Infliximab for Cytokine Release Syndrome Prophylaxis During Teclistamab or Talquetamab Therapy in Patients With Relapsed or Refractory Myeloma

Phase 2 Study of Cytokine Release Syndrome Prophylaxis With Infliximab for Teclistamab/Talquetamab Therapy in Patients With Relapsed/Refractory Myeloma

This phase II trial tests how well giving infliximab works for the prevention of cytokine release syndrome (CRS) during treatment with teclistamab or talquetamab in patients with multiple myeloma that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). CRS and neurologic toxicity (damage to the nervous system which includes the brain, spinal cord, and nerves) are potential risks of treatment with talquetamab and teclistamab. CRS involves a release of a large amount of proteins into the bloodstream causing inflammation. This may cause changes in blood pressure and heartbeat, flu-like symptoms (nausea, fever, and chills), and/or affect the lung/liver/kidney function. It may also cause certain brain-related symptoms, such as dizziness, weakness, confusion, difficulty speaking, and/or decreased brain function (possible paralysis and/or coma). Infliximab is a drug that prevents the tumor necrosis factor-alpha (TNF-α) from working. TNF-α is a cytokine, or chemical messenger, that helps your immune system produce inflammation. Giving infliximab may work well for the prevention of cytokine release syndrome during treatment with teclistamab or talquetamab in patients with relapsed or refractory multiple myeloma.

PRIMARY OBJECTIVE:

I. To determine the efficacy of infliximab as CRS prophylaxis for patients with relapsed/refractory multiple myeloma (RRMM) treated with teclistamab or talquetamab therapy.

SECONDARY OBJECTIVES:

I. To estimate the incidence of grade ≥ 3 CRS within cycle 1 (28 days). II. To estimate the incidence of all-grade and grade ≥ 3 neurologic toxicity (including Immune effector cell-associated neurotoxicity syndrome [ICANS]) within cycle 1 (28 days).

III. To estimate the incidence of grade ≥ 3 infection within cycle 1 (28 days). IV. To estimate the incidence of grade ≥ 3 anemia within cycle 1 (28 days). V. To estimate the incidence of grade ≥3 neutropenia within cycle 1 (28 days). VI. To estimate the incidence of grade ≥ 3 thrombocytopenia within cycle 1 (28 days).

VII. To determine the overall response rate (ORR) (per International Myeloma Working Group [IMWG] criteria).

EXPLORATORY OBJECTIVE:

I. Provide a descriptive summary of changes in plasma cytokine concentrations in patients treated with teclistamab or talquetamab with prophylactic infliximab.

OUTLINE:

Patients receive infliximab intravenously (IV) on day 1, two to four hours prior to treatment with standard of care teclistamab or talquetamab. Patients then receive teclistamab subcutaneously (SC) or talquetamab SC on days 1, 3, 5, 15, 22, and 28 per treating physician discretion. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and may undergo an x-ray or positron emission tomography (PET)-computed tomography (CT) scan during screening and also blood sample collection throughout the study.

After completion of study treatment, patients are followed up at day 28.

Inclusion Criteria:

• Patients 18 years of age or older with evidence of relapsed or refractory disease as defined by IMWG criteria and measurable disease as defined by any of the following:

  • Serum M-protein ≥ 0.5 g/dl
  • Urine monoclonal protein ≥ 200 mg/24h
  • Involved free light chain (FLC) level ≥ 10mg/dl (≥ 100mg/l) and an abnormal serum free light chain ratio (< 0.26, or > 1.65)

• Patients must have had at least 4 prior lines of therapy including an immunomodulatory agent (IMID), a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody.

  • Prior B-cell maturating antigen (BCMA) chimeric antigen receptor (CAR)-T is permitted but at least 6 months must have lapsed from CAR-T exposure
  • Prior tumor necrosis factor alpha (TNFα) inhibitor use for a concomitant condition (ex. Rheumatoid arthritis) is permitted but at least 6 months must have lapsed from exposure

• Patients must have hemoglobin ≥ 7g/dL

• Absolute neutrophil count (ANC) ≥ 1000/µL

• Platelets ≥ 50,000/µL

• Total bilirubin ≤ 1.5 X the upper limit of normal (ULN)

• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase < 2.5 X the ULN

• Calculated creatinine clearance of ≥ 30ml/min using Modification of Diet in Renal Disease (MDRD) formula

• Patients must have adequate cardiac function as evidenced by:

