An Intensive Program With Quadruplet Induction and Consolidation Plus Tandem Autologous Stem Cell Transplantation in Newly Diagnosed High Risk Multiple Myeloma Patients

NCT03606577 | Active Not Recruiting Phase 2

• 1 other identifier: RC18_0206
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 12

Brief Summary

According to international guidelines, upfront therapy for transplant eligible myeloma patients should include triplet induction containing proteasome inhibitor and immunomodulatory agent, autologous stem cell transplant, PI+Imid based triplet consolidation and lenalidomide maintenance. Despite this approach, virtually all MM patients experience disease relapse, especially those with High Risk disease defined by adverse cytogenetic abnormalities (i.e. del(17p), or t(14;16) or t(4;14)) detected by FISH and/or SNP arrays. Indeed, HR myeloma is associated with poorer progression free survival and overall survival and frontline therapy should therefore be improved for this subset of HR patients. The primary objective of this prospective multicenter, open label, interventional phase 2 trial is to evaluate the feasibility of an intensive program including quadruplet induction and consolidation, tandem autologous stem cell transplantation and maintenance in newly diagnosed multiple myeloma patients presenting with HR cytogenetic. Quadruplet induction and consolidation include carfilzomib, lenalidomide, dexamethasone and daratumumab. Maintenance will include lenalidomide and daratumumab. Secondary objectives will include efficacy parameters (i.e. response rate, minimal residual disease, safety, progression free survival, overall survival).

Conditions

Multiple Myeloma

Keywords

Multiple Myeloma; Newly Diagnosed; High Risk; Revlimid; Carfilzomib; Daratumumab; Dexaméthasone

Outcome Measures

Primary Outcomes (1)

• Percentage of patients receiving the second Autologous Stem Cell Transplant

  15 months

Secondary Outcomes (9)

• Number of adverse events

  48 months

• Number of responses

  48 months

• Number of MRD

  48 months

• Number of death

  84 months

• Percentage of time to progression

  84 months

Study Arms (1)

Carfilzomib, Daratumumab, Lenalidomide and Dexaméthasone

EXPERIMENTAL

Drug: Carfilzomib; Drug: Daratumumab; Drug: Lenalidomide; Drug: Dexamethasone

Interventions

Carfilzomib DRUG

Induction 6 cycles 20/36 mg/m² on days 1, 2, 8, 9, 15, 16 (20 mg/m² on D1 and 2 cycle 1 only) Consolidation 4 cycles Carfilzomib 20 or 36 mg/m² on days 1, 2, 8, 9, 15, 16 (20 mg/m² on D1 and 2 first cycle only)

Carfilzomib, Daratumumab, Lenalidomide and Dexaméthasone

Daratumumab DRUG

induction: 6 cycles Daratumumab 8/16mg/kg IV on Days 1, 8, 15, 22 for the first two cycle 2 and on days 1 and 15 for cycles 3 to 6. (8mg/kg on D1 \& D2 cycle 1 only) Consolidation: daratumumab 4 cycles 16mg/kg IV Day 1, Day 15 Maintenance Daratumumab 16mg/kg IV once every 8 weeks for 2 years (or until documented disease progression)

Carfilzomib, Daratumumab, Lenalidomide and Dexaméthasone

Lenalidomide DRUG

induction: 6 cycles Lenalidomide 25 mg/day from day 1 to day 21 Consolidation: 4 cycles 15 mg/day from Day 1 to Day 21 (first cycle ) 25 mg/day from Day 1 to Day 21 (in the following cycle) Maintenance therapy 10mg/day, Day 1 to 21, for 2 years (or until documented disease progression)

Carfilzomib, Daratumumab, Lenalidomide and Dexaméthasone

Dexamethasone DRUG

induction 6 cycles 20 mg/day on days 1-2, 8-9, 15-16 and 22-23 Consolidation 4 cycles 40 mg/Day on Days 1, 8, 15 and 22

Carfilzomib, Daratumumab, Lenalidomide and Dexaméthasone

Eligibility Criteria

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

You may qualify if:

