2 only).

Drug: Carfilzomib; Drug: Isatuximab; Drug: Lenalidomide; Drug: Dexamethasone

Maintenance-High Risk

EXPERIMENTAL

Only patients that have achieved a partial response (PR) or better after induction therapy with or without stem cell transplant will continue on to maintenance therapy. The treatment participants will receive for maintenance will be based on the biological features (or cytogenetics) of participants myeloma and categorized into two groups: Standard-risk and High Risk. High Risk: subjects with high risk cytogenetics (deletion (del 17, translocation (t)(4:14), t(14;16), t(14;20), 1q duplications) will receive the following study treatment for up to two years (24 28-day cycles) until progressive disease (PD) or unacceptable toxicity: Lenalidomide 10 mg orally (PO) Day 1-21 Carfilzomib 56 mg/m2 or last tolerated dose IV Days 1, 15 Isatuximab 10 mg/kg IV Day 1

Drug: Carfilzomib; Drug: Isatuximab; Drug: Lenalidomide; Drug: Dexamethasone

Maintenance- Standard Risk

EXPERIMENTAL

Only patients that have achieved a partial response (PR) or better after induction therapy with or without stem cell transplant will continue on to maintenance therapy. The treatment participants will receive for maintenance will be based on the biological features (or cytogenetics) of participants myeloma and categorized into two groups: Standard-risk and High Risk. Standard Risk: subjects without high risk cytogenetics (deletion (del 17, translocation (t)(4:14), t(14;16), t(14;20), 1q duplications) will receive the following study treatment for up to two years (24 28-day cycles) until progressive disease (PD) or unacceptable toxicity: \- Lenalidomide 10 mg orally (PO) Day 1-21

Drug: Lenalidomide

Interventions

Carfilzomib DRUG

* Induction: protocol determine dose,via IV on 3 days per cycle up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination * Maintenance: protocol determine dose,via IV on 2 days per cycle- Maintenance Cycle until progressive disease (PD) or unacceptable toxicity

Also known as: Kyprolis

Induction; Maintenance-High Risk

Isatuximab DRUG

* Induction: At predetermined dose, via IV up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination: \-- Cycles 1 and 2 once per week, Cycles 3-4 every other week, Cycles 5 and 6 every other week, Cycles 7 and 8 once every 4 weeks. * Maintenance: At predetermined dose, via IV, once per cycle, Maintenance Cycle until progressive disease (PD) or unacceptable toxicity

Also known as: Sarclisa

Induction; Maintenance-High Risk

Lenalidomide DRUG

\- Induction Predetermined Dose, oral, days 1-21 of up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: At predetermined dose, oral days 1-21 per cycle until progressive disease (PD) or unacceptable toxicity

Also known as: REVLIMID

Induction; Maintenance- Standard Risk; Maintenance-High Risk

Dexamethasone DRUG

Induction: Predetermined dosage, oral, Predetermined times per cycle up to 8 cycles dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: orally or IV will be administered as a preinfusion medication prior to isatuximab dosing

Also known as: Decadron

Induction; Maintenance-High Risk

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject must be at least 18 years of age.
• Subject must have documented multiple myeloma satisfying the CRAB criteria and measurable disease defined as:
• Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy-proven Plasmacytoma.
• Measurable disease as defined by any of the following:
• IgG myeloma: Serum monoclonal paraprotein (M-protein) level ≥.5 g/dL or urine M-protein level ≥200 mg/24 hours; or
• IgA, IgM, or IgD multiple myeloma: serum M-protein level ≥0.25 g/dL or urine M-protein level ≥200 mg/24 hours; or
• Light chain multiple myeloma: Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.
• Sixty percent or greater clonal plasma cells on bone marrow examination.
• Serum involved / uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved free light chain is at least 100 mg/L (a patient's "involved" free light chain - either kappa or lambda - is the one that is above the normal reference range; the uninvolved light chain is the one that typically is in, or below, the normal range).
• More than one focal lesion on magnetic resonance image (MRI) that is at least 5 mm or greater in size.
• Newly diagnosed and considered candidate for high-dose chemotherapy with stem cell transplant.
• Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.
• Subject must have pretreatment clinical laboratory values meeting the following criteria during the Screening Phase:
• hemoglobin ≥ 7.5 g/dL (≥ mmol/L; prior RBC transfusion or recombinant human erythropoietin use is permitted);
• absolute neutrophil count ≥1.0 x 109/L (granulocyte colony stimulating factor \[GCSF\] use is permitted);

