Cevostamab following BCMA CAR T Cell Therapy for the Treatment of Relapsed or Refractory Multiple Myeloma

Inclusion Criteria

• Signed informed consent form(s)
• Age >= 18 years at time of signing informed consent form
• Ability to comply with the study protocol
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy of at least 12 weeks
• Subjects must have relapsed and/or refractory multiple myeloma with at least 4 prior lines of therapy that must include a proteasome inhibitor, immunomodulatory drug (IMiD), and anti-CD38 antibody, and have received a BCMA-directed CAR T cell product as standard of care (i.e. not on a clinical trial) between 4 and 8 weeks prior to enrollment, and have not had progressive disease by International Myeloma Working Group (IMWG) criteria since CAR T cell infusion. Patients who have received out-of-specification CAR T cell products are not eligible
• Agreement to provide bone marrow biopsy and aspirate samples
• Non-hematologic adverse events from prior anti-cancer therapy resolved to grade =< 1, with the following exceptions: * Any grade alopecia * Peripheral sensory or motor neuropathy must have resolved to grade =< 2
• Measurable disease is not required for study entry
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)
• Total bilirubin =< 1.5 x ULN; subjects with a history of Gilbert’s syndrome and in whom total bilirubin elevations are accompanied by elevated indirect bilirubin are eligible
• Platelet count >= 50,000/mm^3 without transfusion within 7 days prior to first dose
• Absolute neutrophil count (ANC) >= 1000/mm^3
• Total hemoglobin >= 7 g/dL
• Subjects who do not meet criteria for hematologic function because of multiple myeloma (MM)-related cytopenias (e.g., due to extensive marrow involvement by MM) may be enrolled into the study after discussion with the medical director * Note: Subjects may receive supportive care to meet hematologic function eligibility criteria (e.g., transfusions, granulocyte colony-stimulating factor [G-CSF], etc.).
• Creatinine clearance (CrCl) >= 30 mL/min (either calculated or per 24-hour [hr] urine collection)
• Serum calcium (corrected for albumin) level at or below grade 1 hypercalcemia (subject may receive treatment for hypercalcemia to meet eligibility criteria)
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, as defined below: * Subjects treated with cevostamab: Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period (including treatment interruptions) and for at least 5 months after the last dose of cevostamab was administered * Subjects treated with tocilizumab (if applicable): Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 3 months after the last dose of tocilizumab was administered. Women must refrain from breastfeeding during the same period * A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a post-menopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus) * Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: * With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 60 days after the last dose of cevostamab and tocilizumab (if applicable) to avoid exposing the embryo. Men must refrain from donating sperm during this same period * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception

