Purpose

This phase II trial compares the combination of selinexor, daratumumab, velcade (bortezomib), and dexamethasone (Dara-SVD) to the usual treatment of daratumumab, lenalidomide, bortezomib, and dexamethasone (Dara-RVD) in treating patients with high-risk newly diagnosed multiple myeloma. Selinexor is in a class of medications called selective inhibitors of nuclear export (SINE). It works by blocking a protein called CRM1, which may keep cancer cells from growing and may kill them. Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells, including myeloma cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Bortezomib blocks several molecular pathways in a cell and may cause cancer cells to die. It is a type of proteasome inhibitor and a type of dipeptidyl boronic acid. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Lenalidomide is in a class of medications called immunomodulatory agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells in the bone marrow. The drugs daratumumab, lenalidomide, bortezomib, dexamethasone and selinexor are already approved by the FDA for use in myeloma. But selinexor is not used until myeloma comes back (relapses) after initial treatment. Giving selinexor in the initial treatment may be a superior type of treatment for patients with high-risk newly diagnosed multiple myeloma.

Condition

Eligibility

Eligible Ages
All ages
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • Presence of newly diagnosed (dx) MM as defined by standard International Myeloma working group (IMWG). - Presence of high risk cytogenetics using fluorescent in situ hybridization (FISH) [del(17p), t(4;14), t(14;16), t(14;20), chromosome 1 abnormalities, MYC translocation, tetrasomies, complex karyotype, high lactate dehydrogenase (LDH), or extramedullary MM. - Patients are allowed to have received one cycle of bortezomib-based doublet or triplet therapy. For instance, if a newly diagnosed patient with MM is in need of urgent therapy, they may be enrolled after having received one cycle of bortezomib, cyclophosphamide, dexamethasone. - Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%). - Absolute neutrophil count ≥ 1,000/mcL (> 500 if bone marrow [BM] clonal plasma cell involvement greater than 50%). - Platelets ≥ 100,000/mcL (> 50,000 if BM clonal plasma cell involvement greater than 50%). - Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (with the exception of patients with Gilbert's syndrome who have a high baseline bilirubin). - Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) ≤ 3 × institutional ULN. - Glomerular filtration rate (GFR) ≥ 30 mL/min. - Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. - For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. - Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. - Patients with treated brain involvement are eligible if follow-up brain imaging performed within 10 days after central nervous system (CNS)-directed therapy shows no. - Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. - Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. - The effects of selinexor (KPT-330) on the developing human fetus are unknown. For this reason and because selective nuclear export inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men with partners of women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men (with partners of women of childbearing potential) treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of study treatment administration. Adequate contraception should continue for 7 months for females and for 4 months for males after completion of the study treatment. - Female of childbearing potential (FCBP) must have a negative pregnancy test during screening. They must either commit to continue abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 4 weeks before therapy, while taking lenalidomide, during dose interruptions, and for 7 months after study treatment. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. Lenalidomide treatment must be discontinued during this evaluation. - Men who are sexually active with FCBP must agree to use a latex or synthetic condom while taking lenalidomide, during dose interruptions and for up to 4 weeks after discontinuing lenalidomide, even if they have undergone a successful vasectomy. Male patients taking lenalidomide must abstain from donating blood, semen, or sperm during study participation and for at least 4 weeks after discontinuation from lenalidomide. - Patients who are randomized to receive lenalidomide need to register into the mandatory Risk Evaluation and Mitigation Strategies (REMS) program and be willing and able to comply with the requirements of REMS. - Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria

  • Patients who are in urgent need for MM therapy (such as in the setting of acute kidney injury, or high disease burden concerning for impending organ failure) may begin study treatment immediately after receiving one cycle of bortezomib combination (e.g. bortezomib-dexamethasone or cyclophosphamide-bortezomib-dexamethasone) or one course of pulse dose dexamethasone 20-40mg once daily for four days. No washout period is required. - Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia. - Patients who are receiving any other investigational agents. - History of allergic reactions attributed to compounds of similar chemical or biologic composition to selinexor (KPT-330) or other agents used in study. - Concomitant medications: Supportive care therapies such as bone directed therapies (zoledronic acid, denosumab), intravenous immunoglobulin therapy (IVIG) and anti-viral agents are allowed and recommended as per standard of care (SOC). Strong CYP3A4 inhibitors and strong CYP3A4 inducers are prohibited, due to their respective increase or decrease in bortezomib exposure. If strong CYP3A4 inhibitors cannot be avoided, then patients will be monitored for signs of bortezomib toxicity and a dose reduction of bortezomib will be considered. - Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous. - Pregnant women are excluded because this study involves an investigational drug that may cause genotoxic, teratogenic, and mutagenic effects on the developing fetus and newborn and drugs that have known genotoxic, teratogenic, or abortifacient effect. - Because there is potential risk for adverse events in nursing infants secondary to treatment of the mother with the drugs used in this study, breastfeeding is not allowed during treatment for all drugs and for 2 months after last dose of bortezomib and 1 week after the last dose of selinexor.

