DTPACE. Myeloma group INDICATION

Transcription

1 INDICATION Relapsed or refractory myeloma patients suitable for intensive salvage chemotherapy. Plasma cell leukaemia or presentation with extra-medullary disease. TREATMENT INTENT Disease Modification GENERAL PRE-ASSESSMENT 1. Ensure all the following staging investigations are done: o FBC & film o Clotting screen o U&Es, LFTs, Calcium o Albumin o Uric acid o ECG & Transthoracic echocardiogram to assess LV function if clinically indicated o Virology : HIV, Hepatitis B (including core antibody), and Hepatitis C o Calculated creatinine clearance (CrCl), urine protein/ creatinine ratio o Electrophoresis and immunofixation for quantitation of serum paraprotein and immunoglobulins o Serum free light chain assay (Freelite) o Myeloma FISH should be performed in all patients at diagnosis, and in selected patients at relapse/progression to help guide treatment decisions Samples should be sent to Wessex Regional Genetics Laboratory (address below) Wessex Regional Genetic Laboratory Salisbury NHS Foundation Trust Salisbury Disctrict Hospital Salisbury Wiltshire SP2 8BJ o Urine pregnancy testing for pre-menopausal women younger than 55 before each cycle. o Group and save o Imaging as per NICE/network guidance and clinical presentation o Bone marrow aspirate and trephine (with immunophenotyping for kappa/lambda if appropriate) 2. Consent - ensure patient has received adequate verbal and written information regarding their disease, treatment and potential side effects. Document in medical notes all information that has been given. Obtain written consent for the treatment. Patients should be made aware of higher TRM of 5%-10% with this regimen. 1 of 6

2 3. Document patient s height and weight. 4. Fertility - all patients should be offered fertility advice, as appropriate. 5. Hydration - fluid intake of at least 3 litres /day should be attempted. 6. Document patient s height and weight, dose on actual body weight. 7. Treatment must be agreed at the relevant MDT. 8. Formal assessment of performance status (WHO score) REGIMEN SPECIFIC PRE-ASSESSMENT The conditions of the Thalidomide Celgene Pregnancy Prevention Programme must be fulfilled for all male and female patients Clinical assessment of thrombo-embolic risk. Central Access- Hickman line/picc Line DRUG REGIMEN Hydration Regimen: Daily 1L 0.9% sodium chloride with 20 mmol KCl (potassium chloride) and 8 mmol of magnesium sulphate 12 hourly D1 D4. Days Drug Dose Route Comments 1 to 4 Dexamethason 40 mg daily Oral Available as 2 mg tablets e daily/ If PBSC harvest planned only for days 1 to 4 Thalidomide (See note below) Start 50 mg and increase up to 100 mg as tolerated Oral Nocte Available as 50 mg capsules 1 to 4 Cisplatin* OR Carboplatin (if cisplatin is contraindicated) 10 mg/m 2 /day cycle 40 mg/m 2 ] OR 50 mg/m 2 /d [total dose per cycle 200mg/m 2 ] 1 to 4 Etoposide* 40 mg/m 2 /day cycle 160 mg/m 2 ] 1 to 4 Cyclophospham ide* 400 mg/m 2 /day cycle 1600 mg/m 2 ] 1 to 4 Doxorubicin* 10 mg/m 2 /day cycle 40 mg/m 2 ] Daily dose of Cisplatin, cyclophosphamide and Etoposide combined in a 1 litre 0.9% sodium chloride bag and infused over 24 hours Carboplatin must be diluted separately in 100ml glucose 5% bag and infused over 24 hours. Daily dose of Cisplatin, cyclophosphamide and Etoposide combined in a 1 litre 0.9% sodium chloride bag and infused over 24 hours In 100 ml of 0.9% NaCl and infused over 24 hours Day 5 GCSF Filgrastim 0.5 miu/kg daily from day 5 until neutrophils > 1.0 x 10 9 /L. Filgrastim 1 miu/kg from days 5 onwards if harvesting PBSCs, with aim to collect on days * It is reasonable to consider capping at BSA of 2 m 2 in selected patients 2 of 6

3 CYCLE FREQUENCY Cycle length: 4-6 weeks. Total number of cycles 2-4. Thalidomide can be omitted on clinician s discretion if disease is assessed to be Thalidomide resistant. TOXICITY & DOSE MODIFICATIONS Haematological: Delay subsequent cycles until neutrophils > 1 x 10 9 /L and platelets > 100 x 10 9 /L. Thalidomide: No dose reduction necessary Cisplatin: GFR > 60 ml/min 100% dose GFR ml/min 75% dose GFR < 45 ml/min Consider carboplatin at 50 mg/m 2 /day Days 1-4. No prehydration required for carboplatin. No dose reduction necessary No dose reduction necessary Doxorubicin: No dose reduction necessary clinical Bili % dose decision in severe impairment Bili % dose Bili > 85 Omit AST 2-3 x ULN 75% dose AST > 3 x ULN 50% dose Cumulative max dose of Doxorubicin: mg/m². Prior radiotherapy to the mediastinal / pericardial area 400 mg/m². Cyclophosphamide: Clinical decision GFR > 20 ml/min 100% dose GFR ml/min 75% dose GFR < 10 ml/min 50% dose Exposure to active metabolites may not be increased, suggesting that dose reduction may not be necessary. Clinical decision. Etoposide: GFR > 50 ml/min 100% dose Bili or AST % dose GFR ml/min 75% dose Bili > 51 or AST > 180 clinical decision GFR < 15 ml/min 50% dose Subsequent doses should be based on clinical response 3 of 6

