Амбулаторное и периодическое применение элранатамаба при рецидивирующей/рефрактерной множественной миеломе (EMBRACE)

Inclusion Criteria:

1. Relapsed and/or refractory MM defined as:

   1. Documented evidence of progressive disease (PD) after achieving at least minimal response (MR) for ≥ 1 cycle during a previous MM treatment (i.e., relapsed MM).
   2. Disease progression during or within 60 days from the end of the most recent MM treatment (i.e., refractory MM).

2. Measurable disease based on IMWG criteria, defined as at least one of the following, documented within 28 days before enrollment:

   1. Serum M-protein ≥ 0.5 g/dl.
   2. Urine M-protein excretion ≥ 200 mg/24 h.
   3. Serum-free light chains (FLC) assay: Involved FLC level ≥ 10 mg/dl (≥ 100 mg/l) AND an abnormal serum-free light chain ratio (< 0.26 or > 1.65) only for patients without measurable serum or urine M protein.

3. Receipt of at least three prior classes of drugs either in separate regimens or as combinations.

   The three classes are defined as:

   An immunomodulatory drug (lenalidomide or pomalidomide), a proteasome inhibitor (bortezomib, ixazomib, carfilzomib), and an anti-CD38 drug (daratumumab or isatuximab).

4. At least 18 years of age.

5. Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2.

Exclusion Criteria:

Medical conditions

1. Active plasma cell leukemia (either 20% of peripheral white blood cells or > 2.0 × 109/L circulating plasma cells by standard differential).

2. Amyloidosis.

3. POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder, Skin Changes).

4. Monoclonal gammopathy of unknown significance or smoldering multiple myeloma.

5. Solitary plasmacytoma.

6. Stem cell transplant within 12 weeks prior to enrollment or active graft versus host disease.

7. History of prior treatment with a BCMA targeting agent.

   Laboratory Parameters

8. Laboratory results within 28 days as per below prior to enrollment:

   • Absolute neutrophil count (ANC) ≤ 1.0 x 109 /L) (use of growth factor is permitted if completed at least 7 days prior to enrollment).
   • Platelet count ≤ 25 x 109 /L (transfusion support permitted if completed at least 7 days prior to enrollment).
   • Hemoglobin ≤ 8.0 g/dL (transfusion support permitted if completed at least 7 days prior to enrollment, concurrent erythropoietin stimulating agents allowed).
   • Serum AST and ALT > 2.5 x upper limit of normal (ULN).
   • Creatinine clearance < 30 mL/min (according to the Cockcroft Gault formula, by 24-hour urine collection for creatinine clearance, or according to local institutional standard method).
   • Total bilirubin > 2.0 x ULN (≥ 3.0 unless known to have Gilbert's disease).

   Support Requirement

9. As this protocol requires outpatient administration, the patient will be excluded if they cannot agree to the following for the first 9 days post-first dose of drug administration:

   1. Staying within 60 minutes of travel distance to their trial-based hospital.
   2. Must have a caregiver/support person who will stay with the patient.
   3. Patient and/or their caregiver/support person agree to monitor and record oral temperature q8 hours.
   4. Patients must agree that if they have an oral temperature of (≥38°C), they must report to the study team within 1 hour and can come to the hospital for admission within 2 hours.

   Other co-morbidities

10. Impaired cardiovascular function or clinically significant cardiovascular diseases, defined as any of the following within 6 months before enrollment:

    • Acute myocardial infarction or acute coronary syndromes (eg, unstable angina, coronary artery bypass graft, coronary angioplasty or stenting, symptomatic pericardial effusion).
    • Clinically significant cardiac arrhythmias (eg, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia).
    • Thromboembolic or cerebrovascular events (eg, transient ischemic attack, cerebrovascular accident, deep vein thrombosis [unless associated with a central venous access complication], or pulmonary embolism).
    • Prolonged QT syndrome (or triplicate average QTcF >470 msec at screening).

11. Ongoing Grade ≥2 peripheral sensory or motor neuropathy.

12. History of Guillain-Barre Syndrome (GBS) or GBS variants, or history of any Grade ≥3 peripheral motor polyneuropathy.

13. Unresolved acute effects of any prior therapy for MM in the last three months to either baseline severity or NCI CTCAE ≤Grade 1.

14. Active HBV, HCV, SARS-CoV2, HIV, or any active, uncontrolled bacterial, fungal, or viral infection.

15. Any other active malignancy within 2 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ.

16. Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions (including lab abnormalities), or surgical (major surgery within 14 days prior to enrollment) that could interfere with the patient's safety, obtaining informed consent or compliance to the study procedures.

17. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to elranatamab or any of the components of the study treatment.

    Concomitant Medications

18. Treatment with a chemotherapeutic or anti-MM drug within the last 28 days or 5 half-lives (whichever is shorter) prior to enrollment or are currently enrolled in another interventional clinical study.

19. Receipt of any other therapy to treat cancer (including radiation, biologics, cellular therapies, and/or steroids at doses > 20 mg dexamethasone or equivalent) within 14 days prior to the enrollment.

20. Receipt of any live vaccine within 30 days prior to enrollment or expected need of live vaccination during study participation. (Administration of locally approved non-live vaccine can be done as per local guidelines during the screening and/or treatment period including the COVID-19 mRNA vaccine. Elranatamab should be administered ± 7 days from the SARS-CoV-2 vaccine administration).

    Pregnancy and Contraception

21. Pregnancy or lactating female or inability of female patients of childbearing potential (FCBP) to meet contraception requirements (see Section 5.1.3.).

    Informed Consent

22. Inability to provide signed, informed consent.