• Male or female subjects, 18 years of age or older, younger than 66 years (\< 66 years)
• Voluntary written informed consent must be given before performance of any study-related procedure not part of normal medical care, with the understanding that the subject may withdraw consent at any time without prejudice to future medical care.
• Subject must have documented multiple myeloma satisfying the Diagnostic criteria for symptomatic Myelome Multiple and measurable disease as defined by:
• Monoclonal plasma cells in the bone marrow ≥ 10% or presence of a biopsy proven plasmacytoma AND any one or more of the following myeloma defining events:
• Hypercalcemia: serum calcium \> 0.25 mmol/L higher than ULN or \> 2.75 mmol/L
• Renal insufficiency: creatinine clearance \< 40mL/min or serum creatinine \> 177 μmol/L
• 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 Or in a patient with indolent myeloma
• Clonal bone marrow plasma cell percentage ≥ 60%
• Involved: uninvolved serum free light chain ratio ≥ 100
• Superior 1 focal lesion on MRI studies
• Measurable disease as defined by the following:
• M-component ≥ 5g/l, and/or urine M-component ≥ 200 mg/24h and/or serum Free Light Chain ≥ 100 mg/l.
• Newly diagnosed subjects eligible for high dose therapy and autologous stem cell transplantation
• Subject must have high risk disease according to FISH analysis: del(17p), or t(14;16) or t(4;14). The FISH-positivity cut-off value for defining the presence of del(17p) in this study is 50%

You may not qualify if:

• Subjects must not have been treated previously with any systemic therapy for multiple myeloma. Prior treatment with corticosteroids or radiation therapy does not disqualify the subject (the maximum dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone in a 2-week period). Two weeks must have elapsed since the date of the last radiotherapy treatment. Enrolment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 2 weeks have elapsed since the last date of therapy
• Subject has received daratumumab or other anti-CD38 therapies previously
• Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or solitary plasmacytoma.
• Subject has a diagnosis of Waldenström's macroglobulinemia, 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 had plasmapheresis within 28 days of C1D1.
• Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.
• Myocardial infarction within 6 months prior to enrolment according to NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
• Uncontrolled hypertension
• Subjects with known chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume (FEV1) in 1 second \< 50% of predicted normal. Note that FEV1 testing is required for patients suspected of having COPD and subjects must be excluded if FEV1 \< 50% of predicted normal.
• Subjects with a history of moderate or severe persistent asthma within the past 2 years, or with uncontrolled asthma of any classification at the time of screening (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
• Subject has plasma cell leukemia (according to WHO criterion: ≥ 20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 10\^9/L) or polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes syndrome.
• Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong inhibitors of CYP3A (as clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (as rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, fosphenytoin phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days before the first dose of study treatment.
• Known intolerance to steroid therapy
• History of hypersensitivity to any of the study medications, their analogues, or excipients in the various formulations, or to study-required co medication
• Subject has had major surgery within 2 weeks before the first dose of study treatment or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study. Kyphoplasty or Vertebroplasty are not considered major surgery.

Sponsors & Collaborators

• Nantes University Hospital: lead

Study Sites (12)

CHU de Nantes

Nantes, Pays de la Loire Region, 44000, France

Location

CHU Caen

Caen, France

Location

CHRU Dijon

Dijon, France

Location

CHRU - Hôpital A.Michallon

Grenoble, France

Location

CHD Vendée

La Roche-sur-Yon, France

Location

CHRU - Hôpital Claude Huriez

Lille, France

Location

CH de Lyon Sud

Lyon, France

Location

CHRU Hôpital du Haut Lévêque

Pessac, France

Location

CHRU - Hôpital de Pontchaillou

Rennes, France

Location

CHU Toulouse

Toulouse, France

Location

CHRU Bretonneau

Tours, France

Location

CHRU - Hôpitaux de Brabois

Vandœuvre-lès-Nancy, France

Location

Related Publications (2)

• Touzeau C, Perrot A, Hulin C, Manier S, Macro M, Chretien ML, Karlin L, Escoffre M, Jacquet C, Tiab M, Leleu X, Avet-Loiseau H, Jobert A, Planche L, Corre J, Moreau P. Daratumumab, carfilzomib, lenalidomide, and dexamethasone with tandem transplant for high-risk newly diagnosed myeloma. Blood. 2024 May 16;143(20):2029-2036. doi: 10.1182/blood.2023023597.

  PMID: 38394666 DERIVED

• Pawlyn C. High-risk myeloma: a challenge to define and to determine the optimal treatment. Lancet Haematol. 2021 Jan;8(1):e4-e6. doi: 10.1016/S2352-3026(20)30361-6. Epub 2020 Dec 22. No abstract available.

  PMID: 33357481 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

carfilzomib; daratumumab; 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 Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: One group of subjects who must have documented Multiple Myeloma High Risk satisfying the CRAB and measurable disease.

Study Record Dates

• First Submitted: July 20, 2018
• First Posted: July 31, 2018
• Study Start: July 30, 2019
• Primary Completion: February 8, 2022
• Study Completion (Estimated): November 8, 2027
• Last Updated: April 28, 2021

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share

Locations

FR (12)