Phase 2 Study With Minimal Residual Disease (MRD) Driven Adaptive Strategy in Treatment for Newly Diagnosed Multiple Myeloma (MM) With Upfront Daratumumab-based Therapy

NCT04140162 | Active Not Recruiting Phase 2 FDA Drug

• 2 other identifiers: UMCC 2018.056HUM00147751
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 4

Brief Summary

This phase 2 trial will test whether the combination of DaraRd (daratumumab + lenalidomide + dexamethasone) as induction therapy, followed by DRVd (daratumumab + lenalidomide + bortezomib + dexamethasone) consolidation therapy, if needed, will result in more patients achieving minimal residual disease (MRD)-negative status, relative to the standard of care. Consolidation therapy will be administered only to those patients with MRD-positive status after induction therapy. This is a study based on adaptive design for decision making of treatment options. Duration of therapy (daratumumab cycles) will depend on individual approach, response, evidence of disease progression and tolerance.

Conditions

Multiple Myeloma

Keywords

Dara-R; DaraRd; Dara-RVd; MRD

Outcome Measures

Primary Outcomes (1)

• Proportion of participants who achieve MRD negativity either after induction or, if still MRD-positive after induction, after consolidation.

  Of participants who complete at least one cycle of induction therapy, proportion that achieve MRD-negativity after completion of induction + those who achieve MRD-negativity after completion of consolidation (if still MRD-positive after induction). MRD status determined by International Myeloma Working Group (IMWG) Response Criteria.

  At the end of week 36 (post-consolidation therapy)

Secondary Outcomes (10)

• Overall Survival (OS)

  Up to 3 years after start of study treatment

• Progression-free Survival (PFS)

  Up to 3 years after start of study treatment

• Proportion of participants who were MRD-positive after induction and subsequently achieve MRD-negative after consolidation.

  At the end of week 36 (post-consolidation therapy)

• Proportion of participants who maintain post-induction MRD-negativity to post-consolidation

  At the end of week 36 (post-consolidation therapy)

• Proportion of participants who maintain post-induction MRD-negativity to post-consolidation.

  At the end of week 88 (post 1 year of maintenance therapy)

Study Arms (1)

Dara-Rd followed by Dara-RVd

EXPERIMENTAL

* Induction regimen with Daratumumab, Lenalidomide and Dexamethasone (Dara-Rd) in all study subjects, weeks 1-24 * Consolidation regimen with Daratumumab, Lenalidomide, Bortezomib and Dexamethasone (Dara-RVd) in post-induction MRD+ population, weeks 25-36 * Maintenance regimen with Daratumumab and Lenalidomide (Dara-R) in all study subjects, weeks 37-88 * Maintenance regimen with lenalidomide (R) until progression or intolerance

Drug: Daratumumab; Drug: Lenalidomide; Drug: Bortezomib; Drug: Dexamethasone

Interventions

Daratumumab DRUG

Induction: 16 mg/kg actual body weight IV weekly (weeks 1-8; total of 8 doses) then every 2 weeks (weeks 9-24; total of 8 doses). Consolidation: 16 mg/kg actual body weight IV every four weeks (weeks 25-36) Maintenance: 16 mg/kg actual body weight IV every eight weeks (weeks 37-88) Sites will continue to use IV daratumumab to treat existing study patients until the IV daratumumab stock on site has been exhausted. The sites will then transition existing patient to SQ daratumumab. New patients will be started on SQ 1800mg daratumumab. Induction- Cycles 1-2 (days 1, 8,15, 22), Cycles 3-6 (Weeks 9-24- two weeks (days 1, 15 ) Consolidation- Every 4 weeks on day 1 Maintenance- Every 8 weeks on day 1

Dara-Rd followed by Dara-RVd

Lenalidomide DRUG

Induction: 25 mg PO once daily, on days 1-21 of each 28-day cycle (weeks 1-24) Consolidation: 25 mg PO once daily, on days 1-21 of each 28-day cycle (weeks 25-36) Maintenance: 10 mg PO once daily, on days 1-21 of each 28-day cycle until progression or intolerance Maintenance: 10 mg PO once daily, on days 1-21, weeks 37+ until progression

Dara-Rd followed by Dara-RVd

Bortezomib DRUG

Consolidation: 1.5 mg/m2 SQ on day 1, 8, 15 and 22 of each 28-day cycle (weeks 25-36)

Dara-Rd followed by Dara-RVd

Dexamethasone DRUG

Induction and Consolidation: 40 mg (or reduced dose of 20 mg) PO or IV weekly

Dara-Rd followed by Dara-RVd

Eligibility Criteria

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

You may qualify if:

