Combination Treatment Therapy Approaches for the Treatment of High-Risk Multiple Myeloma, REACH Trial

REsponse Adapted Combination Therapy Approaches for High-Risk Multiple Myeloma (REACH)

This phase II trial test whether combination chemotherapy works to improve blood test results in patients with high-risk multiple myeloma. Chemotherapy drugs, such as carfilzomib, daratumumab, lenalidomide, and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This trial may help determine if patients who have a small amount of cancer left after the initial treatment, called minimal residual disease, will benefit from the drug combination.

Study Overview

• Status: Active, not recruiting
• Conditions: Multiple Myeloma; ISS Stage III Plasma Cell Myeloma
• Intervention / Treatment: Procedure: Magnetic Resonance Imaging; Procedure: Biospecimen Collection; Drug: Lenalidomide; Procedure: Echocardiography; Procedure: Bone Marrow Aspiration and Biopsy; Procedure: Positron Emission Tomography; Drug: Carfilzomib; Procedure: Chest Radiography; Biological: Daratumumab; Drug: Dexamethasone; Procedure: Multigated Acquisition Scan; Procedure: Computed Tomography

Detailed Description

PRIMARY OBJECTIVE:

I. To estimate the rate of sustained minimal residual disease (MRD) negativity (MRD negative status at any point, with a repeated MRD negative status one year later) in subjects with high-risk multiple myeloma.

SECONDARY OBJECTIVES:

I. To describe the toxicities associated with this treatment approach in subjects with high-risk multiple myeloma (MM).

II. To estimate the overall response rate, very good partial response (VGPR) or better rate and complete response (CR) rate at the end of induction, end of consolidation, end of maintenance and at two years after the completion of treatment.

III. To estimate the progression-free survival and overall survival rate.

CORRELATIVE RESEARCH OBJECTIVES:

I. To describe the clonal architecture through a combination of genomic, epigenomic, proteomic and metabolomic studies before and after treatment, in subjects with high-risk MM.

II. To describe the bone marrow microenvironment through various stages of treatment and the time of MRD negative state and at time of relapse.

OUTLINE:

INDUCTION: Patients receive carfilzomib intravenously (IV) on days 1, 2, 8, and 15 of cycle 1 and days 1, 8, and 15 of cycles 2-12, lenalidomide orally (PO) days 1-21 of each cycle, daratumumab subcutaneously (SC) days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 of cycles 3-6, and day 1 of subsequent cycles, and dexamethasone PO or IV on days 1, 8, 15, and 22 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients receive carfilzomib IV on days 1, 8, and 15, lenalidomide PO days 1-21, daratumumab SC day 1 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive carfilzomib IV on day 1, lenalidomide PO days 1-21, daratumumab SC day 1 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

Additionally, patients undergo bone marrow aspirate and biopsy, blood sample collection, echocardiography (ECHO) or multigated acquisition (MUGA) scan, and magnetic resonance imaging (MRI), computed tomography (CT), or positron emission tomography (PET)/CT throughout the study. Patients also undergo chest radiography (x-ray) during screening.

After completion of study treatment, patients are followed up every 6 months for up to 10 years.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Arizona
  • Florida
    • Jacksonville, Florida, United States, 32224-9980
      • Mayo Clinic
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• PRE-REGISTRATION-INCLUSION CRITERIA:
• Age >= 18 years and =< 80 years.
• Patient must have suspected or confirmed newly diagnosed multiple myeloma by International Myeloma Working Group (IMWG) criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
• Provide informed written consent.
• Willing to return to enrolling institution for follow-up during the active treatment phase of the trial.
• Willing to provide blood and bone marrow samples for planned research.
• Life expectancy > 6 months.

• Able to take aspirin (325 mg) daily as prophylactic anticoagulation.

