A Study of Elranatamab Outpatient Administration in Patients With Relapsed/Refractory Multiple Myeloma

A Phase II, Nonrandomized, Single-Arm Study of Elranatamab Outpatient Administration in Patients With Relapsed/Refractory Multiple Myeloma (CORE-MM)

This is a Phase II, open-label, nonrandomized, single-arm study of elranatamab that will be administered in the outpatient setting in 2 sequential cohorts of participants with relapsed or refractory multiple myeloma (RRMM). The primary objective of this study is to evaluate the overall incidence of cytokine release syndrome (CRS) during Cycle 1 of elranatamab treatment following a single prophylactic dose of tocilizumab.

This is a Phase II, open-label, nonrandomized, single-arm study of elranatamab that will be administered in the outpatient setting in 2 sequential cohorts of participants with relapsed or refractory multiple myeloma (RRMM) who have received ≥1 prior line of therapy and are double class exposed (lenalidomide and an anti-CD38). A safety-lead in will be employed for the first 6 evaluable participants (participants who have completed Cycle 1) (Cohort 1), followed by an expansion cohort (Cohort 2) of 40 participants. Eligible participants will receive a single prophylactic dose of tocilizumab followed by treatment with elranatamab. Tocilizumab, an interleukin-6 (IL-6) receptor antagonist, is approved for the treatment of Chimeric Antigen Receptor T-Cell (CAR-T)-associated CRS, and has shown promise in reducing CRS incidence when used prophylactically in bispecific antibody trials. Elranatamab is a bispecific antibody targeting B-cell maturation antigen (BCMA) and CD3, designed to redirect T cells to eliminate malignant plasma cells in multiple myeloma (MM).

Inclusion Criteria:

1. Written informed consent, according to institutional guidelines, signed and dated by the participant or by a legal guardian prior to the performance of any study-specific procedures, sampling, or analyses

2. At least 18 years-of-age at the time of signature of the ICF

3. Has documented diagnosis of MM according to IMWG diagnostic criteria

4. Measurable disease at screening, as assessed by local laboratory, defined by any of the following:

   1. Serum M-protein level ≥0.5 g/dL
   2. Urine M-protein level ≥200 mg/24 hours
   3. Light chain MM without measurable M-protein in the serum or the urine: serum free light chain (sFLC) ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio
   4. For participants without measurable disease in the serum, urine, or involved FLC, presence of plasmacytomas (≥2 cm x 1 cm)

5. Relapsed and/or refractory MM received ≥1 prior line of therapy and must have been exposed to both lenalidomide and an anti-CD38 monoclonal antibody (in the same or separate prior lines)

6. ECOG Performance Status score of 0 or 1

7. Human immunodeficiency virus (HIV)-positive participants are eligible if they meet all of the following:

   1. No detectable viral load (i.e., <50 copies/mL) at screening
   2. CD4+ count >300 cells/mm3 at screening
   3. No acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within 6 months of screening
   4. Receiving highly active antiretroviral therapy (HAART). Any changes in HAART due to resistance/progression should occur at least 3 months prior to enrollment. A change in HAART due to toxicity is allowed up to 4 weeks prior to enrollment. HAART that could interfere with study treatment is excluded (consult the Medical Monitor for a review of medications prior to enrollment, if needed).

8. Adequate organ function, defined as follows:

   1. Hemoglobin (Hgb) ≥8 g/dL (≥5 mmol/L; without prior red blood cell [RBC] transfusion within 7 days before laboratory testing; recombinant human erythropoietin use is permitted)
   2. Platelets >50 x109/L
   3. Absolute neutrophil count (ANC) ≥10.x109/L (prior growth factor support is permitted but must be without support for 7 days for G-CSF or GM-CSF and for 14 days for pegylated G-CSF)
   4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5xupper limit of normal (ULN)
   5. Estimated glomerular filtration rate (eGFR) ≥30 mL/min based on Modified Diet in Renal Disease (MDRD) 4-variable formula calculation or creatinine clearance measured by 24-hour urine collection
   6. Total bilirubin <1.5xULN (isolated total bilirubin) ≥1.5xULN with conjugated [direct] bilirubin <1.5xULN is allowed for those participants with known congenital nonhemolytic hyperbilirubinemias)
   7. Corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L)

9. Participants must be able and willing to receive prophylaxis for Varicella zoster virus (VZV) and Pneumocystis jirovecii pneumonia (PJP) as follows:

   1. VZV prophylaxis (e.g. acyclovir or valacyclovir) must be initiated prior to or on Day 1 of study treatment, continued throughout the treatment period, and maintained for at least 3 months after the final dose
   2. PJP prophylaxis must likewise be initiated prior to or on Day 1 of study treatment, continued throughout the treatment period, and maintained for at least 3 months after the final dose

10. A woman of childbearing potential must have a negative highly sensitive serum pregnancy test at screening and again within 24 hours of the start of study treatment and must agree to further serum or urine pregnancy tests during the study.

11. A woman must be:

    a. Not of childbearing potential, or b. Of childbearing potential and practicing true abstinence; or i. Have a sole partner who is vasectomized; or ii. Practicing ≥1 highly-effective, user-independent method of contraception. R

12. A woman must agree not to donate eggs (ova, oocytes) or freeze for future use, for the purposes of assisted reproduction during the study and for 4 months after receiving the last dose of study treatment.