Study Design

Phase
Phase 2
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Arm I (Dara-SVD)
Patients receive daratumumab and hyaluronidase-fihj SC on days 1, 8, 15, & 22 for cycles 1-2, then days 1 & 15 for cycles 3-4, and selinexor PO, bortezomib SC, and dexamethasone PO on days 1, 8, 15, & 22 of each cycle. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo PET, MRI, or CT, and bone marrow aspiration and biopsy, and collection of blood and urine samples throughout the study.
  • Procedure: Biospecimen Collection
    Undergo collection of blood and urine samples
    Other names:
    • Biological Sample Collection
    • Biospecimen Collected
    • Specimen Collection
  • Procedure: Bone Marrow Aspiration
    Undergo bone marrow aspiration
  • Procedure: Bone Marrow Biopsy
    Undergo bone marrow biopsy
    Other names:
    • Biopsy of Bone Marrow
    • Biopsy, Bone Marrow
  • Drug: Bortezomib
    Given SC
    Other names:
    • [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid
    • LDP 341
    • LDP-341
    • LDP341
    • MLN 341
    • MLN-341
    • MLN341
    • PS 341
    • PS-341
    • PS341
    • Velcade
  • Procedure: Computed Tomography
    Undergo CT
    Other names:
    • CAT
    • CAT Scan
    • Computed Axial Tomography
    • Computerized Axial Tomography
    • Computerized axial tomography (procedure)
    • Computerized Tomography
    • Computerized Tomography (CT) scan
    • CT
    • CT Scan
    • tomography
  • Biological: Daratumumab
    Given SC
    Other names:
    • Daratumumab Biosimilar HLX15
    • Daratumumab-fihj
    • Darzalex
    • HLX15
    • HuMax-CD38
    • JNJ 54767414
    • JNJ-54767414
    • JNJ54767414
  • Drug: Daratumumab and Recombinant Human Hyaluronidase
    Given SC
    Other names:
    • DARA Co-formulated with rHuPH20
    • DARA/rHuPH20
    • Daratumumab + rHuPH20
    • Daratumumab and Hyaluronidase
    • Daratumumab and Hyaluronidase-fihj
    • Daratumumab and vorhyaluronidase
    • Daratumumab and Vorhyaluronidase Alfa
    • Daratumumab with rHuPH20
    • Daratumumab-rHuPH20
    • Daratumumab/Hyaluronidase-fihj
    • Daratumumab/rHuPH20 Co-formulation
    • Darzalex Faspro
    • Darzalex/rHuPH20
    • Darzquro
    • HuMax-CD38-rHuPH20
    • Recombinant Human Hyaluronidase Mixed with Daratumumab
  • Drug: Dexamethasone
    Given PO
    Other names:
    • 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
    • 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
    • Hemady
    • Hexadecadrol
    • Hexadrol
    • LenaDex
    • Lokalison-F
    • Loverine
    • Methylfluorprednisolone
    • Millicorten
    • Mymethasone
    • Orgadrone
    • Spersadex
    • TaperDex
    • Visumetazone
    • ZoDex
  • Procedure: Magnetic Resonance Imaging
    Undergo MRI
    Other names:
    • Magnetic Resonance
    • Magnetic Resonance Imaging (MRI)
    • Magnetic resonance imaging (procedure)
    • Magnetic Resonance Imaging Scan
    • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
    • MR
    • MR Imaging
    • MRI
    • MRI Scan
    • MRIs
    • NMR Imaging
    • NMRI
    • Nuclear Magnetic Resonance Imaging
    • sMRI
    • Structural MRI
  • Procedure: Positron Emission Tomography
    Undergo PET
    Other names:
    • Medical Imaging, Positron Emission Tomography
    • PET
    • PET Scan
    • Positron emission tomography (procedure)
    • Positron Emission Tomography Scan
    • Positron-Emission Tomography
    • PT
  • Drug: Selinexor
    Given PO
    Other names:
    • ATG-010
    • CRM1 Nuclear Export Inhibitor KPT-330
    • KPT 330
    • KPT-330
    • KPT330
    • Nexpovio
    • Selective Inhibitor of Nuclear Export KPT-330
    • SINE KPT-330
    • Xpovio
Active Comparator
Arm II (Dara-RVD)
Patients receive daratumumab and hyaluronidase-fihj SC on days 1, 8, 15, & 22 for cycles 1-2, then days 1 & 15 for cycles 3-4, lenalidomide PO QD on days 1-21 of each cycle, and bortezomib SC and dexamethasone PO on days 1, 8, 15, & 22 of each cycle. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo PET, MRI, or CT, and bone marrow aspiration and biopsy, and collection of blood and urine samples throughout the study.
  • Procedure: Biospecimen Collection
    Undergo collection of blood and urine samples
    Other names:
    • Biological Sample Collection
    • Biospecimen Collected
    • Specimen Collection
  • Procedure: Bone Marrow Aspiration
    Undergo bone marrow aspiration
  • Procedure: Bone Marrow Biopsy
    Undergo bone marrow biopsy
    Other names:
    • Biopsy of Bone Marrow
    • Biopsy, Bone Marrow
  • Drug: Bortezomib
    Given SC
    Other names:
    • [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid
    • LDP 341
    • LDP-341
    • LDP341
    • MLN 341
    • MLN-341
    • MLN341
    • PS 341
    • PS-341
    • PS341
    • Velcade
  • Procedure: Computed Tomography
    Undergo CT
    Other names:
    • CAT
    • CAT Scan
    • Computed Axial Tomography
    • Computerized Axial Tomography
    • Computerized axial tomography (procedure)
    • Computerized Tomography
    • Computerized Tomography (CT) scan
    • CT
    • CT Scan
    • tomography
  • Biological: Daratumumab
    Given SC
    Other names:
    • Daratumumab Biosimilar HLX15
    • Daratumumab-fihj
    • Darzalex
    • HLX15
    • HuMax-CD38
    • JNJ 54767414
    • JNJ-54767414
    • JNJ54767414
  • Drug: Daratumumab and Recombinant Human Hyaluronidase
    Given SC
    Other names:
    • DARA Co-formulated with rHuPH20
    • DARA/rHuPH20
    • Daratumumab + rHuPH20
    • Daratumumab and Hyaluronidase
    • Daratumumab and Hyaluronidase-fihj
    • Daratumumab and vorhyaluronidase
    • Daratumumab and Vorhyaluronidase Alfa
    • Daratumumab with rHuPH20
    • Daratumumab-rHuPH20
    • Daratumumab/Hyaluronidase-fihj
    • Daratumumab/rHuPH20 Co-formulation
    • Darzalex Faspro
    • Darzalex/rHuPH20
    • Darzquro
    • HuMax-CD38-rHuPH20
    • Recombinant Human Hyaluronidase Mixed with Daratumumab
  • Drug: Dexamethasone
    Given PO
    Other names:
    • 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
    • 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
    • Hemady
    • Hexadecadrol
    • Hexadrol
    • LenaDex
    • Lokalison-F
    • Loverine
    • Methylfluorprednisolone
    • Millicorten
    • Mymethasone
    • Orgadrone
    • Spersadex
    • TaperDex
    • Visumetazone
    • ZoDex
  • Drug: Lenalidomide
    Given PO
    Other names:
    • CC 5013
    • CC-5013
    • CC5013
    • CDC 501
    • Revlimid
  • Procedure: Magnetic Resonance Imaging
    Undergo MRI
    Other names:
    • Magnetic Resonance
    • Magnetic Resonance Imaging (MRI)
    • Magnetic resonance imaging (procedure)
    • Magnetic Resonance Imaging Scan
    • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
    • MR
    • MR Imaging
    • MRI
    • MRI Scan
    • MRIs
    • NMR Imaging
    • NMRI
    • Nuclear Magnetic Resonance Imaging
    • sMRI
    • Structural MRI
  • Procedure: Positron Emission Tomography
    Undergo PET
    Other names:
    • Medical Imaging, Positron Emission Tomography
    • PET
    • PET Scan
    • Positron emission tomography (procedure)
    • Positron Emission Tomography Scan
    • Positron-Emission Tomography
    • PT

