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The Relapse From MRD Negativity as Indication for Treatment (REMNANT) Study

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ClinicalTrials.gov Identifier: NCT04513639
Recruitment Status : Recruiting
First Posted : August 14, 2020
Last Update Posted : June 18, 2021
Sponsor:
Collaborators:
St. Olavs Hospital
Haukeland University Hospital
University Hospital of North Norway
University Hospital, Akershus
Helse Stavanger HF
Førde Central Hospital
Sorlandet Hospital HF
Nordlandssykehuset HF
The Hospital of Vestfold
Levanger Hospital
Alesund Hospital
Sykehuset Ostfold
Information provided by (Responsible Party):
Fredrik Hellem Schjesvold, Oslo University Hospital

Brief Summary:
The REMNANT study will evaluate whether treating minimal residual disease (MRD) relapse after first line treatment prolongs progression free survival and overall survival for myeloma patients versus treating relapse after first line treatment at progressive disease. To establish a homogenous group of MRD negative patients after first line treatment including autologous stem cell transplantation, patients are enrolled at diagnosis and treated with Norwegian standard of care first line treatment. MRD negative patients will move on to the randomized part.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Early treatment of relapse with carfilzomib, dexamethasone, daratumumab Drug: Standard treatment of relapse with carfilzomib, dexamethasone, daratumumab Phase 2 Phase 3

Detailed Description:
391 patients with newly diagnosed multiple myeloma eligible for high dose therapy with autologous stem cell support will be included in the phase II part of the study and receive standard of care first line treatment according to Norwegian national guidelines; bortezomib- lenalidomide - dexamethasone for 4 pre-transplant induction and 4 post-transplant consolidation cycles (all 21-d cycles). After induction patients will undergo tandem or single ASCT, depending on toxicity and response to first ASCT. The primary endpoint of the phase 2 part of the study is the number of patients who achieve MRD negative (Euroflow NGF 10 -5 ) complete response 30-45 days post consolidation. Patients (176) achieving MRD negative complete response will be randomly assigned in a 1:1 ratio to receive second line treatment at MRD reappearance (arm A) or at progressive disease as defined by the IMWG criteria (arm B). Randomization will be stratified by R-ISS stage at diagnosis and single vs tandem ASCT. Patients in arm A will be followed with MRD assessment every 4 month and start second line treatment at loss of MRD negative CR. Patients in arm B will be followed up by standard criteria and start second line treatment at progressive disease. Both arms will receive the same 2.L treatment; carfilzomib - dexamethasone - daratumumab. (all 28-d cycles) Second line treatment will continue until disease progression, unacceptable AEs or patient withdrawal. In arm A MRD Euroflow will be assessed after 6 and 18 months of 2L therapy. In arm B MRD Euroflow will be assessed if >CR is achieved but not before 6 months of 2 L therapy, and again after 12 consecutive months.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 176 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Relapse From MRD Negativity as Indication for Treatment (REMNANT) Study
Actual Study Start Date : August 27, 2020
Estimated Primary Completion Date : June 1, 2030
Estimated Study Completion Date : June 1, 2031

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arm Intervention/treatment
Experimental: Arm A
Patients will be followed with MRD assessment every 4 month and start 2.L treatment at loss of MRD negative complete response.
Drug: Early treatment of relapse with carfilzomib, dexamethasone, daratumumab
Second line treatment will start at MRD reapperance
Other Name: DKd

Active Comparator: Arm B
Patients will be followed up by standard criteria and start 2.L treatment at progressive disease.
Drug: Standard treatment of relapse with carfilzomib, dexamethasone, daratumumab
Second line treatment will start at progressive disease
Other Name: DKd




Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: 10 years ]
    Median PFS of Arm A (MRD guided) vs Arm B (PD guided) defined as the time from randomization to disease progression or death due to any cause following 2.L treatment.

  2. Overall survival (OS) [ Time Frame: 11 years ]
    Median OS of Arm A vs Arm B (MRD guided) defined as the time from randomization to death of any cause following 2.L treatment.

  3. Minimal residual disease negativity after first line treatment [ Time Frame: 30-45 days post consolidation ]
    The number of participants who achieve MRD negativity measured by Euroflow NGF at 30-45 after consolidation therapy has ended


Secondary Outcome Measures :
  1. Time-to-next treatment [ Time Frame: 10 years ]
    Time from end of first line treatment to start of 3.L therapy

  2. Minimal residual disease negativity during second line treatment [ Time Frame: 6 months after starting second line treatment ]
    The proportion of patients who achieve MRD negativity during 2.L treatment, monitored by MRD Euroflow NGF at 6 and 18 months in arm A and after achieving CR in arm B (first MRD testing after 6 months).

  3. Health-related quality of life (HRQOL) [ Time Frame: 10 years ]
    Patient reported outcome HRQOL forms will be filled out by patients at defined time points during the study and finally at relapse after 2.L therapy.