• Participants ≥18 years of age or legal age of consent per local regulations (whichever is greater).
• Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
• ECOG status (Appendix A) of ≤2 and able to tolerate all applicable treatments per investigator's evaluation and standard institutional criteria.
• Both transplant eligible and ineligible myeloma patients can be included in this study. If applicable, participant should be able to tolerate all treatments per investigator's evaluation, including high-dose chemotherapy and autologous stem cell transplant (ASCT) based on standard criteria at the institution where this treatment will be administered.
• Participant must have a diagnosis of active MM according to International Myeloma Working Group (IMWG) diagnostic criteria.
• Participant must also have measurable disease per protocol.
• Baseline bone marrow or tissue sample available for Clonality ID in ClonoSEQ
• Participant must be registered in and must comply with all requirements of REMSTM program for lenalidomide.
• Female participant who:
• Is post-menopausal for at least one year prior to study enrollment, OR
• Is surgically sterile, OR
• If of childbearing potential, must have a negative urine or serum pregnancy test within 10-14 days prior to and again within 24 hours of starting lenalidomide. They must also be willing to use TWO effective forms of contraception simultaneously from the time of signing the study consent until 90 days following the administration of the last dose of lenalidomide and 7 months following the administration of the last dose of bortezomib, OR
• Agree to practice complete abstinence if that is aligned with their lifestyle, which does not include periodic abstinence or withdrawal.
• Male participant, even if surgically sterilized, must agree to one of the following:
• Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of lenalidomide and 4 months following the administration of the last dose of bortezomib, OR

You may not qualify if:

• Diagnoses of smoldering MM (SMM), monoclonal gammopathy of undetermined significance (MGUS), non-secretory MM, plasma cell leukemia, AL amyloidosis, Waldenstrom's. macroglobulinemia, POEMS syndrome. History of SMM and/or MGUS is not excluded.
• Known disease involvement of the CNS.
• History of prior hematopoietic stem cell transplant of any type.
• Received more than one cycle of anti-myeloma therapy prior to enrollment. Up to one cycle of myeloma therapy is allowed. Concomitant treatment is allowed with low-dose corticosteroids and bisphosphonates. The dose of corticosteroids for myeloma treatment should not exceed the equivalent of 160 mg of dexamethasone over a two-week period before initiation of protocol. Prednisone up to but no more than 10 mg po daily or its equivalent is allowed, for symptom management and comorbid conditions.
• Significant renal insufficiency, defined as creatinine clearance \<30ml/min per Cockcroft-Gault formula.
• Hepatic impairment, defined as bilirubin \>1.5 x institutional upper limit of normal (ULN) or AST (SGOT), ALT (SGPT), or alkaline phosphatase \> 3x institutional ULN.
• Absolute neutrophil count (ANC) \< 1000 cells/mm3 within 14 days of enrollment. Growth factor may not be used to meet ANC eligibility criteria.
• Hemoglobin (Hgb) \< 8g/dL within 7 days of enrollment.
• Platelet count \< 75,000 cells/mm3 within 7 days of enrollment. Transfusion may not be used to meet platelet eligibility criteria.
• Any condition, including laboratory abnormalities, that in the opinion of the investigator places the subject at unacceptable risk if subject were to participate in the study.
• Major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from complications of the surgery.
• Clinically significant peripheral neuropathy not well controlled with treatment, defined as symptoms limiting activities of daily living (basic ADLs).
• Symptomatic uncontrolled cardiac disease including congestive heart failure with New York Heart Association class III-IV symptoms, arrhythmia, unstable angina or myocardial infarction within the past six months, or any other uncontrolled or severe cardiovascular condition.
• Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) \<50% of predicted normal.
• Clinically uncontrolled asthma of any classification or known moderate or severe persistent asthma within the past two years (see asthma guidelines. https://www.nhlbi.nih.gov/files/docs/guidelines/asthma\_qrg.pdf).

Sponsors & Collaborators

• University of Michigan Rogel Cancer Center: lead
• Janssen Scientific Affairs, LLC: collaborator

Study Sites (4)

University of Michigan Rogel Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

University of Rochester

Rochester, New York, 14642, United States

Location

University of Texas Southwestern -- Simmons Comprehensive Cancer Center

Dallas, Texas, 75390, United States

Location

Related Publications (2)

• Mohan M, Gundarlapalli S, Szabo A, Yarlagadda N, Kakadia S, Konda M, Jillella A, Fnu A, Ogunsesan Y, Yarlagadda L, Thalambedu N, Munawar H, Graziutti M, Al Hadidi S, Alapat D, Thanendrarajan S, Zangari M, van Rhee F, Schinke C. Tandem autologous stem cell transplantation in patients with persistent bone marrow minimal residual disease after first transplantation in multiple myeloma. Am J Hematol. 2022 Jun 1;97(6):E195-E198. doi: 10.1002/ajh.26530. Epub 2022 Mar 21. No abstract available.

  PMID: 35285981 DERIVED

• Mohan M, Hari P, Szabo A, Dhakal B, Chhabra S, D'Souza A. Long term follow up of newly diagnosed multiple myeloma patients treated with pembrolizumab consolidation post-autologous stem cell transplantation. Leuk Res. 2021 Oct;109:106648. doi: 10.1016/j.leukres.2021.106648. Epub 2021 Jun 23. No abstract available.

  PMID: 34182226 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

daratumumab; Lenalidomide; Bortezomib; 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; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Pyrazines; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Jing Ye, M.D.

  MD Anderson

  STUDY DIRECTOR

Study Design

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

Study Record Dates

• First Submitted: October 21, 2019
• First Posted: October 25, 2019
• Study Start: October 5, 2020
• Primary Completion: May 2, 2024
• Study Completion: May 2, 2026
• Last Updated: October 9, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)