Reading list

• Practical
  • Talquetamab Prescribing Information (Janssen)
  • Teclistamab Prescribing Information
  • Practical paper myeloma teclistamab

Myeloma and lymphoma bispecific antibodies available

• Commonly used bispecifics and their target, MoA, approval for what condition / disease?
• How the CRS is managed and similar
• Mostly on compassionate access schemes

Practical management things?

• Other hospitals don’t have access
• Practical management of administering to patients - how do they differ?
  • Side effects happens at different times compared to other forms - important for clinicians to know when what they are giving might cause an adverse reaction
• How to help the job of a haematologist in a DGH to administer them
• Review on how patients should be managed

Back on 22nd April

Currently approved bispecific antibodies for multiple myeloma

• elranatamab (anti-BCMA)
• teclistamab (anti-BCMA)
• talquetamab (anti-GPRC5d)
• linvoseltamab
• cevostamab (orphan)
• EU/3/21/2471
  • humanised IgG2k Fc-modified bispecific monoclonal antibody against CD3 and BCMA

Currently approved bispecific antibodies for lymphoma

• Mosunetuzumab
• Glofitamab
• Epcoritamab
• Odronexamab (orphan)

Angle would be a review of the data and then practical management approaches - differences and similarities for a general haematologist

• Glossary

  • Cytokine release syndrome: systemic inflammatory response with fever and multiple organ dysfunction which may range from mild to life-threatening
  • Multiple myeloma: clonal plasma cell disorder (terminally differentiated B-cells)
  • Bispecific antibodies:
    • Redirecting by binding to tumour antigen and CD3 on a T-cell, resulting in T-cell binding to tumour cell, activation and tumour cell lysis (Ref)
    • BsAbs activate T-cells independently from antigen presentation on major histocompatibility complex (MHC) class I, as well as in absence of co-stimulation, bypassing the normal dependence on antigen presenting cells or cytokines and reducing the risk of anergy associated with T-cell receptor stimulation in the absence of co-stimulatory signal
    • Bispecific antibodies may have different structures, which affects their affinity, binding site location, etc.
  • B-cell maturation antigen (BCMA): common target for immunotherapy in multiple myeloma, present in all stages of disease in multiple myeloma
    • Promotes cell survival and proliferation
    • Highly expressed in myeloma cells, but also in mature B-cells and plasma cells
    • Member of the tumour necrosis factor receptor superfamily
  • Clinical signs and symptoms of immune effector cell-associated neurotoxicity syndrome (ICANS)
    • Confusional state
    • Depressed level of consciousness
    • Disorientation
    • Somnolence
    • Lethargy
    • Bradyphrenia (slowness of thought)

• BsAbs are artificially engineered antibodies whereas BiTEs are recombinant proteins composed of two linked scFvs (single-chain variable fragment, reference)

• Small, BsAbs have a short half-life and require continuous IV infusion, newer agents include a fragment crystallisable (Fc) region (IgG), these makes them larger and able to be administered via intermittent infusion or subcutaneous (SC) injection (reference)

Cancer Drug Fund to get pre-NICE approved drugs early

Myeloma

Elranatamab (Elrexfio)