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria part one:

  • Each patient must meet all of the following inclusion criteria to be enrolled in the study:

    1. Patient with newly diagnosed multiple myeloma (IMWG criteria) eligible for high-dose therapy and ASCT.
    2. Patient must be >18 and < 75 years of age at the time of signing the informed consent
    3. Must have measurable disease as defined by the International Myeloma Working Group; serum monoclonal paraprotein (M-protein) level > 10 g/L or light chain multiple myeloma without measurable disease in the serum; serum immunoglobulin FLC > 100 mg/L and abnormal serum immunoglobulin kappa lambda FLC ratio.
    4. Voluntary written informed consent
    5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2. ECOG 3 can be enrolled if caused by myeloma.
    6. Patient must be willing and able to adhere to the study protocol visit schedule and other protocol requirements.
    7. Female of childbearing potential (FCBP) must have a confirmed negative serum pregnancy test within 7 days prior to inclusion.
    8. FCBP and male subject who are sexually active with FCBP must agree to use highly effective concomitant methods of contraceptive during the study and for at least 28 days following the last study drug dose. Male subjects must use contraception and refrain from donating sperm for at least 28 days after the last dose of lenalidomide according to Pregnancy Prevention Plan (Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information).

      Inclusion Criteria part two:

  • Each patient must meet all of the following inclusion criteria to be enrolled in the study

    1. Patient must be MRD negative measured by Euroflow NGF after 1.L therapy. The cutoff for inclusion into part 2 will be 100 PC per 10 mill. nucleated cells monitored in BM.
    2. Has received 1.L treatment in part 1 of the study.
    3. ECOG performance status score 0, 1 or 2

Exclusion Criteria part one:

  1. Received more than one cycle of induction treatment for multiple myeloma.
  2. Patient with ongoing or active systemic infection, active hepatitis B or C virus infection or known human immunodeficiency virus (HIV) positive
  3. Concurrent medical or psychiatric condition or disease that is incompatible to HDM and ASCT or that will likely result in reduced study compliance and reduce ability to follow study procedures, or that in the opinion of the investigator, would constitute a hazard for participating in this study.
  4. No active malignancy with a lower life expectancy than myeloma
  5. Female patient who have a positive serum pregnancy test during the screening period.
  6. Female patient who is lactating during the screening period but are not willing to stop lactating prior to the first treatment cycle starts.
  7. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.

Exclusion Criteria part two:

  1. No active malignancy with a lower life expectancy than myeloma
  2. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04513639


Contacts
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Contact: Anne-Marie Rasmussen, PhD +4799791064 annemra55@gmail.com
Contact: Anna Lysen, MSC +4747246569 annaly@ous-hf.no

Locations
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Norway
Haukeland University Hospital Recruiting
Bergen, Norway
Contact: Tor-Henrik Tvedt, MD, PhD       tor.henrik.anderson.tvedt@helse-bergen.no   
Nordland Hospital Bodø Recruiting
Bodø, Norway
Contact: Randi F Halstensen, MD    +4775534000    randi.fykse.hallstensen@nordlandssykehuset.no   
Sykehuset Ostfold Recruiting
Fredrikstad, Norway
Contact: Birgitte D. Eiken, MD       birgitte.dahl.eiken@so-hf.no   
Førde Central Hospital Recruiting
Førde, Norway
Contact: Damian Szatkowski, MD    +4757839000    damian.szatkowski@helse-forde.no   
Sørlandet Hospital Kristiansand Recruiting
Kristiansand, Norway
Contact: Jurgen Rolke, MD    +4790610600    jurgen.rolke@sshf.no   
Levanger Hospital Recruiting
Levanger, Norway
Contact: Jon Hjalmar Sørbø, MD    +4774098000    jonhjalmar.sorbo@helse-nordtrondelag.no   
Akershus University Hospital Recruiting
Lørenskog, Norway
Contact: Anette L. Eilertsen, MD, PhD.       anette.loken.eilertsen@ahus.no   
Oslo University Hospital Recruiting
Oslo, Norway
Contact: Fredrik Schjesvold, MD, PhD       fredrikschjesvold@gmail.com   
Contact: Frida Askeland, MD       friask@ous-hf.no   
Helse Stavanger HF Recruiting
Stavanger, Norway
Contact: Einar Haukås, MD, PhD       einar.haukas@sus.no   
University Hospital North Norway Recruiting
Tromsø, Norway
Contact: Anders Vik, MD, PhD       Anders.Vik@unn.no   
St. Olavs Hospital Recruiting
Trondheim, Norway
Contact: Tobias Slørdahl, MD, PhD       Tobias.Schmidt.Slordahl@stolav.no   
The Hospital of Vestfold Recruiting
Tønsberg, Norway
Contact: Magnus Moksnes, MD       magmok@siv.no   
Ålesund Hospital Recruiting
Ålesund, Norway
Contact: Robert Brudevold, MD    +4740622848    robert.brudevold@helse-mr.no   
Sponsors and Collaborators
Oslo University Hospital
St. Olavs Hospital
Haukeland University Hospital
University Hospital of North Norway
University Hospital, Akershus
Helse Stavanger HF
Førde Central Hospital
Sorlandet Hospital HF
Nordlandssykehuset HF
The Hospital of Vestfold
Levanger Hospital
Alesund Hospital
Sykehuset Ostfold
Investigators
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Principal Investigator: Fredrik Schjesvold, MD, PhD Oslo University Hospital
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Responsible Party: Fredrik Hellem Schjesvold, Head of Oslo Myeloma Center, Oslo University Hospital
ClinicalTrials.gov Identifier: NCT04513639    
Other Study ID Numbers: OMC01/19
First Posted: August 14, 2020    Key Record Dates
Last Update Posted: June 18, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Dexamethasone acetate
Daratumumab
BB 1101
Antibodies, Monoclonal
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents