Selinexor With Alternating Bortezomib or Lenalidomide Plus Dexamethasone in TIE Newly Diagnosed MM Patients (SABLe)

Selinexor With Alternating Bortezomib or Lenalidomide Plus Dexamethasone in Transplant Ineligible Newly Diagnosed Multiple Myeloma Patients (SABLe): An Investigator Sponsored Trial

An unrandomized phase 2 study of selinexor in combination with lenalidomide/ bortezomib and dexamethasone to newly diagnosed, transplant in-eligible symptomatic multiple myeloma patients in a multicenter international set-up within the Nordic Multiple Myeloma Study Group

Study Overview

• Status: Active, not recruiting
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Bortezomib Injection; Drug: Lenalidomide capsule; Drug: Dexamethasone Oral; Drug: Selinexor 20 MG Oral Tablet

Detailed Description

An unrandomized phase 2 study evaluating selinexor in combination with lenalidomide/ bortezomib and dexamethasone to newly diagnosed transplant in-eligible symptomatic multiple myeloma patients in a multicenter international set-up with in the Nordic Multiple Myeloma Study Group.

The study will include 50 patients, recruited within the NMSG collaborating countries. After induction patient will be treated with continued lenalidomide-dexamethasone according to SWOG, with continuous 40mg selinexor weekly in the selinexor arm (experimental arm B).

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ida B Kristensen, MD; Phone Number: +4565411152; Email: ida.bruun.kristensen@rsyd.dk

Study Locations

• Denmark
  • Aalborg, Denmark
    • Aalborg University Hospital
  • Esbjerg, Denmark
    • Sydvestjysk Sygehus Esbjerg
  • Gødstrup, Denmark
    • Regionshospitalet Gødstrup
  • Odense, Denmark
    • Odense University Hospital
• Estonia
  • Tallinn, Estonia, 13419
    • North Estonia Medical Centre Foundation
• Norway
  • Bergen, Norway
    • Haukeland University Hospital
  • Førde, Norway
    • Førde Central Hospital
  • Kristiansund, Norway
    • Kristiansund Hospital
  • Oslo, Norway
    • Oslo Universitets Hospital
  • Stavanger, Norway
    • Stavanger University Hospital
  • Trondheim, Norway
    • St. Olavs University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Inclusion Criteria:

Patients must meet all of the following inclusion criteria to be eligible to enroll in this study:

1. Age > 18 years
2. Willing and able to provide written informed consent in accordance with national, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure
3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of ≤ 2. ECOG 3 allowed if caused by myeloma
4. Newly diagnosed multiple myeloma with treatment demanding disease as defined by IMWG (Rajkumar, Dimopoulos et al. 2014) and measurable disease as defined IMWG 2016 criteria (Table 5) (Kumar, Paiva et al. 2016)
5. By treating physician considered in-eligible for high-dose therapy with stem-cell transplant
6. Patients must have received no prior chemotherapy for multiple myeloma. Patients must have received no prior radiotherapy to a large area of the pelvis (more than half of the pelvis). Patients must have received no prior steroid treatment for myeloma with the exception of a maximum of 14 days of treatment for symptom control (including dexamethasone 40mg).

7. Adequate hepatic function within 7 days prior to C1D1:

   1. Total bilirubin < 1.5 × upper limit of normal (ULN) (except patients with Gilbert's syndrome who must have a total bilirubin of < 3 × ULN), and
   2. Alanine aminotransferase (ALT) normal to <2 × ULN.

8. Adequate renal function within 7 days prior to C1D1 as determined by estimated GFR of ≥ 30 mL/min, calculated using standard formula.

   1. Adequate hematopoietic function within 7 days prior to C1D1: Absolute neutrophil count ≥1000/mm3, and platelet count ≥100,000/mm3 (patients for whom <50% of bone marrow nucleated cells are plasma cells). If cytopenias are due a plasma cell infiltration in the bone marrow (biopsy-proven heavy-marrow involvement, as defined by having at least 30% marrow cellularity, with > 50% of the cells being malignant plasma cells (documented marrow results required)); in this case, although there are no required lower limits of normal for the blood counts, the treating physician must use his/her medical judgment as to the appropriateness of this study therapy for these patients.
   2. Erythropoietin-analogues are allowed.

   3. Patients must have:

      • At least a 1-week interval from the last platelet transfusion prior to the screening platelet assessment.

   However, patients may receive RBC and/or platelet transfusions as clinically indicated per institutional guidelines during the study.

