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

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.

Study Overview

• Status: Recruiting
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Early treatment of relapse with carfilzomib, dexamethasone, daratumumab; Drug: Standard treatment of relapse with carfilzomib, dexamethasone, daratumumab

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.

• Study Type: Interventional
• Enrollment (Anticipated): 176
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Anne-Marie Rasmussen, PhD; Phone Number: +4799791064; Email: annemra55@gmail.com
• Study Contact Backup: Name: Anna Lysén, MSc; Phone Number: +4747246569; Email: annaly@ous-hf.no

Study Locations

• Norway
  • Bergen, Norway
    • Recruiting
    • Haukeland University Hospital
    • Contact: Galina Tsykonova, MD; Email: tor.henrik.anderson.tvedt@helse-bergen.no
  • Bodø, Norway
    • Recruiting
    • Nordland Hospital Bodø
    • Contact: Randi F Halstensen, MD; Phone Number: +4775534000; Email: randi.fykse.hallstensen@nordlandssykehuset.no
  • Fredrikstad, Norway
    • Recruiting
    • Sykehuset Ostfold
    • Contact: Birgitte D. Eiken, MD; Email: birgitte.dahl.eiken@so-hf.no
  • Førde, Norway
    • Recruiting
    • Førde Central Hospital
    • Contact: Damian Szatkowski, MD; Phone Number: +4757839000; Email: damian.szatkowski@helse-forde.no
  • Kristiansand, Norway
    • Recruiting
    • Sørlandet Hospital Kristiansand
    • Contact: Jurgen Rolke, MD; Phone Number: +4790610600; Email: jurgen.rolke@sshf.no
  • Levanger, Norway
    • Recruiting
    • Levanger Hospital
    • Contact: Jon Hjalmar Sørbø, MD; Phone Number: +4774098000; Email: jonhjalmar.sorbo@helse-nordtrondelag.no
  • Lørenskog, Norway
    • Recruiting
    • Akershus University Hospital
    • Contact: Anette L. Eilertsen, MD, PhD.; Email: anette.loken.eilertsen@ahus.no
  • Oslo, Norway
    • Recruiting
    • Oslo University Hospital
    • Contact: Fredrik Schjesvold, MD, PhD; Email: fredrikschjesvold@gmail.com
    • Contact: Frida Askeland, MD; Email: friask@ous-hf.no
  • Stavanger, Norway
    • Recruiting
    • Helse Stavanger HF
    • Contact: Einar Haukås, MD, PhD; Email: einar.haukas@sus.no
  • Tromsø, Norway
    • Recruiting
    • University Hospital North Norway
    • Contact: Anders Vik, MD, PhD; Email: Anders.Vik@unn.no
  • Trondheim, Norway
    • Recruiting
    • St. Olavs Hospital
    • Contact: Tobias Slørdahl, MD, PhD; Email: Tobias.Schmidt.Slordahl@stolav.no
  • Tønsberg, Norway
    • Recruiting
    • The Hospital of Vestfold
    • Contact: Magnus Moksnes, MD; Email: magmok@siv.no
  • Ålesund, Norway
    • Recruiting
    • Alesund Hospital
    • Contact: Robert Brudevold, MD; Phone Number: +4740622848; Email: robert.brudevold@helse-mr.no

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: DKd

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	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.	10 years
Overall survival (OS)	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.	11 years
Minimal residual disease negativity after first line treatment	The number of participants who achieve MRD negativity measured by Euroflow NGF at 30-45 after consolidation therapy has ended	30-45 days post consolidation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-to-next treatment	Time from end of first line treatment to start of 3.L therapy	10 years
Minimal residual disease negativity during 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).	6 months after starting second line treatment
Health-related quality of life (HRQOL)	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.	10 years

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: University Hospital of North Norway; Helse Stavanger HF; Haukeland University Hospital; Sorlandet Hospital HF; St. Olavs Hospital; The Hospital of Vestfold; Helse Nord-Trøndelag HF; Alesund Hospital; University Hospital, Akershus; Nordlandssykehuset HF; Førde Central Hospital; Sykehuset Ostfold
• Investigators: Principal Investigator: Fredrik Schjesvold, MD, PhD, Oslo University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 27, 2020
• Primary Completion (Anticipated): June 1, 2031
• Study Completion (Anticipated): June 1, 2032

Study Registration Dates

• First Submitted: August 12, 2020
• First Submitted That Met QC Criteria: August 12, 2020
• First Posted (Actual): August 14, 2020

Study Record Updates

• Last Update Posted (Actual): September 21, 2022
• Last Update Submitted That Met QC Criteria: September 20, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Multiple Myeloma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Dexamethasone; Dexamethasone acetate; BB 1101; Daratumumab; Antibodies, Monoclonal
• Other Study ID Numbers: OMC01/19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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