Inclusion Criteria: 

Disease Related Criteria

• Patient must have relapsed or refractory primary systemic AL Amyloidosis, histologically-confirmed by positive Congo red stain with green birefringence on polarized light microscopy, OR characteristic appearance by electron microscopy AND confirmatory AL amyloid typing (mass spectrometry-based proteomic analysis or immunofluorescence). If there is question regarding diagnosis, consult Study Chairs prior to submission via e-mail to terri.parker@yale.edu and vaishali.sanchorawala@bmc.org.
• Patient must have measurable disease within 28 days prior to registration. Serum β2 microglobulin, Serum Quantitative Immunoglobulins (IgG, IgA, and IgM), serum free kappa and lambda, SPEP with M-protein quantification, and urine immunofixation electrophoresis must be obtained within 28 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 ≥ 4.5mg/dL within 28 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 at baseline (defined as within 28 days prior to registration) and must be documented on the AL Baseline Tumor Assessment Form. Note that the following organ disease assessments are required if there is suspected involvement of the organ(s). Only one organ is required to be involved for the patient to be eligible for the study. Assessment of each organ at baseline is not required if organ involvement is not suspected.
  • Kidney: Albuminuria greater than or equal to 500 mg per day on a 24-hour urine specimen, 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 NT-pro BNP greater than 332 pg/mL provided that patient does not have impaired renal function (as defined by calculated creatinine clearance less than 25 mL/min), 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 involvement: Hepatomegaly (total liver span >15cm) as demonstrated by CT, ultrasound, or MRI OR elevated alkaline phosphatase (ALP) greater than 1.5 times the upper limit of normal, OR prior liver biopsy (at time of diagnosis) showing amyloid deposition;
  • Gastrointestinal tract: For patients with suspected baseline GI involvement (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]), a 24-hour fecal fat test must be obtained at baseline;
  • Autonomic or peripheral nervous system: Orthostatic symptoms including dizziness or light-headedness with standing, nausea, early satiety, diarrhea or constipation, abnormal sensory and/or motor findings on neurologic exam, or gastric atony by gastric emptying scan. Patients suspected to have neurologic involvement, must have neurologic assessment including orthostatic measurements at baseline. NIS score at baseline is also suggested as a clinical tool for measurement of peripheral neuropathy, but it is not required. NCS/EMG studies are not required and can be obtained as clinically indicated. Orthostatic measurements must be repeated on 2 separate occasions (at least 1 day apart; e.g., Day -3 and Day -1);
  • Soft tissue: Macroglossia, or soft tissue deposits (including lymphadenopathy, recurrent peri-orbital purpura, peri-articular, skin or other soft tissue) requiring therapy. Imaging (CT, MRI, or ultrasound) is not required but may be performed as clinically indicated to measure soft tissue involvement.
• Patients must not have active symptomatic multiple myeloma, as defined by 2015 IMWG criteria (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 (Hgb < 8g/dL).

Prior/Concurrent Therapy Criteria

• 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 supplements which have been known to have some anti-amyloidogenic effect (such as: doxycycline; curcuramin; 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 as determined by the treating investigator or if the patient declined/refused.

Clinical/Laboratory Criteria

• Patients must have a complete medical history and physical exam within 28 days prior to registration.
• Patients must be ≥ 18 years of age.
• Patients must have adequate hepatic function within 28 days prior to registration, as defined by the following:
• Total bilirubin ≤ 2.0 x IULN (institutional upper limit of the norm) (patients with Gilbert's Syndrome must have a total bilirubin less than 3.0 mg/dL); AND
• SGOT/AST and SGPT/ALT ≤ 4.0 x IULN
• Patients must have adequate renal function, as defined by:
  • 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 28 days prior to registration.
  • Estimated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female)
                                                                       72 creatinine (mg/dl)
• Patients must have bone marrow aspirate and biopsy within 35 days prior to registration. The following are required:
  • quantitative percent clonal plasma cell involvement,
  • standard immunophenotyping,
  • immunohistochemistry,
  • cytogenetics,
  • fluorescent in situ hybridization (FISH) (via participating site local laboratory) to assess for del 17p; t11;14; t4;14, t14;16; and del 13q.
• Additionally, FISH and cytogenetic testing (normal – XY; and all abnormalities) are required to have been performed and to be reported, even if "no results" was achieved (i.e. due to too few cells in specimen). If FISH was performed, then the patient is eligible. If FISH was not performed, then patient is not eligible. Central pathology analysis will not be required, however the local pathology report and FISH/Cytogenetic data must be submitted in Medidata RAVE.
• Patients must have adequate bone marrow function as defined by the following within 28 days prior to registration: ANC ≥ 1,000 cells/mcl without growth factor support, AND platelets ≥ 75,000 cells/mcl.
• Patients must have hemoglobin ≥ 8 g/dL within 28 days prior to registration. Patients may have received transfusion if greater than 7 days prior to registration.
• Patients must have adequate cardiac function as defined by the following:
  • New York Heart Association (NYHA) < Class IV heart failure; and
  • LVEF by ECHO ≥ 35% within 28 days prior to registration; and
  • NT-proBNP ≤ 8500 pg/mL within 28 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 Hb A1C < 7% within 28 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 28 days prior to registration must be SBP ≤ 160 and 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 blood pressure within the parameters above.
• 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. Men must agree to use a condom with either cap, diaphragm or sponge with spermicide (double barrier method) during sexual contact with a FCBP, even if they have had a successful vasectomy for the study duration and for 12 weeks after the discontinuation of treatment.
• 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 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 PCR clinical assay;
  • Patient is willing to maintain adherence to combination antiretroviral therapy;
  • Patient has no history of AIDS defining condition (other than CD4 cell count < 200 mm3);
  • 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.

Specimen Submission Criteria

• Patients must be offered participation in specimen banking. With patient consent, pretreatment specimens must be collected and submitted via the SWOG Specimen Tracking System.

Regulatory Criteria

• Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.
• As a part of the OPEN registration process, the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.