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Systemic Anti Cancer Therapy Protocol

VTD – Bortezomib, Thalidomide &

Multiple Myeloma

PROTOCOL REF: MPHAVTDHA (Version No: 1.0)

Approved for use in:  First line treatment of in patients who are eligible for high-dose with haematopoietic stem cell transplantation.  EGOG PS 0-2

Blueteq registration is not required

Dosage:

Drug Dose Route Frequency Bortezomib 1.3mg/m2 S/C Day 1, 4, 8 and 11 of a 28 day cycle 50mg once daily at night. Titrate Thalidomide up to max daily Oral Days 1 to 28 (continuous) dose of 200mg nocte Dexamethasone 40mg Oral Days 1 to 4 and days 8 to 11

Maximum of 6 cycles (28 day cycle).

Administration and Counselling Points:  Anticoagulation is required throughout treatment due to thrombotic effect of thalidomide.  There must be a gap of at least 72 hours between bortezomib doses.  The prescriber must inform male and female patients about the expected teratogenic risk and the strict prevention measures as specified in the pregnancy

Issue Date: 12th June 2020 Page 1 of 7 Protocol reference: MPHAVTDHA Review Date: June 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

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prevention programme and provide patients with appropriate patient educational brochure and patient card.

Anti-emetic risk: Mildly emetogenic

Supportive treatments:  Allopurinol 300mg daily (first cycle only)  Anticoagulation – options include prophylactic dose of low molecular weight (LWMH) and treatment dose of LMWH in high risk patients. For patients established on DOACs, patients may continue DOAC treatment or be switched to a LMWH.  Aciclovir PO 400mg twice daily  Co-trimoxazole PO 480mg daily  Nystatin 1ml topically four times a day or fluconazole PO 50mg daily  Metoclopramide 10mg three times a day when required for up to 7 days  Omeprazole 20mg daily

Extravasation risk: Bortezomib – non-vesicant

Interactions: Thalidomide Thalidomide has properties, thus may enhance the sedation induced by anxiolytics,

hypnotics, antipsychotics, H1antihistamines, opiate derivatives, and alcohol. Caution should be used when thalidomide is given in combination with medicinal products that cause drowsiness.

Due to thalidomide's potential to induce , caution should be exercised with medicinal products having the same pharmacodynamic effect such as active substances known to induce torsade de pointes, beta blockers or anticholinesterase agents. Medicinal products known to be associated with (e.g. vincristine and bortezomib) should be used with caution in patients receiving thalidomide.

Issue Date: 12th June 2020 Page 2 of 7 Protocol reference: MPHAVTDHA Review Date: June 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

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Bortezomib A drug-drug interaction study assessing the effect of , a potent CYP3A4 inhibitor, on the of bortezomib (injected intravenously), showed a mean

bortezomib AUC increase of 35% (CI90% [1.032 to 1.772]) based on data from 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir).

A drug-drug interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC reduction of 45% based on data from 6 patients. Therefore, the concomitant use of bortezomib with strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital and St. John's Wort) is not recommended, as efficacy may be reduced.

Treatment schedule: Day Drug Dose Route Diluent and rate 1 50 to Thalidomide PO Nocte 200mg Dexamethasone 40mg PO Bortezomib 1.3mg/m2 S/C 2 & 50 to Thalidomide PO Nocte 3 200mg Dexamethasone 40mg PO 4 50 to Thalidomide PO Nocte 200mg Dexamethasone 40mg PO Bortezomib 1.3mg/m2 S/C 5 to 50 to Thalidomide PO Nocte 7 200mg 8 50 to Thalidomide PO Nocte 200mg Dexamethasone 40mg PO Bortezomib 1.3mg/m2 S/C 9 & 50 to Thalidomide PO Nocte 10 200mg Dexamethasone 40mg PO 11 50 to Thalidomide PO Nocte 200mg

Issue Date: 12th June 2020 Page 3 of 7 Protocol reference: MPHAVTDHA Review Date: June 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

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Dexamethasone 40mg PO Bortezomib 1.3mg/m2 S/C 12 50 to to Thalidomide PO Nocte 200mg 28

Main toxicities: , , anaemia, nausea, vomiting, diarrhoea, peripheral neuropathy, drowsiness and venous thromboembolism.