4 Neuropathy: Grade 3-4 toxicity stop thalidomide, usually permanently. If resolution of symptoms, re-introduce at 50 mg daily with the next or subsequent cycle, as appropriate. Assuming tolerance at the lower dose, escalation may be considered in 50 mg increments (up to the full dose of 200 mg) if symptoms resolve and do not recur. Grade 1-2 toxicity consider reducing dose (usually by 50%). Consider stopping thalidomide if grade 2 toxicity develops until toxicity resolves to baseline or to less than grade 1 and then restart with a 50% dose reduction. Patients unable to tolerate doses as low as 50 mg/day may need to discontinue thalidomide. INVESTIGATIONS Urine pregnancy testing for pre-menopausal women younger than 55 before each cycle. FBC & U&E s, Ca ++, LFTs Ig's, paraprotein, urinary BJP and serum free light chain levels in patients with light chain disease - monthly. CONCURRENT MEDICATIONS Allopurinol 300 mg daily for 7 days for first cycle only. Proton pump inhibitor or H2 antagonist at clinician s discretion. Prophylactic aciclovir 200 mg bd to tid (depending on renal function) and for 3 months post therapy. Prophylactic fluconazole. Filgrastim 0.5 miu/kg daily from day 5 until neutrophils > 1.0. Filgrastim 1 miu/kg from days 5 onwards if harvesting PBSCs, with aim to collect on days Consider prophylactic co-trimoxazole 480 mg daily Mon/ Wed/ Fri if heavily pre-treated or previous autograft. VTE prophylaxis/treatment as below. Bone protection as per NSSG Bone Protection protocol MM.3 EMETIC RISK High emetic risk on days 1-4, otherwise minimal or low 4 of 6

5 ADVERSE EFFECTS/REGIEMN SPECIFIC COMPLICATIONS Drowsiness, somnolence and sedation: Prescribe as night time dose. Thalidomide may potentiate the drowsiness caused by alcohol and other sedative medication. If affected, patients should be instructed not to drive cars, use machinery or perform hazardous tasks whilst taking thalidomide. Teratogenicity: A risk management programme should be observed. The concomitant use of 2 effective methods of contraception is mandatory in all female patients of childbearing potential. Male patients should also use a condom when having sexual intercourse with women of childbearing potential. Prescribing and dispensing of thalidomide must be in line with the pregnancy prevention programme. Venous thromboembolism (VTE): There is an increased risk of thrombosis, and some form of prophylaxis is recommended as follows: 1. Aspirin can be appropriate for patients with no additional risk factors for thrombosis 2. If additional risk factors consider: Prophylactic low-molecular weight heparin OR Vitamin K antagonists at a therapeutic dose, to maintain an international normalised ratio (INR) of 2 3, OR Direct oral anticoagulant e.g. apixaban for thromboprophylaxis or treatment dose as indicated. Aspirin is generally not preferred for higher risk patients with additional risk factors such as immobility. If VTE occurs, thalidomide can be continued and the patient should be fully anticoagulated according to standard guidelines. Peripheral neuropathy: Patients should be advised to report prickling, numbness and paraesthesia. Dizziness and orthostatic hypotension: Patients should be advised that thalidomide may cause orthostatic hypotension and that they should sit upright for a few minutes prior to standing up from a recumbent position. Skin toxicity: in the event of toxic skin reactions such as Stevens-Johnson syndrome, thalidomide should be discontinued permanently. Other warnings: Patients should be informed not to donate blood or semen during or within 8 weeks of stopping thalidomide treatment. Cyclophosphamide may irritate the bladder mucosa. Patients should be encouraged to drink a minimum of three litres of fluid per 24 hours. Cardiotoxicity: monitor cardiac function. Doxorubicin may be stopped in future cycles if signs of cardiotoxicity, e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. Cisplatin: Nephrotoxicity and ototoxicity Steroids: Monitor BMs 5 of 6

6 TREATMENT RELATED MORTALITY 5-10% REFERENCES 1. Lee C-K et al. : an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma. J Clin Oncol. 2003; 21: University College London Hospitals NHS Foundation Trust Internet. Dose Adjustement for Cytotoxics in Impairment. Online. Available at: (last accessed ) 3. University College London Hospitals NHS Foundation Trust Internet. Dose Adjustment for Cytotoxic in hepatic impairment. Online. Available at: Guidelines/ DosageAdjustment.pdf (last accessed on 27/6/16) 4. emc, UK Summary of Product Characteristics for Thalidomide, Celgene, February North West London Cancer Network. v 1 3 Jul09 (2) protocol. Available online on: 03%20Jul09%20(2).pdf REVIEW Name Revision Date Version Review date Nadjoua Maouche Pharmacist Formatting, concurrent medication section, pre-assessment, adverse effect section, contraindication May May 2018 Nadjoua Maouche Pharmacist Faouzi Djebbari (Haematology Pharmacist) deleted, Treatment mortality added Clarification of Carboplatin administration in case of contraindication to cisplatin. Reference added. Updated renal and hepatic impairment, concurrent medication and references July May 2018 July July of 6