Elranatamab for the Treatment of Patients with Relapsed or Refractory AL Amyloidosis

Inclusion Criteria

• Previously diagnosed with AL amyloidosis based on International Myeloma Working Group (IMWG) criteria who have relapsed or refractory disease after treatment with at least one prior line of therapy (minimum 2 cycles)
• Participants must have progression of light chain disease, defined as difference in involved and uninvolved free light chain (dFLC) > 20mg/L
• For Phase 2 only, measurable hematologic disease, satisfying one of the following criteria: * Difference between involved and uninvolved free light chain (FLC) over 40 mg/L * Abnormal level of FLC with an abnormal κ/λ ratio (except in participants with chronic kidney disease [CKD] stage 3 or higher where a rise of lambda FLC to an abnormal level and of at least 50% over the nadir with a normal κ/λ ratio is acceptable) * A serum M spike measuring ≥ 0.5 g/dL
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 or Karnofsky ≥ 60%
• Absolute leukocyte count* ≥ 3,000/mcL * If criteria are not met, check Duffy null genotype. If positive, participant will be allowed on study
• Absolute neutrophil count* ≥ 1,000/mcL. Screening absolute neutrophil count (ANC) should be independent of granulocyte- and granulocyte/macrophage colony stimulating factor (G-CSF and GMCSF) support for at least 1 week and of pegylated G-CSF for at least 2 weeks * If criteria are not met, check Duffy null genotype. If positive, participant will be allowed on study
• Absolute platelet count ≥ 75,000/mcL. Platelet transfusions to help participants meet eligibility criteria are not allowed within 2 weeks before study enrollment
• Direct bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 × institutional ULN
• Creatinine Calculated clearance ≥ 30 mL/min using Cockcroft-Gault equation
• Participants who received belantamab mafodotin are eligible if discontinued due to intolerance or adverse event
• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• AL Amyloidosis Cardiac stage I, II or IIIa disease based on the 2013 European Modification of the 2004 Standard Mayo Clinic Staging in participants with advanced cardiac involvement (Dispenzieri et al., 2004; Wechalekar et al., 2013). * Staging system defined by: N-Terminal Fragment Brain Natriuretic Protein (NT-proBNP) cut off of < 332 pg/mL and troponin I cut-off of < 0.10 ng/mL (in the absence of Troponin T, Troponin I ≥ 0.1 ng/mL can be used) as thresholds for stages I, II and III; NT-proBNP ≤ 8500 pg/ml for stage IIIa. * Stage I, both under threshold; * Stage II, either troponin or NT-proBNP (but not both) over threshold; * Stage III, both over threshold; * Stage IIIa, both over threshold but NT-proBNP ≤ 8500 pg/mL ** Stage I: Zero markers above threshold: *** NT-proBNP < 332 ng/L AND troponin T (TnT) < 0.035 ng/mL *** NT-proBNP < 332 ng/L AND troponin I (TnI) <0.1 ng/mL *** NT-proBNP < 332 ng/L AND high sensitivity cardiac troponin T (hs-cTnT) < 50 ng/L ** Stage II: One marker above threshold: *** NT-proBNP ≥ 332 ng/L OR TnT ≥ 0.035 ng/mL *** NT-proBNP ≥ 332 ng/L OR TnI ≥ 0.1 ng/mL *** NT-proBNP < 332 ng/L OR hscTnT ≥ 50 ng/L ** Stage IIIa: Two markers above threshold: *** NT-proBNP ≥ 332 ng/L BUT < 8,500 ng/L AND TnT ≥ 0.035 ng/mL *** NT-proBNP ≥ 332 ng/L BUT < 8,500 ng/L AND TnI ≥ 0.1 ng/mL *** NT-proBNP ≥ 332 ng/L BUT < 8,500 ng/L AND hs-cTnT ≥ 50 ng/L ** Stage IIIb: Two markers above threshold: *** NT-proBNP ≥ 8,500 ng/L AND TnT ≥ 0.035 ng/mL *** NT-proBNP ≥ 8,500 ng/L AND TnI ≥ 0.1 ng/mL *** NT-proBNP ≥ 8,500 ng/L AND hs-cTnT ≥ 50 ng/L **** Stage IIIb not eligible to participate
• The effects of elranatamab on the developing human fetus are unknown. Based on the mechanism of action, elranatamab may cause fetal harm when administered to a pregnant woman and therefore should not be used during pregnancy. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and until 90 days since the last dose of elranatamab. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 90 days after completion of elranatamab administration
• Ability to understand and the willingness to sign a written informed consent document
• Willingness to undergo study procedures, including bone marrow biopsies as detailed in the schedule of events
• Patients must have received at least one cycle of daratumumab monotherapy (or in combination with other anti-plasma cell directed therapy), cyclophosphamide/bortezomib/dexamethasone (CyBorD), or Daratumumab + CyBorD
• Anti-plasma cell directed therapy discontinued for at least 5 half-lives or a minimum of 2 weeks (whichever is shorter) prior to the initiation of elranatamab
• Patients who have received a stem cell transplant must wait at least 1 year prior to the initiation of elranatamab
• Patients who have received a monoclonal antibody such as daratumumab, would need drug discontinued for at least 2 weeks prior to the initiation of elranatamab

