Idelalisib for Immunoglobulin M (IgM)-Associated Primary (AL) Amyloidosis

This study includes the use of Idelalisib to treat previously treated patients with
IgM-associated AL Amyloidosis at Boston Medical Center. Boston Medical Center is
internationally recognized as a leader in amyloidosis research and patient care through the
activities of the multidisciplinary Amyloid Center at Boston University. The problematic
cell in most forms of AL amyloidosis shares similarities with multiple myeloma. However, in
the small subset of AL Amyloidosis patients with an IgM paraprotein, the cells are more
typically related to lymphoplasmacytic lymphoma or Waldenstrom's macroglobulinemia. Because
clonal CD20+ lymphoplasmacytic cells are usually responsible for IgM paraproteins, treatment
paradigms based on Waldenstrom's macroglobulinemia (WM) may be more appropriate than
myeloma-based strategies. Idelalisib has been shown to be active and well tolerated in
patients with relapsed/refractory non-Hodgkin lymphoma including chronic lymphocytic
lymphoma, and lymphoplasmacytic lymphoma with or without Waldenström's macroglobulinemia
(WM). The side effect profile of idelalisib merges well with the known predisposition to
toxicity of amyloidosis patient.

The investigators expect to enroll 15 participants with IgM-associated AL amyloidosis onto
this Phase II clinical trial. Idelalisib will be self-administered orally at a dose of 100
mg (1 tablet) twice daily (may be escalated to 150 mg (one tablet) twice daily after 3
months at investigator discretion). Participants will be treated until disease progression,
unacceptable toxicity, or decision to withdraw from the trial. Disease evaluations will be
performed every three months until disease progression.

Inclusion Criteria:

3.1.1 IgM paraprotein identified on serum immunofixation electrophoresis OR light
chain-restricted CD20+ lymphoplasmacytic population on biopsy of bone marrow or lymph node
(identified by H&E/immunohistochemistry or flow cytometry) OR positive myeloid
differentiation primary response gene 88 (MYD88-L265P) OR CXCR4WHIM mutation on submitted
samples

3.1.2 Biopsy-proven relapsed or refractory AL amyloidosis

3.1.3 Age ≥ 18 years

3.1.4 Eastern Cooperative Oncology Group (ECOG) performance status <2 (see Appendix A.)

3.1.5 Difference between serum free light chains (FLC) of >30 mg/L or quantifiable IgM
paraprotein >0.5 g/L

3.1.6 Participants must have normal organ and marrow function as defined below:

- Absolute neutrophil count > 1,000/mm3

- Platelets > 50,000/mm3

3.1.7 Ability to understand and the willingness to sign a written informed consent
document.

Exclusion Criteria:

3.2.1 Previous treatment with idelalisib

3.2.2 Glomerular filtration rate (GFR) <15 ml/min

3.2.3 Cardiac biomarker Stage III disease as determined by B-type natriuretic peptide
(BNP) >100 pg/mL and Troponin-I >0.1 ng/mL (Girnius 2014)

3.2.4 ALT/AST values >2.5x ULN, Bilirubin >1.5 upper limit of normal (ULN)

3.2.5 Central nervous system (CNS) malignancy or other active malignancy

3.2.6 Lactating or pregnant women

3.2.7 Exposure to another investigational drug within 4 weeks prior to start of study
treatment

3.2.8 Ongoing alcohol or drug addiction as determined by investigator

3.2.9 Amyloid-directed therapy within the past 28 days

3.2.10 History of Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV)
(assessed by positive Hepatitis B polymerase chain reaction assay (PCR) or HepB Surface
Antigen), and/or Hepatitis C Virus (HCV) infection

3.2.11 t(11,14) translocation identified on bone marrow cytogenetics or by FISH

3.2.12 Known lytic bone lesions

3.2.13 Positive CMV PCR

3.2.14 Previously untreated AL amyloidosis (Newly diagnosed)

3.2.15 Unwilling or unable to comply with the protocol