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

Inclusion Criteria:

• Presence of newly diagnosed (dx) MM as defined by standard International Myelomaworking 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, MYCtranslocation, tetrasomies, complex karyotype, high lactate dehydrogenase (LDH), orextramedullary MM.

• Patients are allowed to have received one cycle of bortezomib-based doublet ortriplet therapy. For instance, if a newly diagnosed patient with MM is in need ofurgent 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 cellinvolvement 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 theexception 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-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial.

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated.

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load.

• Patients with treated brain involvement are eligible if follow-up brain imagingperformed within 10 days after central nervous system (CNS)-directed therapy showsno.

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial.

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better.

• The effects of selinexor (KPT-330) on the developing human fetus are unknown. Forthis reason and because selective nuclear export inhibitors as well as othertherapeutic agents used in this trial are known to be teratogenic, women ofchild-bearing potential and men with partners of women of childbearing potentialmust agree to use adequate contraception (hormonal or barrier method of birthcontrol; abstinence) prior to study entry and for the duration of studyparticipation. Should a woman become pregnant or suspect she is pregnant while sheor her partner is participating in this study, she should inform her treatingphysician immediately. Men (with partners of women of childbearing potential)treated or enrolled on this protocol must also agree to use adequate contraceptionprior to the study, for the duration of study participation, and 4 months aftercompletion of study treatment administration. Adequate contraception should continuefor 7 months for females and for 4 months for males after completion of the studytreatment.

• Female of childbearing potential (FCBP) must have a negative pregnancy test duringscreening. They must either commit to continue abstinence from heterosexualintercourse or begin TWO acceptable methods of birth control, one highly effectivemethod and one additional effective method AT THE SAME TIME, at least 4 weeks beforetherapy, while taking lenalidomide, during dose interruptions, and for 7 monthsafter study treatment. If menstrual cycles are irregular, the pregnancy testingshould occur every 2 weeks. Pregnancy testing and counseling should be performed ifa patient misses her period or if there is any abnormality in her menstrualbleeding. Lenalidomide treatment must be discontinued during this evaluation.

• Men who are sexually active with FCBP must agree to use a latex or synthetic condomwhile taking lenalidomide, during dose interruptions and for up to 4 weeks afterdiscontinuing lenalidomide, even if they have undergone a successful vasectomy. Malepatients taking lenalidomide must abstain from donating blood, semen, or spermduring study participation and for at least 4 weeks after discontinuation fromlenalidomide.

• Patients who are randomized to receive lenalidomide need to register into themandatory Risk Evaluation and Mitigation Strategies (REMS) program and be willingand able to comply with the requirements of REMS.

• Ability to understand and the willingness to sign a written informed consentdocument. Legally authorized representatives may sign and give informed consent onbehalf of study participants.

Exclusion Criteria:

• Patients who are in urgent need for MM therapy (such as in the setting of acutekidney injury, or high disease burden concerning for impending organ failure) maybegin study treatment immediately after receiving one cycle of bortezomibcombination (e.g. bortezomib-dexamethasone orcyclophosphamide-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 orbiologic 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) andanti-viral agents are allowed and recommended as per standard of care (SOC). StrongCYP3A4 inhibitors and strong CYP3A4 inducers are prohibited, due to their respectiveincrease or decrease in bortezomib exposure. If strong CYP3A4 inhibitors cannot beavoided, then patients will be monitored for signs of bortezomib toxicity and a dosereduction of bortezomib will be considered.

• Patients with uncontrolled intercurrent illness or any other significantcondition(s) that would make participation in this protocol unreasonably hazardous.

• Pregnant women are excluded because this study involves an investigational drug thatmay cause genotoxic, teratogenic, and mutagenic effects on the developing fetus andnewborn and drugs that have known genotoxic, teratogenic, or abortifacient effect.

• Because there is potential risk for adverse events in nursing infants secondaryto treatment of the mother with the drugs used in this study, breastfeeding isnot allowed during treatment for all drugs and for 2 months after last dose ofbortezomib and 1 week after the last dose of selinexor.