  • Note: subjects intolerant to aspirin may use warfarin, novel oral anticoagulants, or low dose molecular weight heparin.
• Patients must have monoclonal protein studies (serum free light chain assay, serum immunofixation or serum matrix-assisted laser desorption ionization time-of-flight mass-spectrometry [MASS-FIX]) at time of diagnosis before induction therapy initiated and available for review to be enrolled. Note: Patients are allowed to participate in this study if urine electrophoresis immunofixation study was not done at time of diagnosis or cannot be obtained
• REGISTRATION-INCLUSION CRITERIA:

• High risk myeloma, which is untreated, defined as any two of:

  • Beta-2 microglobulin >5.5
  • Gain or amplification of chr1q
  • del17p or monosomy 17 or TP53 mutation (if known)
  • t(4;14) or t(14;16)
  • >= 5% circulating plasma cells
  • presence of extramedullary disease (does not include bone contiguous disease)
• Creatinine clearance >= 30 mL/min (using Cockroft-Gault equation) (obtained =< 14 days prior to registration).
• Absolute neutrophil count (ANC) >= 1000/mm^3 (without the use of growth factors) (obtained =< 14 days prior to registration).
• Platelet count >= 75000/mm^3 (obtained =< 14 days prior to registration).
• Hemoglobin >= 8.0 g/dL.
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 14 days prior to registration).
• Alanine transaminase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (obtained =< 14 days prior to registration).
• Registration must be completed =< 30 days after pre-registration.
• Patients must not have received more than one cycle of treatment between pre-registration and registration.
• All 4 drugs in the study regimen approved by insurance.
• Left ventricular ejection fraction (LVEF) >= 40% =< 30 days prior to pre-registration

Exclusion Criteria:

• PRE-REGISTRATION EXCLUSION:
• Monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, light chain amyloidosis with organ involvement.

• Diagnosed or treated for another malignancy =< 1 year prior to pre- registration or previously diagnosed with another malignancy and have any evidence of residual disease.

  • NOTE: Subjects with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
• Other co-morbidity which would interfere with subject's ability to participate in trial, e.g. uncontrolled infection, uncompensated heart or lung disease.

• Other concurrent chemotherapy, or any ancillary therapy considered investigational. NOTE: Concurrent chemotherapy is any treatment not related to multiple myeloma.

  • NOTE: Concurrent chemotherapy is any treatment not related to multiple myeloma
  • NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment.
• Peripheral neuropathy >= grade 3 on clinical examination or grade 2 with pain =< 30 days prior to registration.
• Major surgery =< 14 days prior to pre-registration.
• Any medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
• Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or investigator's brochure) or known sensitivity to mammalian-derived products. Known allergies, hypersensitivity, or intolerance to trial drugs.
• Inability to comply with protocol/procedures.
• Received prior treatment for multiple myeloma prior to pre-registration. Note: results can still be pending as long as the tests have been performed
• REGISTRATION-EXCLUSION CRITERIA:

• If any of the following exist at screening, subject will not be eligible for trial because this trial involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:

  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception (per protocol).

• Evidence of current uncontrolled cardiovascular conditions, including hypertension, cardiac arrhythmias, congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.

  • Note: Prior to trial entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevant.
• New York Heart Association (NYHA) II, III, IV heart failure.
• Known human immunodeficiency virus (HIV) positive.

• Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded.

  • EXCEPTION: subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
• Known or suspected active hepatitis C infection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (combination chemotherapy); INDUCTION: Patients receive carfilzomib IV on days 2, 8, and 15 of cycle 1 and days 1, 8, and 15 of cycles 2-12, lenalidomide PO days 1-21 of each cycle, daratumumab SC days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 of cycles 3-6, and day 1 of subsequent cycles, and dexamethasone PO or IV on days 1, 8, 15, and 22 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive carfilzomib IV on days 1, 8, and 15, lenalidomide PO days 1-21, daratumumab SC day 1 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive carfilzomib IV on day 1, lenalidomide PO days 1-21, daratumumab day 1 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and biopsy, MRI and, CT/PET.

Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Drug: Lenalidomide; Given PO; Other Names: CC-5013; Revlimid; CC5013; CDC 501; Procedure: Echocardiography; Undergo ECHO; Other Names: EC; Procedure: Bone Marrow Aspiration and Biopsy; Undergo bone marrow aspiration and biopsy; Procedure: Positron Emission Tomography; Undergo PET/CT; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; proton magnetic resonance spectroscopic imaging; Drug: Carfilzomib; Given IV; Other Names: Kyprolis; PR-171; Procedure: Chest Radiography; Undergo chest x-ray; Other Names: chest x-ray; Biological: Daratumumab; Given SC; Other Names: Darzalex; HuMax-CD38; JNJ-54767414; Daratumumab Biosimilar HLX15; Daratumumab-fihj; Drug: Dexamethasone; Given IV/PO; Other Names: Decadron; Hemady; Aacidexam; Adexone; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Amplidermis; Anemul mono; Auricularum; Auxiloson; Baycadron; Baycuten; Baycuten N; Cortidexason; Cortisumman; Decacort; Decadrol; Decadron DP; Decalix; Decameth; Decasone R.p.; Dectancyl; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasone Intensol; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Dinormon; Dxevo; Fluorodelta; Fortecortin; Gammacorten; Hexadecadrol; Hexadrol; Lokalison-F; Loverine; Methylfluorprednisolone; Millicorten; Mymethasone; Orgadrone; Spersadex; TaperDex; Visumetazone; ZoDex; Procedure: Multigated Acquisition Scan; Undergo MUGA scan; Other Names: Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; MUGA; RNVG; SYMA Scanning; Synchronized Multigated Acquisition Scanning; MUGA Scan; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Gated Heart Pool Scan; Radionuclide ventriculography; Procedure: Computed Tomography; Undergo CT or PET/CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of sustained minimal residual disease (MRD) negativity	MRD negative status at any point, with a repeated MRD negative status one year later. All subjects meeting the eligibility criteria who have signed a consent form and have begun treatment will be evaluable, with the exception of subjects determined to be a major violation.	At 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	Adverse Events: All eligible subjects that have initiated treatment will be considered evaluable for assessing adverse event rate(s). The maximum grade for each type of adverse event will be recorded for each subject, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the trial treatment will be taken into consideration. AEs will be summarized overall, as well as by treatment phase (induction, consolidation, maintenance with carfilzomib and lenalidomide and daratumumab).	Up to 30 days after administration of study therapy
Overall response rate [>= confirmed very good partial response (VGPR)]	Exact binomial 95% confidence intervals for the true response proportion at each time point will be calculated.	End of induction, end of consolidation, and every 3 cycles of maintenance, up to two years or 24. One cycle is 28 days.
Overall survival	Defined as the time from registration to death due to any cause. The distribution of overall survival will be estimated using the method of Kaplan-Meier.	Up to 3 years
Progression-free survival	Defined as the time from registration to the earliest date of documentation of disease progression or death due to any cause. The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.	Up to 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clonal architecture before treatment	To determine the clonal architecture before treatment, after treatment in subjects with residual disease and in subjects who have disease progression after attaining MRD negativity.	Before and after treatment, up to two years or 24 months
Bone marrow microenvironment	To evaluate the bone marrow microenvironment before and after treatment and the time of MRD negative state.	Before and after treatment, up to two years or 24 months

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Shaji K. Kumar, MD, Mayo Clinic in Rochester

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): September 22, 2022
• Primary Completion (Actual): February 12, 2026
• Study Completion (Estimated): September 4, 2028

Study Registration Dates

• First Submitted: August 3, 2022
• First Submitted That Met QC Criteria: August 9, 2022
• First Posted (Actual): August 11, 2022

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 8, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Neoplasms, Plasma Cell; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Hemic and Lymphatic Diseases; Multiple Myeloma; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Hydrocarbons; Hydrocarbons, Cyclic; Physical Phenomena; Carboxylic Acids; Hydrocarbons, Aromatic; Polycyclic Compounds; Piperidines; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Benzene Derivatives; Diagnostic Techniques, Surgical; Chemistry Techniques, Analytical; Sulfonic Acids; Sulfur Acids; Spectrum Analysis; Pregnadienetriols; Electromagnetic Phenomena; Magnetic Phenomena; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Piperidones; Isoindoles; Electromagnetic Radiation; Radiation; Radiation, Ionizing; Benzenesulfonates; Arylsulfonates; Arylsulfonic Acids; Lenalidomide; Dexamethasone; Calcium Dobesilate; Biopsy; Specimen Handling; Magnetic Resonance Spectroscopy; carfilzomib; dexamethasone 21-phosphate; X-Rays; daratumumab; auricularum; dexamethasone acetate
• Other Study ID Numbers: MC210811 (Mayo Clinic in Rochester); P50CA186781 (U.S. NIH Grant/Contract); 22-002687 (Other Identifier: Mayo Clinic Institutional Review Board)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No