• Target: BCMA, CD3
• Drug class: humanised immunoglobulin 2-alanine kappa (IgG2Δa) antibody derived from two monoclonal antibodies (BCMA, CD3) (ref)
• Mode of administration:
  • Ready-to-use solution
    • Single dose vials
      • 76 mg / 1.9 mL (40mg/mL)
      • 44mg / 1.1 mL (40mg/mL)
  • Characteristics
    • Clear to slightly opalescent
    • Colourless to pale brown solution
    • Free from particulate matter or discolouration
  • Storage
    • Refrigerate at 2-8 °C
    • Remove vial from storage and equilibrate to ambient temperature with aseptic technique, no rewarming, until 15-30 °C (ready for administration)
  • Technique
    • Withdraw required volume using stainless steel injection needles (30G or wider) and polypropylene or polycarbonate syringe material
    • Do not inject into
      • Tattoos
      • Scars
      • Red, bruised, tender, hard, non-intact skin
• Dose escalation:
  • Step-up dose 1: 12mg SC (day 1)
  • Step-up dose 2: 32mg SC (day 4, ≥2 days after step-up dose 1)
  • Full dose: 76mg SC (day 8, ≥3 days after step-up dose 2)
  • Weekly 76mg SC (full dose, ≥6 days apart) for at least 24 weeks with partial response or better maintained for ≥2 months
    • If successful, switch to biweekly dosing and continue until disease progression or unacceptable toxicity
  • Reference
• Clinical trials: MagnetisMM-1
• Side effects:
  • Anaemia 48.8%
  • Neutropenia 48.8%
  • Thrombocytopenia 30.9%
  • Lymphopaenia 26.8%
  • Cytokine release syndrome (CRS) 57.7%, grade 3 or 4, 0%
    • IL-2, IL-6, IL-8, IL-10, TNF-α, and IFN-γ elevated (Pfizer)
  • Diarrhoea 42.3%
  • Fatigue 36.6%
  • Decreased appetite 33.3%
  • Pyrexia 30.1%
  • COVID-19 related 29.3%
  • Injection site reaction 26.8%
  • Nausea 26.8%
  • Hypokalemia 26%
  • Cough 25.5%
  • Headache 23.6%
  • Opportunistic infections 5%
    • Pneumocystitis jirovecii pneumonia 4.9%
  • Reference
• Onset of CRS:
• Notes:
  • Due to risk of CRS, patients should be hospitalised after 1st and 2nd doses of elranatamab for 48 hours (step-up dose 1) and 24 hours (step-up dose 2)
  • Pre-treatment medications which should be administered 1 hour prior to each step-up dose
    • Paracetamol 650mg PO
    • Dexamethasone 20mg PO / IV
    • Diphenhydramine 25mg PO
• Licensed for:

Talquetamab (Talvey)

• Target: GPRC5d, CD3
  • Talquetamab promotes enhanced T cell-mediated cytotoxicity through recruitment of CD3-expressing T cells to GPRC5D-expressing cells. This leads to the activation of T cells and induces subsequent lysis of GPRC5D-expressing cells mediated by secreted perforin and various granzymes stored in the secretory vesicles of cytotoxic T cells. Based on the expression of GPRC5D on plasma cells with 17 minimal to no expression detected on B cells and B cell precursors, talquetamab targets multiple myeloma cells particularly (link)
• Drug class: humanised IgG4 proline, alanine, alanine (IgG4 PAA) bispecific antibody (GPRC5d, CD3)
• Mode of administration:
  • 3mg/1.5mL (2mg/mL) in a single-dose vial
  • 40mg/mL in a single-dose vial
• Dose escalation:
  • Step-up dose 1: 0.01mg/kg (day 1)
  • Step-up dose 2: 0.06mg/kg (day 4)
  • Full dose: 0.4mg/kg (day 7)
  • Patients should be hospitalised for 48 hours after all doses within the step up dosing schedule
• Clinical trials: MonumenTAL-1
• Side effects:
  • Safety information
  • CRS 77%, median time of onset 27 hours from last dose, with 91% of events within 48 hours from last dose and median duration of 17 hours
  • ICANS 9.8% of patients, grade 3 or 4 in 2.3%, median time of onset 28 hours from last dose, 68% within 48 hours from last dose, 32% after 48 hours, median duration for 9 hours
  • Dysgeusia 72%
  • Anaemia 47%
  • Trial SE profile
    • Anaemia 48.8%
    • Neutropenia 48.8%
    • Thrombocytopenia 30.9%
    • Lymphopaenia 26.8%
    • Cytokine release syndrome (CRS) 57.7%, grade 3 or 4, 0%
    • Diarrhoea 42.3%
    • Fatigue 36.6%
    • Decreased appetite 33.3%
    • Pyrexia 30.1%
    • COVID-19 related 29.3%
    • Injection site reaction 26.8%
    • Nausea 26.8%
    • Hypokalemia 26%
    • Cough 25.5%
    • Headache 23.6%
    • Opportunistic infections 5%
      • Pneumocystitis jirovecii pneumonia 4.9%
    • Reference
• Onset of CRS:
• Notes:
  • Pre-treatment medications (to reduce the risk of CRS)
    • Corticosteroid (PO / IV dexamethasone) 16mg
    • Antihistamines (PO / IV diphenhydramine) 50mg
    • Antipyretics (PO / IV paracetamol) 650mg-1000mg
• Licensed for: relapsed or refractory multiple myeloma after 3 therapies NICE