  • Left ventricular ejection fraction ≥ 30%; baseline echocardiography (ECHO) is not required if ECHO was done within the preceding 6 months and patients do not have new signs/symptoms suggestive of heart failure
  • No uncontrolled arrhythmias
  • No New York Heart Association class III-IV heart failure
  • 12-lead electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec

• Negative test result for latent tuberculosis at screening

• Patients must provide informed consent

• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of ≤ 2

• Fertility requirements

  • Women of child bearing potential (WOCBP) must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device [IUD], hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing and continue to 6 months after study treatment ending or teclistamab/talquetamab ending, whichever is longer. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy
  • Investigators shall counsel WOCBP and male participants who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy
  • A negative pregnancy test will be required for all WOCBP at screening and within 24 hours before starting treatment drugs, and with each cycle
  • Breast feeding is not permitted
  • Male patients must agree to use an adequate method of contraception (latex or synthetic condom) for the duration of the study and up to 6 months after study treatment ending
  • Criteria also applies to azoospermic males
  • Males should refrain from sperm donation during this time and continue for 6 months after study treatment ending

Exclusion Criteria:

• Patients with Waldenstrom macroglobulinemia, primary amyloid light chain (AL) amyloidosis, primary plasma cell leukemia, or polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome

• Patients receiving concurrent corticosteroids at the time protocol therapy is initiated other than for physiologic maintenance treatment

• Concurrent use of complementary or alternative medicines that would confound the interpretation of toxicities and antitumor activity of the study drugs

• Live vaccines should not be given concurrently with infliximab. Vaccination with live virus vaccines is not recommended for at least 4 weeks prior to the start of treatment, during treatment and least 4 weeks after treatment

• Clinically active rheumatoid arthritis (RA), psoriatic arthritis (PsA), and/or ankylosing spondylitis (AS), or concurrent use of abatacept, anakinra, rituximab, or other biologic products approved to treat these diseases within the preceding 6 months

• Patients with history of anaphylaxis or hypersensitivity to etanercept, infliximab, adalimumab, certolizumab pegol, or golimumab

• Unacceptable respiratory risk factors defined by any one of the following criteria:

  • Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) less than 50% of predicted normal
  • Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification

• Unacceptable cardiac risk factors defined by any of the following criteria:

  • Left ventricular ejection fraction < 30%
  • Complete left bundle branch, bifascicular block or clinically significant abnormal electrocardiogram (EKG) finding at screening
  • A prolongation of QT interval on Screening ECG as defined by repeated demonstration of a QTc interval > 470 msec using Fridericia's QT correction formula; a family history of Long QT Syndrome
  • Myocardial infarction within 6 months
  • Unstable angina

• Unacceptable infectious risk factors defined by any of the following criteria:

  • Active tuberculosis:

    • History of active or latent tuberculosis (TB) before screening
    • Any signs or symptoms suggestive of active TB upon medical history and/or physical examination
    • Any known recent close contact with a person with active TB.

  • Active invasive fungal infections

  • Other active infections, including clinically important localized infections, and patients with a history of opportunistic infections

• Unacceptable demyelinating neurologic risk factors including history or active multiple sclerosis, Guillain-Barre syndrome, optic neuritis, or peripheral demyelinating polyneuropathy

• Patients who have received targeted or investigational agents within 2 weeks or within 5 half-lives of the agent and active metabolites (whichever is shorter) and who have not recovered from side effects of those therapies

• Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from the side-effects of surgery

• Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required

• Patients with active hepatitis B (defined as hepatitis B surface antigen positive [HBsAg+]); hepatitis B virus (HBV) screening is required prior to beginning therapy

  • Patients with prior hepatitis B vaccine are permitted (defined as hepatitis B surface antigen negative [HbsAg-], anti hepatitis B virus surface antibody positive [Anti-HBs+], anti hepatitis C virus surface antibody negative [Anti-HBc-])
  • Non-active hepatitis B (HbsAg-, Anti-HBs+, Anti-HBc+) may be enrolled if on suppressive antiviral therapy and have no detectable viral load (additional monitoring for hepatitis B reactivation is advised)

• Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention, other than non-melanoma skin cancer and carcinoma in situ of the cervix or breast, should not be enrolled

• Patients with any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to them by the study staff

• Any other medical condition, including mental illness or substance abuse, deemed by the investigator(s) to likely interfere with the patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results