A Phase II Study of Isatuximab (SAR650984) (NSC-795145) for Patients With Previously Treated AL Amyloidosis

• Patient must have relapsed or refractory primary systemic AL amyloidosis, histologically-confirmed by positive Congo red stain with green by birefringence on polarized light microscopy, OR characteristic appearance by electron microscopy AND confirmatory AL amyloid typing (mass spectrometry-based proteomic analysis or immunofluorescence)

• Patient must have measurable disease within 28 days prior to registration; serum beta2 microglobulin, serum quantitative immunoglobulins (immunoglobulin \[Ig\]G, IgA, and IgM), serum free kappa and lambda, and serum protein electrophoresis (SPEP) with M-protein quantification must be obtained within 14 days prior to registration

• Patient must demonstrate a difference in the involved serum free light chains (kappa or lambda) versus the uninvolved serum free light chain of \>= 4.5 mg/dL within 14 days prior to registration

• Patient must have objective organ involvement defined by ONE (or more) of the following; all disease for involved organs must be assessed and documented on the AL baseline tumor assessment form

‣ Kidney: albuminuria greater than or equal to 500 mg per day on a 24-hour urine specimen within 35 days prior to registration, OR prior kidney biopsy (at time of diagnosis) showing amyloid deposition

⁃ Heart: mean left ventricular wall thickness on echocardiogram greater than or equal to 12 mm in the absence of hypertension or valvular heart disease, OR N-terminal fragment brain natriuretic protein (NT-pro) brain natriuretic peptide (BNP) greater than 332 ng/mL provided that patient does not have impaired renal function (as defined by calculated creatinine clearance less than 25 mL/min) within 14 days prior to registration, OR prior cardiac biopsy (at time of diagnosis) showing amyloid deposition with past documented or presently noted clinical symptoms and signs supportive of a diagnosis of heart failure in the absence of an alternative explanation for heart failure

⁃ Liver: hepatomegaly (total liver span \> 15 cm) as demonstrated by computed tomography (CT) or magnetic resonance imaging (MRI) within 35 days prior to registration OR elevated alkaline phosphatase (ALP) greater than 1.5 times the upper limit of normal within 14 days prior to registration, OR prior liver biopsy (at time of diagnosis) showing amyloid deposition

⁃ Gastrointestinal tract: prior biopsy showing amyloid deposition AND symptoms such as GI bleeding or persistent diarrhea (\> 4 loose stools/day on most days over a consecutive 28-day period)

⁃ Autonomic or peripheral nervous system: orthostatic blood pressure, symptoms of nausea, early satiety, diarrhea or constipation, abnormal sensory and/or motor findings on neurologic exam, or gastric atony by gastric emptying scan; Note: pulse and blood pressure must be recorded with the patient supine (lying down), and then again after at least 1 minute, but less than 3 minutes of standing; this assessment must be repeated on 2 separate occasions (at least 1 day apart; e.g. day -3 and day -1) within a 28-day screening period

⁃ Soft tissue: macroglossia, or soft tissue deposits (including lymphadenopathy, recurrent peri-orbital purpura, peri-articular, skin or other soft tissue) requiring therapy

• Patients must not have active symptomatic multiple myeloma, as defined by 2015 International Myeloma Working Group (IMWG) criteria (hypercalcemia, renal failure, anemia, and bone \[CRAB\] criteria; bone marrow plasmacytosis \> 60%); kappa: lambda ratio \> 100 is acceptable only if the clinical symptoms and sign are attributable only to amyloidosis and not multiple myeloma (hemoglobin \[Hgb\] \< 8 g/dL)

• Patient must be relapsed or refractory to at least one prior line of therapy (such as: transplant, radiation, or chemotherapy)

• Patients must have completed other systemic therapy \>= 14 days or investigational drug \>= 28 days prior to registration, surgery (other than biopsies) \>= 21 days prior to registration, and any autologous stem cell transplant (ASCT) \>= 100 days prior to registration

• Patients must not have received any or supplements which have been known to have some anti-amyloidogenic effect (such as: doxycycline; curcumin; prednisone; dexamethasone; epigallocatechin gallate \[EGCG\]) within 14 days prior to registration