9. Female patients of childbearing potential must have a negative serum pregnancy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must use highly effective methods of contraception throughout the study and for 3 months following the last dose of study treatment.
10. Patients must be able to take prophylactic anticoagulation as recommended by study
11. Patients with pathologic fractures, infection at diagnosis or symptomatic hyperviscosity must have these conditions attended to prior to registration (i.e., intramedullary rod, I.V. antibiotics, plasmapheresis)

Exclusion Criteria:

Exclusion Criteria:

Patients meeting any of the following exclusion criteria are not eligible to enroll in this study:

1. Has received selinexor or another XPO1 inhibitor previously.
2. Has any concurrent medical condition or disease (eg, uncontrolled active hypertension, uncontrolled active diabetes, active systemic infection, etc.) that is likely to interfere with study procedures.
3. Known intolerance, hypersensitivity, or contraindication to glucocorticoids, bortezomib, lenalidomide and selinexor.
4. Pregnant or breastfeeding females.
5. Life expectancy of less than 6 months.

6. Active, unstable cardiovascular function, as indicated by the presence of:

   1. Symptomatic ischemia, or
   2. Uncontrolled clinically significant conduction abnormalities (eg, patients with ventricular tachycardia on anti-arrhythmics are excluded; patients with first degree atrioventricular block or asymptomatic left anterior fascicular block/right bundle branch block will not be excluded), or
   3. Congestive heart failure of New York Heart Association Class ≥3 or known left ventricular ejection fraction <40%, or
   4. Myocardial infarction within 6 months prior to C1D1.
7. Any active gastrointestinal dysfunction interfering with the patient's ability to swallow tablets, or any active gastrointestinal dysfunction that could interfere with absorption of study treatment.
8. Inability or unwillingness to take supportive medications such as anti-nausea and anti-anorexia agents as recommended by the National Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines in Oncology (CPGO) (NCCN CPGO) for antiemesis and anorexia/cachexia (palliative care).
9. Any active, serious psychiatric, medical, or other conditions/situations that, in the opinion of the Investigator, could interfere with treatment, compliance, or the ability to give informed consent.
10. Contraindication to any of the required concomitant drugs or supportive treatments.
11. Patients unwilling or unable to comply with the protocol

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: B -selinexor-lenalidomide/bortezomib-dexamethasone; Alternating cycles of: Selinexor oral 40mg once weekly Lenalidomide oral 25mg d 1-21 Dexamethasone 20mg d 1+2, 8+9 and 15+16 i 28 days cycles and Selinexor oral 80mg once weekly Bortezomib sc 1.3mg/sqm once weekly Dexamethasone 20mg d 1+2, 8+9 and 15+16 in 28 days cycles for up to 16 cycles (8 of each, alternating) followed by continuos selinexor 40mg(once weekly)-lenalidomide-dexamethasone for up to 16 cycles followed by continuos lenalidomide-dexamethasone

Drug: Bortezomib Injection; Comparing an alternating regimen of selinexor-lenalidomide/bortezomib-dexamethasone to standard bortezomib-lenalidomide-dexamethasone; Other Names: Velcade; Drug: Lenalidomide capsule; Comparing an alternating regimen of selinexor-lenalidomide/bortezomib-dexamethasone to standard bortezomib-lenalidomide-dexamethasone; Other Names: Revlimid; Drug: Dexamethasone Oral; Comparing an alternating regimen of selinexor-lenalidomide/bortezomib-dexamethasone to standard bortezomib-lenalidomide-dexamethasone; Other Names: Neofordex; Drug: Selinexor 20 MG Oral Tablet; Comparing an alternating regimen of selinexor-lenalidomide/bortezomib-dexamethasone to standard bortezomib-lenalidomide-dexamethasone; Other Names: Xpovio

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Increased ORR in arm B (defined as ≥PR) at end of induction, defined according to IMWG response criteria	ORR at end of induction, with response defined according to IMWG response criteria	Estimated at 4-8 weeks after end of induction

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Increased VGPR rate at end of induction in arm B	VGPR rate at end of induction	Estimated at 4-8 weeks after end of induction
Increased rate of MRD negativity at end of induction in arm B	MRD negativity by NGS at end of induction	Estimated at 4-8 weeks after end of induction
Decreased time to response in arm B	Time to at least PR from start of treatment	Estimated monthly during the first 64 weeks
Evaluate toxicity rates between arm A and B, including rates of secondary primary malignancies	Comparison of toxicity rates according to NCI-CTCAE v4.03	Estimated at 4-8 weeks after end of induction
Decreased time to at least VGPR	Time to at least VGPR from start of treatment	Estimated monthly during the first 64 weeks

Collaborators and Investigators

• Sponsor: Ida Bruun Kristensen
• Collaborators: Odense Patient Data Explorative Network; Karyopharm Therapeutics Inc
• Investigators: Principal Investigator: Ida B Kristensen, MB, Odense University Hospital; Principal Investigator: Hanne Norseth, MD, Oslo University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 18, 2021
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: January 18, 2021
• First Submitted That Met QC Criteria: January 18, 2021
• First Posted (Actual): January 22, 2021

Study Record Updates

• Last Update Posted (Actual): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 19, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: selinexor
• 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; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Dexamethasone; Lenalidomide; Bortezomib
• Other Study ID Numbers: NMSG 29/21

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