13. A man must wear a condom (with or without spermicidal foam/gel/film/cream/suppository when engaging in any activity that allows for passage of ejaculate to another person during the study and for a minimum of 90 days after receiving the last dose of study treatment. If a female partner is of childbearing potential, she must also be practicing a highly effective method of contraception.

14. A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 90 days after receiving the last dose of study treatment.

Exclusion Criteria:

1. History of antitumor therapy as follows, before the first dose of study drug

   1. Targeted therapy, epigenetic therapy, or treatment with an investigational drug or used an invasive investigational medical device within 21 days or at least 5 half-lives, whichever is shorter.
   2. Monoclonal antibody treatment for MM within 21 days.
   3. Cytotoxic therapy within 21 days.
   4. PI therapy within 14 days.
   5. Immunomodulatory agent therapy within 7 days.
   6. Radiotherapy within 14 days or focal radiation within 7 days.
   7. Prior gene modified adoptive cell therapy (e.g., chimeric antigen receptor modified [CAR]-T cells) ≤12 weeks before the first dose of study drug

2. Has received any of the following:

   1. Packed red blood cells within the last 7 days prior to dosing
   2. Platelet transfusions within the last 7 days prior to dosing
   3. Live vaccine within 1 month prior to screening or plans to receive a live vaccine during the study

3. History of Grade ≥3 CRS or ICANS with prior therapies.

4. Current treatment with strong or moderate inducers of cytochrome P450 (CYP) 3A4 (CYP3A4) that cannot be discontinued at least 7 days prior to the start of elranatamab treatment and during the study.

5. Has myelodysplastic syndrome or active malignancies (i.e., progressing or requiring treatment change in the last 12 months) other than RRMM. The only allowed exceptions are:

   a. Malignancies treated within the last 12 months and considered at very low risk for recurrence: i. Non-muscle invasive bladder cancer (solitary Ta-PUNLMP or low grade, <3 cm, no CIS).

   ii. Skin cancer (non-melanoma or melanoma). iii. Noninvasive cervical cancer. iv. Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, localized breast cancer and receiving antihormonal agents.

   v. Localized prostate cancer (M0, N0) with a Gleason Score ≤7a, treated locally only (RP/RT/focal treatment).

   b. Other malignancy that is considered at minimal risk of recurrence. In the event of any questions, consult with the Medical Monitor prior to enrolling a participant.

6. Has active autoimmune disease or documented history autoimmune disease with exception of vitiligo, type I diabetes mellitus, or prior autoimmune thyroiditis currently euthyroid based on symptoms and labs.

7. Has active plasma cell leukemia (≥20% peripheral blood plasma cells and ≥2.0×109/L plasma cells by standard differential), Waldenström's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or primary amyloid light-chain amyloidosis.

8. Any of the following cardiac criteria currently or within the last 6 months:

   1. Have documented major electrocardiogram (ECG) abnormalities which are clinically significant at the Investigator's discretion (for example, symptomatic or sustained atrial or ventricular arrhythmias, second- or third-degree atrioventricular block, bundle-branch blocks, ventricular hypertrophy, or recent myocardial infarction or a mean QTc of >470 ms [calculated using Fridericia's Correction, confirmed by triplicate ECG])
   2. Cardiac function: left ventricular ejection fraction (LVEF) assessed by ECHO or MUGA <45% (evaluation based on institutional lower limit of normal) and the patient has a significant cardiac history, or the investigator suspects ongoing cardiac pathology
   3. Have the presence of cardiac disease, including a myocardial infarction or any other arterial thrombotic event including cerebrovascular accident or transient ischemic attack within 6 months prior to enrollment, unstable angina pectoris, New York Heart Association (NYHA) Class III-IV congestive heart failure, aneurysm of major vessels or heart, uncontrolled hypertension.
   4. Overall cardiac ineligibility determined by the Investigator based on medical history and clinically indicated evaluations

9. Any significant neurologic or psychiatric conditions diagnosed and/or ongoing in the last 6 months prior to anticipated treatment start date including but not limited to severe brain injury, stroke, intracranial hemorrhage, seizure, dementia, or Parkinson's disease. Participants with a history of uncontrolled epilepsy requiring anticonvulsants are excluded if therapy not stable within 6 months prior to enrollment.

10. Active central nervous system (CNS) multiple myeloma involvement.

11. Has fever or active infection (bacterial, viral, or uncontrolled systemic fungal) at time of study enrollment.

12. Has hepatitis B infection (i.e., HBsAg or HBV-DNA positive). In the event the infection status is unclear, quantitative viral levels are necessary to determine the infection status. See Section 7.4.7 for further required assessments.

13. Has active hepatitis C infection as measured by positive HCV-RNA testing. Participants with a history of HCV antibody positivity must undergo HCV-RNA testing. If a participant with history of chronic hepatitis C infection (defined as both HCV antibody and HCV-RNA positive) completed antiviral therapy and has undetectable HCV-RNA 12 weeks following the completion of therapy, the participant is eligible for the study.

14. Women who are pregnant, nursing, or plan to become pregnant while in the study and for at least 4 months after the last administration of study treatment.

15. Men who plan to father a child while in the study and for at least 6 months after the last administration of study treatment.

16. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, uncontrolled diabetes mellitus, active bleeding diatheses, or active infection, including hepatitis B, hepatitis C, and human immunodeficiency virus. Screening for chronic conditions is not required.

17. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.