• Patients must not have any known allergies to isatuximab or other monoclonal antibody therapies

• Patients must not have received daratumumab within 56 days prior to registration nor have been refractory to daratumumab

• Patients must not be eligible for autologous stem cell transplantation

• Patients must have a complete medical history and physical exam within 14 days prior to registration

• Within 14 days prior to registration: Total bilirubin =\< 2.0 x IULN (institutional upper limit of the norm) AND

• Within 14 days prior to registration: Serum glutamic-oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) and serum glutamate pyruvate transaminase (SGPT)/alanine aminotransferase (ALT) =\< 4.0 x IULN

• Creatinine clearance (CrCl) \>= 25 mL/min, as measured by a 24-hour urine collection or as estimated by the Cockcroft and Gault formula; the serum creatinine value used in the calculation must have been obtained within 35 days prior to registration

• Patients must have bone marrow aspirate, including fluorescence in situ hybridization (FISH) (including: del 17p; t11;14; t4;14, t14;16; and del 13q) and cytogenetic testing (normal ? XY; and all abnormalities) within 35 days prior to registration; central pathology analysis will not be required, however the local pathology report and FISH/cytogenetic data must be submitted in Medidata RAVE

• Within 14 days prior to registration: Absolute neutrophil count (ANC) \>= 1,000 cells/mcl without growth factor support, AND

• Within 14 days prior to registration: Platelets \>= 75,000 cells/mcl

• Patients must have hemoglobin \>= 8 g/dL within 14 days prior to registration; patients may have received transfusion if greater than 7 days prior to registration

• New York Heart Association (NYHA) \< class IV heart failure

• Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) \>= 35% within 35 days prior to registration; and

• NT-proBNP =\< 8500 ng/L within 14 days prior to registration

• Patients must have a Zubrod performance status =\< 2

• Patients must not have any clinically significant uncontrolled systemic illness, including but not limited to uncontrolled, active infection requiring intravenous antibiotics, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmias, uncontrolled hypertension, or uncontrolled diabetes mellitus

‣ Uncontrolled diabetes: patients who have a diagnosis of diabetes must have an glycosylated hemoglobin (HbA1C) \< 7% within 14 days prior to registration; the same criterion will be used in patients with confirmed diagnosis of diabetes mellitus who have been on a stable dietary or therapeutic regimen for this condition in the last three months

⁃ Uncontrolled blood pressure and hypertension: all blood pressure measurements within the 14 days prior to registration must be systolic blood pressure (SBP) =\< 160 and diastolic blood pressure (DBP) =\< 100; an exception can be made by a healthcare provider for a patient with a single blood pressure elevation who upon rechecking has a normal blood pressure

• Females of childbearing potential must have a negative baseline pregnancy test within 14 days prior to registration; this may be either a serum or urine pregnancy test, with a sensitivity of at least 50 mIU/mL; females of childbearing potential (FCBP) must also agree: (1) to have a pregnancy test prior to the start of each treatment cycle and (2) to either commit to continued abstinence from heterosexual intercourse or to use effective contraception while receiving study drug and for at least 12 weeks after receiving the last dose of study drug; females are considered to be of ?childbearing potential? if they have had menses at any time in the preceding 24 consecutive months; in addition to routine contraceptive methods, ?effective contraception? also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, she is responsible for beginning contraceptive measures

• Patients with evidence of hepatitis B virus (HBV) are eligible provided there is minimal hepatic injury and the patient has undetectable HBV on suppressive HBV therapy; patient must be willing to maintain adherence to HBV therapy; patients with previously treated and eradicated hepatitis C virus (HCV) who have minimal hepatic injury are eligible

• Patients who are known to be human immunodeficiency virus (HIV)-positive at registration are eligible if at time of registration they meet all other protocol eligibility criteria in addition to the following:

‣ Patient has undetectable HIV viral load by standard polymerase chain reaction (PCR) clinical assay

⁃ Patient is willing to maintain adherence to combination antiretroviral therapy

⁃ Patient has no history of acquired immunodeficiency syndrome (AIDS) defining condition (other than CD4 cell count \< 200 mm\^3)

⁃ Patient is otherwise likely to have a near normal lifespan if not for the presence of relapsed/refractory amyloid

• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for at least two years