Ixazomib Citrate, Lenalidomide, Dexamethasone, and Daratumumab in Treating Patients With Newly Diagnosed Multiple Myeloma

This phase II trial studies how well ixazomib citrate, lenalidomide, dexamethasone, and daratumumab work in treating patients with newly diagnosed multiple myeloma. Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as lenalidomide and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as daratumumab, may block cancer growth in different ways by targeting certain cells. Giving ixazomib citrate, lenalidomide, dexamethasone, and daratumumab may work better in treating patients with newly diagnosed multiple myeloma.

PRIMARY OBJECTIVES:

I. To determine the complete response rate (CR) of the four-drug combination of ixazomib, lenalidomide, dexamethasone and daratumumab in patients with previously untreated symptomatic multiple myeloma (MM).

SECONDARY OBJECTIVES:

I. To determine the overall response rate (ORR), and very good partial response (VGPR) rate with the four drug combination of ixazomib, lenalidomide, dexamethasone and daratumumab, when used as initial therapy in patients with previously untreated symptomatic MM.

II. To determine the progression free survival and overall survival among patients with previously untreated symptomatic MM following treatment with the four drug combination of Ixazomib, lenalidomide, dexamethasone and daratumumab followed by ixazomib and daratumumab maintenance till progression.

II. To determine the toxicities associated with the four drug combination of ixazomib, lenalidomide, dexamethasone and daratumumab in patients with previously untreated symptomatic MM.

TERTIARY OBJECTIVES:

I. To examine the proportion of minimal residual disease (MRD) negativity following induction therapy with the four-drug combination of ixazomib, lenalidomide, dexamethasone and daratumumab.

II. To assess the quality of life using patient completed Functional Assessment of Cancer Treatment (FACT)/Gynecologic Oncology Group (GOG) questionnaires.

OUTLINE:

INDUCTION PHASE: Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15 and lenalidomide PO on days 1-21. Patients receive daratumumab intravenously (IV) over 3-7 hours on days 1, 8, 15, and 22 of courses 1 and 2, on days 1 and 15 of courses 3, 4, and 5, and on day 1 of courses 7 and beyond. Patients also receive dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE PHASE: Patients receive ixazomib citrate PO on days 1, 8, and 15 and daratumumab IV over 3-7 hours on day 1. Courses repeat every 28 days for up to 36 months from registration in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 or 6 months.

Eligibility Criteria:
Inclusion Criteria:

* Calculated creatinine clearance (using Cockcroft-Gault equation) \>= 30 mL/min
* Absolute neutrophil count (ANC) \>= 1500/mm\^3
* Untransfused platelet count \>= 75000/mm\^3
* Hemoglobin \>= 8.0 g/dL
* Total bilirubin =\< 1.5 x upper limit of normal (ULN)
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 2.5 x ULN
* Measurable disease of multiple myeloma as defined by at least ONE of the following:

  * Serum monoclonal protein \>= 1.0 g/dL
  * \>= 200 mg of monoclonal protein in the urine on 24 hour electrophoresis
  * Serum immunoglobulin free light chain \>= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
* Previously untreated for myeloma or have received no more than one cycle of any treatment regimen; NOTE: Prior radiation therapy for the treatment of solitary plasmacytoma is permitted; prior therapy with clarithromycin, dehydroepiandrosterone (DHEA), anakinra, pamidronate or zoledronic acid is permitted; any additional agents not listed must be approved by the principal investigator
* Provide informed written consent
* Negative pregnancy test done =\< 7 days prior to registration, for women of childbearing potential only
* Willing to follow strict birth control measures

  * Female patients: if they are of childbearing potential, agree to one of the following:

    * Practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, AND must also adhere to the guidelines of any treatment specific pregnancy prevention program, if applicable, OR
    * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception)
  * Male patients: even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following:

    * Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
    * Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
    * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception)
* Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
* Willing to follow the requirements of the Revlimid Risk Evaluation and Mitigation Strategy (REMS) program
* Willing to provide bone marrow and blood samples for planned research

Exclusion Criteria:

* Monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma
* Diagnosed or treated for another malignancy =\< 2 years prior to registration or previously diagnosed with another malignancy and have any evidence of residual disease; NOTE: Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
* Any of the following:

  * Pregnant women
  * Nursing women
  * Men or women of childbearing potential who are unwilling to employ adequate contraception
* Other concurrent chemotherapy, or any ancillary therapy considered investigational; NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment
* Peripheral neuropathy \>= grade 2 on clinical examination or grade 1 with pain during the screening period
* Major surgery =\< 14 days prior to registration
* Systemic treatment with strong CYP3A4 inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital, St. John's wort) =\< 14 days prior to registration
* Evidence of current uncontrolled cardiovascular conditions, including hypertension, cardiac arrhythmias, congestive heart failure, unstable angina, or myocardial infarction =\< 6 months; Note: Prior to entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant
* Radiotherapy =\< 14 days prior to registration; NOTE: If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the ixazomib
* Known human immunodeficiency virus (HIV) positive
* Known hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection
* Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
* Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or investigator's brochure), or known sensitivity to mammalian-derived products
* Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib, lenalidomide or dexamethasone including difficulty swallowing
* Diarrhea \> grade 1, based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grading, in the absence of antidiarrheals