Exclusion Criteria

• Inability to comply with protocol-mandated hospitalization and activities restrictions
• Pregnant or breastfeeding, or intending to become pregnant during the study or within 3 months after the last dose of study drug * Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study drug
• Subjects who had >= grade 3 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) by American Society for Transplantation and Cellular Therapy (ASTCT) criteria, or any grade macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH) after CAR-T therapy are excluded
• Subjects who had any grade movement and/or neurocognitive disorder attributed to CAR T cells are excluded
• Prior treatment with systemic immunotherapeutic agents, including, but not limited to, cytokine therapy and anti-CTLA4, anti−PD-1, and anti−PD-L1 therapeutic antibodies, within 12 weeks or 5 half-lives of the drug, whichever is shorter, before first cevostamab infusion
• Known treatment-related, immune-mediated adverse events associated with prior immunotherapeutic agents as follows: * Prior PD-L1/PD-1 or CTLA-4 inhibitor: Grade >= 3 adverse events with the exception of grade 3 endocrinopathy managed with replacement therapy * Grade 1−2 adverse events that did not resolve to baseline after treatment discontinuation
• Treatment with any chemotherapeutic agent, or any other anti-cancer agent (investigational or otherwise) during the time period between CAR T cell infusion and first cevostamab infusion, with the following exceptions: * Therapies used for treatment of CAR T cell-related toxicities (e.g. steroids, cyclophosphamide) will not be a cause for exclusion, as long as washout period listed below (2 weeks) is met * Short course palliative radiation post-CAR T cell therapy (e.g. for severe bone pain, impending fracture) is allowed as long as completed at least 1 week prior to first dose of cevostamab
• Received systemic immunosuppressive medications (including, but not limited to, steroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, tocilizumab, siltuximab, anakinra, ruxolitinib, and anti-tumor necrosis factor agents), with the exception of corticosteroid treatment =< 10 mg/day prednisone or equivalent, within 2 weeks prior to first dose of cevostamab * Subjects who received acute, low-dose, systemic immunosuppressant medications (e.g., single dose of dexamethasone for nausea) may be enrolled in the study ** The use of inhaled corticosteroids is permitted ** The use of mineralocorticoids for management of orthostatic hypotension is permitted ** The use of physiologic doses of corticosteroids for management of adrenal insufficiency is permitted
• Autologous stem cell transplantation (SCT) within 100 days prior to first cevostamab infusion
• Prior allogeneic SCT within 12 months prior to first cevostamab infusion. Subjects with prior allogeneic SCT must have no evidence for active graft-versus-host-disease (GVHD) and be off all therapy for GVHD for at least 3 months prior to first cevostamab infusion
• Prior solid organ transplantation
• History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis * Subjects with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study
• Subjects with history of confirmed progressive multifocal leukoencephalopathy
• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (or recombinant antibody-related fusion proteins)
• History of other malignancy that could affect compliance with the protocol or interpretation of results * Subjects with a history of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix are allowed * Subjects with a malignancy that has been treated with curative intent will also be allowed if the malignancy has been in remission prior to first cevostamab infusion
• Current or past history of central nervous system (CNS) disease, such as stroke, epilepsy, CNS vasculitis, neurodegenerative disease, or CNS involvement by MM * Subjects with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 2 years and have no residual neurologic deficits as judged by the investigator are allowed * Subjects with a history of epilepsy who have had no seizures in the past 2 years while not receiving any anti-epileptic medications are allowed
• Significant cardiovascular disease (such as, but not limited to, New York Heart Association class III or IV cardiac disease, myocardial infarction within the last 6 months, uncontrolled arrhythmias, or unstable angina) that may limit a subject's ability to adequately tolerate a cytokine release syndrome (CRS) event
• Symptomatic active pulmonary disease or requiring supplemental oxygen
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics within 14 days prior to first cevostamab infusion. Empiric or prophylactic antibiotics administered during neutropenia or neutropenic fever without microbiologic evidence of infection do not exclude subjects * Subjects with asymptomatic cytomegalovirus (CMV) reactivation (i.e. positive CMV polymerase chain reaction [PCR]) found at screening may enroll after discussion with the medical director
• Known or suspected chronic active Epstein-Barr virus (EBV) infection. Guidelines for diagnosing chronic active EBV infection are provided by Okano et al. (2005)
• Recent major surgery within 4 weeks prior to first cevostamab infusion * Protocol-mandated procedures (e.g., bone marrow biopsies) are permitted
• Positive serologic or polymerase chain reaction (PCR) test results for acute or chronic hepatitis B virus (HBV) infection * Subjects whose HBV infection status cannot be determined by serologic test results (www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf) must be negative for HBV by PCR to be eligible for study participation
• Acute or chronic hepatitis C virus (HCV) infection * Subjects who are positive for HCV antibody must be negative for HCV by PCR to be eligible for study participation
• Known history of human immunodeficiency virus (HIV) seropositivity
• Administration of a live, attenuated vaccine within 4 weeks before first cevostamab infusion or anticipation that such a live attenuated vaccine will be required during the study * Influenza vaccination should be given during influenza season (approximately October to May in the Northern Hemisphere). Subjects must not receive live, attenuated influenza vaccine (e.g., FluMist [registered trademark]) at any time during the study treatment period * Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines may be given in accordance with the approved/authorized vaccine label and official/local immunization guidance. SARS-CoV-2 vaccines must not be administered within 1 week before first study treatment or during cycle 1 * Investigators should review the vaccination status of potential study subjects being considered for this study and follow the United States (U.S.) Centers for Disease Control and Prevention guidelines for adult vaccination with any other non-live vaccines intended to prevent infectious diseases prior to study
• Any medical condition or abnormality in clinical laboratory tests that, in the medical director’s judgment, precludes the subject's safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results