Comparing the Combination of Selinexor-Daratumumab-Velcade-Dexamethasone (Dara-SVD) With the Usual Treatment (Dara-RVD) for High-Risk Newly Diagnosed Multiple Myeloma

Study Overview
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Brief Summary
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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.

Detailed Description
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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) or daratumumab intravenously (IV) 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 biopsy and collection of blood samples during screening and at the end of treatment. ARM II (Dara-RVD): Patients receive daratumumab and hyaluronidase-fihj SC or daratumumab IV 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. Patients also undergo PET, MRI, or CT, and bone marrow biopsy and collection of blood samples during screening and at the end of treatment. After completion of study treatment, patients are followed up at 6 months and 1 and 2 years.

Official Title
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A Randomized Phase 2 Study of Daratumumab-Selinexor-Velcade-Dexamethasone (Dara-SVD) for High-Risk Newly Diagnosed Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Procedure: Bone Marrow Biopsy
* Drug: Bortezomib
* Procedure: Computed Tomography
* Biological: Daratumumab
* Drug: Daratumumab and Hyaluronidase-fihj
* Drug: Dexamethasone
* Drug: Lenalidomide
* Procedure: Magnetic Resonance Imaging
* Procedure: Positron Emission Tomography
* Drug: Selinexor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presence of newly diagnosed (dx) MM as defined by standard International Myeloma working group (IMWG). Presence of high risk cytogenetics [del(17p), t(4;14), t(14;16), t(14;20), chromosome 1 abnormalities, MYC translocation, tetrasomies, complex karyotype, high-risk gene expression signature (if available), high 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 Creatinine < 2.0 mg/dL OR glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m^2 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 after central nervous system (CNS)-directed therapy shows no evidence of progression. 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 3 months after the last dose of selinexor and 7 months for female and 4 months for male patients after the last dose of bortezomib. Female of childbearing potential (FCBP) must have 2 negative pregnancy tests before initiating lenalidomide. The first test should be performed within 10-14 days and within 24 hours prior to prescribing lenalidomide and must either commit to continued 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 at least 4 weeks after the last dose of lenalidomide. 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). 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.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (Dara-SVD)<br>Patients receive daratumumab and hyaluronidase-fihj SC or daratumumab IV 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 biopsy and collection of blood samples during screening and at the end of treatment. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Drug: Bortezomib<br>* Given SC<br>* Other names: Velcade;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Biological: Daratumumab<br>* Given IV<br>* Other names: JNJ-54767414;Drug: Daratumumab and Hyaluronidase-fihj<br>* Given SC<br>* Other names: Recombinant Human Hyaluronidase Mixed with Daratumumab;Drug: Dexamethasone<br>* Given PO<br>* Other names: ZoDex;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Procedure: Positron Emission Tomography<br>* Undergo PET<br>* Other names: PT;Drug: Selinexor<br>* Given PO<br>* Other names: Xpovio;|
| Active Comparator: Arm II (Dara-RVD)<br>Patients receive daratumumab and hyaluronidase-fihj SC or daratumumab IV 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 biopsy and collection of blood samples during screening and at the end of treatment. | Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Drug: Bortezomib<br>* Given SC<br>* Other names: Velcade;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Biological: Daratumumab<br>* Given IV<br>* Other names: JNJ-54767414;Drug: Daratumumab and Hyaluronidase-fihj<br>* Given SC<br>* Other names: Recombinant Human Hyaluronidase Mixed with Daratumumab;Drug: Dexamethasone<br>* Given PO<br>* Other names: ZoDex;Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Procedure: Positron Emission Tomography<br>* Undergo PET<br>* Other names: PT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Deep clinical response | Defined as complete response (CR) + stringent CR. | Up to the end of cycle 4 (each cycle = 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimal residual disease-negativity (10^-5) | Will be assessed by next generation flow cytometry. | Up to end of cycle 4 (each cycle = 28 days) |