Exclusion Criteria

• Prior BCMA-targeting bispecific antibodies or BCMA-targeting chimeric antigen receptor (CAR)-T therapy
• Participants refractory to belantamab mafodotin OR participants that have received belantamab as the immediate past line of therapy
• Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
• Participants who are receiving any other investigational agents for this condition
• Participants with Stage IIIB Amyloidosis as defined by the 2004 Mayo Clinic Criteria
• History of allergic reactions to elranatamab
• Participants with an active malignancy (including lymphoma) with the following exceptions: * Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical cancer * Adequately treated stage I cancer from which the patient is currently in remission and has been for over 2 years * Low-risk prostate cancer with a Gleason score < 7 and prostate specific antigen < 10ng/mL * Other localized, indolent and/or low risk cancer may be permitted
• Women who are pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or 4 months following discontinuation of elranatamab, whichever is longer. Pregnant women are excluded from this study because elranatamab is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with elranatamab, breastfeeding should be discontinued if the mother is treated with elranatamab
• Have any other medical, social or psychological factors that could affect the participant’s safety or ability to consent personally or comply with study procedures
• Participants meeting criteria for active multiple myeloma (MM) based on presence of CRAB criteria (a ratio of involved versus uninvolved FLC over 100 is allowed in the absence of CRAB criteria)
• Participants with active clinically significant autoimmune diseases
• Participants seropositive for the human immunodeficiency virus (HIV)
• Severe, uncontrolled orthostatic hypotension resulting in syncopal/pre-syncopal events despite optimized medical management (e.g., midodrine, pyridostigmine) and in the absence of volume depletion
• Plan for autologous stem cell transplant during the first 6 months of protocol therapy
• History of acute coronary syndrome or uncontrolled ventricular arrhythmias within 3 months prior to screening
• Evidence of left ventricular (LV) systolic dysfunction as defined by left ventricular ejection fraction (LVEF) is < 30% by echocardiogram at screening per site cardiology interpretation
• Presence of severe valvular stenosis (e.g., aortic or mitral stenosis with a valve area < 1.0 cm^2) or severe congenital heart disease
• Have history of sustained ventricular tachycardia or aborted ventricular fibrillation or a history of atrioventricular nodal or sinoatrial nodal dysfunction if a permanent pacemaker (PPM) or implantable cardioverter-defibrillator (ICD) is not placed
• QT corrected by Fridericia (QTcF) is > 550 msec on screening electrocardiogram (ECG) unless they have a PPM/ICD implanted
• Screening electrocardiogram (EKG) showing acute myocardial ischemia or active conduction system abnormalities with the exception of any of the following: * First degree atrioventricular block * Second degree atrioventricular block Type 1 (Mobitz Type 1/Wenckebach type) * Right or left bundle branch block (e.g., Left Bundle Branch Block, Right Bundle Branch Block, Left Anterior Fascicular Block, or Left Posterior Fascicular Block) * Atrial fibrillation with a controlled ventricular rate. * Bifascicular block assessed as benign by the Investigator
• Major surgery that required general anesthesia within 4 weeks of study registration or is planning major surgery during the study
• New York Heart Association (NYHA) class IV symptoms or participants with acute decompensation of congestive heart failure
• Transplant eligible participants who have not undergone transplant are not eligible