PRIMARY OBJECTIVE:~I. To evaluate the progression-free survival of subjects with daratumumab, bortezomib, and dexamethasone (DVd) treatment followed by daratumumab, ixazomib, and dexamethasone (DId) treatment.~SECONDARY OBJECTIVES:~I. To evaluate overall response rate (ORR) as assessed by International Myeloma Working Group Criteria (IMWG).~II. To evaluate time to response (TTR). III. To evaluate time to progression (TTP). IV. To evaluate duration of response (DOR). V. To evaluate overall survival (OS). VI. To evaluate the safety and tolerability. VII. To evaluate minimal residual disease (MRD) rate. VIII. To evaluate quality of life (QoL) using the Treatment Satisfaction Questionnaire for Medication (TSMQ-9) and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) patient reported questionnaires.~EXPLORATORY OBJECTIVE:~I. To evaluate biomarkers of response to treatment and mechanisms of resistance with pretreatment and post-treatment bone marrow and blood samples with deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) sequencing and immune profiling by flow cytometry.~OUTLINE:~Patients receive daratumumab intravenously (IV) over 3.5-6.5 hours on days 1, 8, and 15, bortezomib subcutaneously (SC) on days 1, 4, 8, and 11, and dexamethasone IV over 15 minutes on days 1, 8, and 15 and orally (PO) on days 2, 4, 5, 9, 11, 12, and 16. Treatment repeats every 28 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive daratumumab IV over 3.5 hours on days 1 and 15 of cycles 4-7 and day 1 of subsequent cycles, ixazomib PO on days 1, 8, and 15, and dexamethasone IV over 15 minutes or PO once weekly. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.~After completion of study, patients are followed up at 30 days and then periodically for up to 24 months.
This phase II trial studies how well daratumumab, bortezomib, and dexamethasone followed by daratumumab, ixazomib, and dexamethasone in treating patients with multiple myeloma that has come back (relapsed) or does not response to treatment (refractory). Immunotherapy with monoclonal antibodies, such as daratumumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as 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. Bortezomib and ixazomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving daratumumab, bortezomib, and dexamethasone followed by daratumumab, ixazomib, and dexamethasone may work better and help to control cancer in patients with multiple myeloma.