Teclistamab (Tecvayli)

• Target: BCMA, CD3
• Drug class: fully humanised IgG4 bispecific antibody redirecting CD3+ T-cells to BCMA
• Mode of administration: subcutaneous (SC) weekly, given step-ward to reduce side-effects and toxicities
• Dose escalation: once weekly dose of 1.5mg/kg, preceded by step-up doses of 0.06mg/kg and 0.3mg/kg 2-4 days apart with the last step-up dose administered 2-4 days prior to first full dose
  • Step-up dose 1: 0.06mg/kg (day 1)
  • Step-up dose 2: 0.3mg/kg (day 4)
  • Full dose: 1.5mg/kg (day 7)
• Clinical trials: MajesTEC-1, MajesTEC-3
• Side effects:
  • Cytokine release syndrome (CRS) in 72.1% (119 patients), all grade 1 or 2 events
  • Neutropenia in 65%, grade 3 or 4 in 40%
  • Immune effector cell-associated neurotoxicity syndrome (ICANS) in 3% (MajesTEC-1)
  • Anaemia, thrombocytopaenia, lymphopaenia
  • Infections in 76%
  • Pneumonia (18%)
  • Covid-19 (18%)
  • Diarrhoea (29%)
  • Fatigue (28%)
  • Nausea (27%)
  • Injection site reactions (36%)
  • Fever (27%)
  • Headache (24%)
  • Arthralgia (22%)
  • Constipation (21%)
  • Cough (20%)
  • Neurotoxic event (15%)
  • References
• Onset of CRS: after step-up and cycle 1 doses
• Notes: co-administration of aciclovir to prevent shingles
• Licensed for: adults with relapsed or refractory multiple myeloma after at least 3 prior treatments including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrated disease progression on the last treatment NICE

Lymphoma

Glofitamab (Columvi)

• Target: CD20, CD3
• Drug class: humanised bispecific T-cell engager antibody produced using recombinant DNA technology (CD20, CD3) (ref)
• Mode of administration:
  • Ready-to-use solution
    • Single dose vials
      • 76 mg / 1.9 mL (40mg/mL)
      • 44mg / 1.1 mL (40mg/mL)
  • Characteristics
    • Clear to slightly opalescent
    • Colourless to pale brown solution
    • Free from particulate matter or discolouration
  • Storage
    • Refrigerate at 2-8 °C
    • Remove vial from storage and equilibrate to ambient temperature with aseptic technique, no rewarming, until 15-30 °C (ready for administration)
  • Technique
    • Withdraw required volume using stainless steel injection needles (30G or wider) and polypropylene or polycarbonate syringe material
    • Do not inject into
      • Tattoos
      • Scars
      • Red, bruised, tender, hard, non-intact skin
• Dose escalation:
  • Step-up dose 1: 12mg SC (day 1)
  • Step-up dose 2: 32mg SC (day 4, ≥2 days after step-up dose 1)
  • Full dose: 76mg SC (day 8, ≥3 days after step-up dose 2)
  • Weekly 76mg SC (full dose, ≥6 days apart) for at least 24 weeks with partial response or better maintained for ≥2 months
    • If successful, switch to biweekly dosing and continue until disease progression or unacceptable toxicity
  • Reference
• Clinical trials: RO7082859
  • NP30179
• Side effects:
  • Anaemia 48.8%
  • Neutropenia 48.8%
  • Thrombocytopenia 30.9%
  • Lymphopaenia 26.8%
  • Cytokine release syndrome (CRS) 57.7%, grade 3 or 4, 0%
  • Diarrhoea 42.3%
  • Fatigue 36.6%
  • Decreased appetite 33.3%
  • Pyrexia 30.1%
  • COVID-19 related 29.3%
  • Injection site reaction 26.8%
  • Nausea 26.8%
  • Hypokalemia 26%
  • Cough 25.5%
  • Headache 23.6%
  • Opportunistic infections 5%
    • Pneumocystitis jirovecii pneumonia 4.9%
  • Reference
• Onset of CRS:
• Notes:
  • Due to risk of CRS, patients should be hospitalised after 1st and 2nd doses of elranatamab for 48 hours (step-up dose 1) and 24 hours (step-up dose 2)
  • Pre-treatment medications which should be administered 1 hour prior to each step-up dose
    • Paracetamol 650mg PO
    • Dexamethasone 20mg PO / IV
    • Diphenhydramine 25mg PO
• Licensed for:

Epcoritamab (Tepkinly)

• Target: CD20, CD3
• Drug class: humanised immunoglobulin G1 (IgG1) antibody against CD20 and CD3 antigens(ref)
• Mode of administration:
  • Subcutaneous (SC) injection in lower part of abdomen or thigh
    • Alternate between left to right side for injection especially on cycles 1-3 (weekly administration)
• Dose escalation:
  • Weekly (Cycle 1)
    • Day 1: 0.16mg (step-up priming dose 1)
    • Day 8: 0.8mg (step-up intermediate dose 2)
    • Day 15: 48mg (full dose)
    • Day 22: 48mg
  • Weekly (Cycles 2-3)
    • Day 1: 48mg
    • Day 8: 48mg
    • Day 15: 48mg
    • Day 22: 48mg
  • Biweekly (Cycles 4-9)
    • Day 1: 48mg
    • Day 15: 48mg
  • Four weekly (Cycles 10 onwards)
    • Day 1: 48mg
• Clinical trials: EPCORE NHL-1
• Side effects:
  • Anaemia 48.8%
  • Neutropenia 48.8%
  • Thrombocytopenia 30.9%
  • Lymphopaenia 26.8%
  • Cytokine release syndrome (CRS) 57.7%, grade 3 or 4, 0%
  • Diarrhoea 42.3%
  • Fatigue 36.6%
  • Decreased appetite 33.3%
  • Pyrexia 30.1%
  • COVID-19 related 29.3%
  • Injection site reaction 26.8%
  • Nausea 26.8%
  • Hypokalemia 26%
  • Cough 25.5%
  • Headache 23.6%
  • Opportunistic infections 5%
    • Pneumocystitis jirovecii pneumonia 4.9%
  • Reference
• Onset of CRS:
• Notes:
  • Due to risk of CRS, patients should be hospitalised after 1st and 2nd doses of elranatamab for 48 hours (step-up dose 1) and 24 hours (step-up dose 2)
  • Pre-treatment medications which should be administered 1 hour prior to each step-up dose
    • Paracetamol 650mg PO
    • Dexamethasone 20mg PO / IV
    • Diphenhydramine 25mg PO
• Licensed for: adult patients with relapsed or refractory diffuse large B-cell lymphoma after 2 or more lines of systemic therapy

Overview

1. Overview of multiple myeloma and lymphoma
2. Overview of bispecific antibodies
3. Bispecific antibodies used in clinical practice for multiple myeloma
   1. Talquetamab
   2. Elranatamab
   3. Teclistamab
4. Bispecific antibodies used in clinical practice for lymphoma
   1. Glofitamab
   2. Epcoritamab
5. Patient-specific characteristics favouring use of a certain bispecific in myeloma and lymphoma
   1. Health problem and target population
6. Practical considerations of bispecific antibody administration in myeloma and lymphoma (time-frame to CRS and ICANS, other AEs)
   1. Pre-medication, dose adjustments, hospital admission requirements
   2. Adverse effect grading and management guidance as per SmPC
      1. How to differentiate CRS from other conditions (e.g. sepsis)
   3. Poster / flowchart / spreadsheet with all SmPC information in one area?

Plan:

• Table with practical considerations for management while on bispecifics

Clinical Progress Note

• 1,800 words, 1-2 tables or figures, up to 15 references (3 journal pages)
• Highlight clinical question
• Critique of gaps of literature and potential areas of future study
• Conclusion to address major recommendations in regards to the clinical question posed