Recruiting Locations

Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee 37232
Contact:
Site Public Contact
800-811-8480

More Details

Status
Recruiting
Sponsor
National Cancer Institute (NCI)

Study Contact

Detailed Description

PRIMARY OBJECTIVE: I. To compare deep response (complete response [CR] + stringent CR [sCR]) by the end of induction cycle 4 in newly diagnosed high-risk multiple myeloma patients (HR NDxMM), in both study arms. SECONDARY OBJECTIVES: I. To assess the minimal residual disease (MRD)-negativity (10^-5). II. To assess overall response rate (ORR), very good partial response (VGPR), and partial response (PR). III. To assess progression-free survival (PFS) and duration of response (DOR). CORRELATIVE OBJECTIVE: I. To identify differential gene expression signature that predicts response to selinexor through ribonucleic acid sequencing (RNAseq) and cell-free deoxyribonucleic acid (cfDNA) studies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I (Dara-SVD): Patients receive daratumumab and hyaluronidase-fihj subcutaneously (SC) on days 1, 8, 15, & 22 for cycles 1-2, then days 1 & 15 for cycles 3-4, and selinexor orally (PO), bortezomib SC, and dexamethasone PO on days 1, 8, 15, & 22 of each cycle. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo positron emission tomography (PET), magnetic resonance imaging (MRI), or computed tomography (CT), and bone marrow aspiration and biopsy, and collection of blood and urine samples throughout the study. ARM II (Dara-RVD): Patients receive daratumumab and hyaluronidase-fihj SC on days 1, 8, 15, & 22 for cycles 1-2, then days 1 & 15 for cycles 3-4, lenalidomide PO once daily (QD) on days 1-21 of each cycle, and bortezomib SC and dexamethasone PO on days 1, 8, 15, & 22 of each cycle. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo PET, MRI, or CT, and bone marrow aspiration and biopsy, and collection of blood and urine samples throughout the study. After completion of study treatment, patients are followed up at 6 months and 1 and 2 years.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.