New drug cocktail targets rare protein disease in early trial

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

Inclusion Criteria: * Diagnosis of primary systemic AL amyloidosis of tissue as determined by: a. Congo red staining of tissue showing apple green birefringence AND b. Clonal plasma cell disorder as determined by: i. Immunohistochemistry, in situ hybridization (ISH) or flow cytometry demonstrating kappa or lambda light chain restriction on bone marrow biopsy AND/OR ii. Monoclonal protein on serum or urine electrophoresis/immunofixation OR abnormal free light chain ratio * Newly diagnosed OR relapsed and/or refractory AL amyloidosis. Newly diagnosed patients must be treatment naive without previous plasma cell-directed therapy with the exception of a maximum of 160 mg dexamethasone or equivalent prior to dosing on protocol. Relapsed and/or refractory is defined as follows: a. Clonal relapse after at least one previous line of therapy or high-dose chemotherapy and autologous stem cell transplantation OR b. Refractory disease to prior therapy defined as less than a hematologic very good partial response (VGPR). If previous therapy was autologous stem cell transplant (SCT), must be \>= 3 months after SCT * Measurable disease defined by: a. Monoclonal protein in the serum or urine by immunofixation OR plasmacytosis of bone marrow with monoclonal staining for kappa or lambda light-chain isotype b. dFLC \>= 50 mg/L (dFLC=difference in involved and uninvolved serum free light-chain levels) * Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care * Female patients who: * Are postmenopausal for at least 1 year before the screening visit, OR * Are surgically sterile, OR * If they are of childbearing potential, agree to 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, 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) * Male patients, even if surgically sterilized (ie, 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 * 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) * Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or 2 * Absolute neutrophil count (ANC) \>= 1,000/mm\^3 * Platelet count \>= 75,000/mm\^3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment * Total bilirubin =\< 1.5 x the upper limit of the normal range (ULN) * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3 x ULN * Calculated creatinine clearance \>= 10 mL/min Exclusion Criteria: * Non-AL amyloidosis * Clinically overt myeloma a.) Lytic bone lesions or biopsy proven plasmacytoma b.) Hypercalcemia (corrected for albumin) \> 11 mg/dL unexplained by other causes * Clinically significant cardiac disease defined by any of the following criteria: a.) New York Heart Association (NYHA) class IV heart failure b.) N-terminal prohormone of brain natriuretic peptide (NT-ProBNP) \> 8500 ng/L c.) Symptomatic orthostatic hypotension with supine systolic blood pressure \< 90 mm Hg d.) Unstable cardiac arrhythmia e.) Unstable angina f.) Myocardial infarction within the past 6 months * Severe obstructive airway disease defined by forced expiratory volume at one second (FEV1) \< 50% * Female patients who are lactating or have a positive serum pregnancy test during the screening period * Failure to have fully recovered (ie, =\< grade 1 toxicity) from the reversible effects of prior chemotherapy * Major surgery within 14 days before enrollment * Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the ixazomib * Infection requiring systemic intravenous antibiotic therapy or other serious infection within 14 days before study enrollment * Systemic treatment, within 14 days before the first dose of and dexamethasone (DId), with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort * Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive * 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 allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent * Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing * Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection * Patient has \>= grade 3 peripheral neuropathy, or grade 2 with pain on clinical examination during the screening period * Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial * Patients that have previously been treated with daratumumab or ixazomib, or participated in a study with ixazomib whether treated with ixazomib or not