You may not qualify if:

• Any potential subject who meets any of the following criteria will be excluded from participating in the study.
• Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma. Monoclonal gammopathy of undetermined significance is defined by presence of serum M-protein \<3 g/dL; absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the M-protein; and (if determined) proportion of plasma cells in the bone marrow of 10% or less. Smoldering multiple myeloma is defined as asymptomatic MM with absence of related organ or tissue impairment end organ damage.
• Subject has a diagnosis of Waldenström's disease, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions
• Subject has prior or current systemic therapy or SCT for MM, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment.
• Subject has a history of malignancy (other than MM) within 5 years before the date of enrollment (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 5 years).
• Subject has had radiation therapy within 14 days of enrollment.
• Subject has had plasmapheresis within 28 days of enrollment.
• Subject is exhibiting clinical signs of meningeal involvement of MM.
• Subject has known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume \[FEV\] in 1 second \<60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years (intermittent asthma is allowed). Subjects with known or suspected COPD or asthma must have a FEV1 test during screening.
• Subject is known to be seropositive for history of human immunodeficiency virus (HIV) or known to have active hepatitis B or hepatitis C.
• Subject has any concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.
• Subject has clinically significant cardiac disease, including:
• myocardial infarction within 1 year before enrollment, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV;
• uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] Version 4 Grade ≥2) or clinically significant ECG abnormalities;
• screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) \>470 msec.

Sponsors & Collaborators

• Amgen: collaborator
• Sanofi: collaborator
• Massachusetts General Hospital: lead

Study Sites (3)

Massachusetts General Hospital

Boston, Massachusetts, 02115, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• O'Donnell E, Mo C, Yee AJ, Nadeem O, Laubach J, Rosenblatt J, Munshi N, Midha S, Cirstea D, Chrysafi P, Horick N, Richardson PG, Raje N. Isatuximab, carfilzomib, lenalidomide, and dexamethasone in patients with newly diagnosed, transplantation-eligible multiple myeloma (SKylaRk): a single-arm, phase 2 trial. Lancet Haematol. 2024 Jun;11(6):e415-e424. doi: 10.1016/S2352-3026(24)00070-X. Epub 2024 Apr 24.

  PMID: 38677302 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

carfilzomib; isatuximab; Lenalidomide; Dexamethasone; Calcium Dobesilate

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; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Limitations and Caveats

Results up to cycle 6/8 of KRDI are currently available and entered in CT.gov, including the primary endpoint and secondary endpoints that can be reported at this time. Data after the beginning of maintenance therapy (post-cycle 6 for patients who had stem cell transplants, and post-cycle 8 for patients who deferred stem cell transplant), including adverse event data, is still being collected and analyzed as of August 2023.

Results Point of Contact

• Title: Elizabeth K. O'Donnell, MD
• Organization: Dana-Farber Cancer Institute

Elizabeth_ODonnell@DFCI.HARVARD.EDU

617-632-3000

Study Officials

• Elizabeth O'Donnell, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 11, 2020
• First Posted: June 12, 2020
• Study Start: July 10, 2020
• Primary Completion: July 30, 2022
• Study Completion: March 30, 2026
• Last Updated: January 29, 2026
• Results First Posted: October 26, 2023

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: MGH - Contact the Partners Innovations team at http://www.partners.org/innovation

Locations

US (3)