Issue Date: 12th June 2020 Page 4 of 7 Protocol reference: MPHAVTDHA Review Date: June 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

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Investigations and treatment plan:

Cycle Cycle Cycle Cycle Cycle Pre Ongoing 1+ D1 1 D2 1+ D4 1+ D8 1+ D11 Informed consent x Clinical Assessment x x Thalidomide prescription authorization form x SACT Assessment (including performance status toxicity assessment) x x x x FBC x x U&E, LFTs and profile x x Hepatitis B core and surface antigens & Hep C & HIV 1+2 x Dental Assessment x If clinically indicated HbA1c and glucose x Repeat if clinically indicated Serum Igs/electrophoresis/serum free light chains (if indicated) x x Neurological assessment (for neuropathy) – performed at medical x x review Blood pressure x x x x x Weight x x Height x If clinically indicated. Repeat each cycle if Pregnancy test x women of childbearing potential Imaging as per NICE/network To restage as indicated guidance and clinical indication x

Issue Date: 12th June 2020 Page 5 of 7 Protocol reference: MPHAVTDHA Review Date: June 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

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Dose Modifications and Toxicity Management: Haematological toxicity: Proceed on day 1 if- ANC ≥ 0.5 x 109/L Plt ≥ 25 x 109/L

Once the symptoms of the toxicity have resolved, bortezomib treatment may be re- initiated at a 25% reduced dose (1.3 mg/m2 reduced to 1.0 mg/m2; 1.0 mg/m2 reduced to 0.7 mg/m2). If the toxicity is not resolved or if it recurs at the lowest dose, discontinuation of bortezomib must be considered unless the benefit of treatment clearly outweighs the risk.

These haematological guidelines assume that patients are well with good performance status, that other acute toxicities have resolved and the patient has not had a previous episode of neutropenic sepsis.

Dosing in renal and hepatic impairment: Thalidomide Thalidomide has not formally been studied in patients with impaired renal or hepatic function. No specific dose recommendations for these patient populations are available. Patients with severe organ impairment should be carefully monitored for adverse reactions.

Bortezomib Renal No dose adjustments required but bortezomib should be administered after dialysis. Hepatic function Dose adjustment Moderate to severe impairment Reduce to 0.7mg/m2

Peripheral Neuropathy Bortezomib If there are symptoms of peripheral neuropathy the dose reduction schedule below must be invoked. Bortezomib should be stopped if symptoms or signs progress despite this

Grade 1 with no pain or loss of Dose adjustment function Grade 1 with pain or grade 2 Reduce to 1.0mg/m2 or reduce to 1.3mg/m2 weekly (day 1 and 8) Grade 2 with pain of grade 3 Withhold treatment until symptoms of toxicity have

Issue Date: 12th June 2020 Page 6 of 7 Protocol reference: MPHAVTDHA Review Date: June 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

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resolved. When toxicity resolves re-initiate treatment at 0.7mg/m2 weekly (day 1 and 8) Grade 4 and/or severe Discontinue autonomic neuropathy

Thalidomide Thalidomide should be stopped or dose reduced if there are symptoms of progressive peripheral neuropathy causing functional disability (grade 2 or above). Consider cautious re-introduction of thalidomide at a dose of 50mg daily if symptoms resolve to grade 1 or better after a two-week gap Subsequent cautious dose escalation should be considered if symptoms permit. Switching to CyBorD is a reasonable alternative.

References: 1. https://www.medicines.org.uk/emc bortezomib (accessed March 2020) 2. https://www.medicines.org.uk/emc thalidomide (accessed March 2020) 3. Krens S D, Lassche, Jansman G F G A, et al. Dose recommendations for anticancer drugs in patients with renal or hepatic impairment. Lancet Oncol 2019;20: e201–08 4. Cheshire and Merseyside Strategic Clinical Network VTD Protocol

Issue Date: 12th June 2020 Page 7 of 7 Protocol reference: MPHAVTDHA Review Date: June 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0