MCCN Ref OPCS Proc OPCS Del

MMCTD X71.1 X73.1

Haematology Chemotherapy Protocol

CTD (Cyclophosphamide, Thalidomide and Dexamethasone)

Indications Multiple Myeloma (newly diagnosed and relapsed / refractory patients) AL Amyloidosis Pre-treatment Evaluation 1. Blood and urine tests FBC, U&Es, bone profile, LFTs, b2-microglobulin, blood glucose, TFTs Serum immunoglobulins & electrophoresis / immunofixation Urine for BJP or serum free light chains (if indicated) 2. Bone marrow aspirate / trephine (if indicated) 3. Skeletal survey (if indicated). 4. Clinical assessment for neuropathy. 5. Give adequate verbal and written information for patients and relatives concerning disease, treatment strategy and side effects. Obtain written consent from patient. 6. Where pregnancy is possible advice on the use of contraception during and after therapy. Advice on the duration of contraception use after therapy depends on individual circumstances, including risk of relapse. Offer sperm cryopreservation in suitable male patients. 7. Women of child bearing potential and males must use contraception as outlined by an MHRA approved Risk Management Programme. Drug Regimen THALIDOMIDE MUST BE SUPPLIED VIA an MHRA approved RISK MANAGEMENT PROGRAMME ONLY. Days Drugs Dose Route Comments 1,8,15 Continuous (daily) 1 to 4 and 12 to 15 Cyclophosphamide Thalidomide 500mg 100mg (increasing to 200mg after 3 weeks) 40mg oral oral Once weekly After 3 weeks, increase to 200mg od if tolerated (maximum dose) Take in the morning, with food

Dexamethasone

oral

Women of child bearing potential must have a NEGATIVE BLOOD PREGNANCY TEST within 72 hours before starting thalidomide therapy, and then once a month during treatment until one month after stopping treatment (every 2 weeks if irregular periods). If a woman taking thalidomide thinks she may be pregnant the drug must be stopped immediately. Men taking thalidomide must use a barrier method of contraception if their partner is capable of bearing children. Women of child-bearing potential must use two methods of contraception (one barrier and one medical) while on thalidomide and for one month after. Patients must be clearly instructed to store the drug in a secure place and to return any unused drug to the hospital pharmacy.

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Cycle Frequency : Repeat every 21 days, although thalidomide is given continuously, for a minimum of 4 cycles and a maximum of 6 cycles depending on response and timing of harvest. At this time continuous thalidomide is stopped. Dose modifications Haematological: Dose modification is not usually indicated if cytopenias are thought be due to marrow infiltration. If cytopenias (i.e. neutrophils <1 and platelets < 50 prior to a cycle) are treatment-related: Omit cyclophosphamide for 1to3 weeks and reduce dose (e.g. to 400mg or 300mg) and / or Add GCSF for 2to3 days per cycle or week (usually only requires low doses e.g. Lenograstim 105mcg) Renal: If serum creatinine > 300umol/l (despite vigorous hydration), thalidomide and dexamethasone only are given and cyclophosphamide is omitted. Peripheral Neuropathy: usually sensory. It generally occurs following chronic use over a period of months, however, reports following relatively short-term use also exist. Neuropathy usually presents with sensory or motor symptoms, such as numbness, tingling, pain in the hands and feet, or weakness, with or without interference with daily activities.

Neurological toxicity

SENSORY

MOTOR

NCI Common Toxicity Criteria for neuropathy Grade Grade 1 Grade 2 Grade 3 0 Sensory Sensory Loss of None alteration or alteration or deep or no paraesthesi paraesthesia change tendon a interfering (including reflexes or with ADL tingling), mild paraesthesi interfering with function, but as not (including tingling) but interfering with ADL not interfering with function Weakness Asymptoma Symptomatic None interfering weakness tic, or no interfering with with ADL; change weakness bracing or function, on assistance exam/testin but not interfering with to walk g only (e.g., cane ADL or walker) indicated

Grade 4 Disability

Lifethreateni ng; disabling (e.g., paralysis )

Grade 3-4 toxicity stop thalidomide, usually permanently. If resolution of symptoms, re-introduce at 50mg daily with the next or subsequent cycle, as appropriate. Assuming tolerance at the lower dose, escalation may be considered in 50mg increments (up to the full dose of 200mg) if symptoms resolve and do not recur.

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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 50mg/day may need to discontinue thalidomide.

Other thalidomide-related toxicity: constipation, fatigue, sedation, rash, tremor, oedema. Grade 3-4 toxicity stop for remainder of cycle, then re-introduce at 50mg daily with the next or subsequent cycle, as appropriate. Escalation may be considered if symptoms resolve and do not recur. Steroid effects: Patients unable to tolerate dexamethasone at the protocol dose can dose reduce to e.g. 20mg daily or omit one of the two 4 day pulses of dexamethasone in a 3 week cycle. Switching to an alternative corticosteroid can also be considered. Thromboembolism: If thromboembolism occurs full anticoagulation should be given following standard treatment guidelines. Thalidomide may be stopped, but can be reintroduced, initially at 50mg daily with escalation at subsequent cycles to 100mg daily (assuming good anticoagulant control) Investigations prior to each subsequent treatment cycle 1. FBC, U&Es, LFTs, bone profile, serum Igs and paraprotein, urine for BJP (if indicated), SFLC (if indicated) 2. Clinical assessment for neuropathy 3. Negative pregnancy test in women of chid bearing age. 4. Blood glucose and BP monitoring to be tailored according to individual patient needs. 5. TFTs every 3-6 months Support Therapy Suggested regimen only, follow local protocol 1. Encourage about 3 litre/24h oral fluid intake 2. Allopurinol 300mg OD during first 4 weeks (100mg OD if CrCl < 20 mls/min) 3. PPI or H2-antagonist 4. Aciclovir 400mg bd 5. Nystatin or Fluconazole 6. Septrin 480mg bd on Mon, Wed, Fri 7. Laxatives 8. Anti-emetics especially on the day of cyclophosphamide 9. Anticoagulation options include prophylactic dose of a LMWH or full anticoagulation with warfarin (to achieve a target INR of 2-3). If these 2 options are not considered suitable, aspirin 75-300mg may be considered. Patients at higher risk of thrombosis should receive full anti-coagulation. Anticipated toxicity Toxicity Thromboembolism Neuropathy (sensory & motor) Fatigue Somnolence Hyperglycaemia Ref 2 (thal and dex) % of Grade 3 or 4 toxicity 17% 11% 15% 15% Ref 3 (CTD) 11.5% 50% grade 1 or 2

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Constipation Neutropenia Infections

8% 9%

57.7% (grade not known) 23% ( grade 3) 26.9% (no neutropenic sepsis & no infection related deaths; 19.2% required hospitalization)

Confusion 8% Oedema 6% 9.6% Muscle weakness 6% Hypothyroidism 5.8% Rash 4% 5.8% ( grade not known) Nausea 4% Treatment related deaths 4% Tremors, ataxia, seizures, hearing loss, impotence, headaches, orthostatic hypotension, menstrual irregularities (usually thalidomide) Myelosuppression, bruising and bleeding, anaemia Bradycardia (thalidomide) rarely severe Loss of appetite, nausea and vomiting, taste changes, sore mouth and ulcers, diarrhoea. Alopecia Haemorrhagic cystitis Hepatic toxicity usually transient Secondary cancers Infertility, loss of periods (ovarian failure) or irregular, teratogenicity Interstitial pulmonary fibrosis rarely in patients receiving high doses of cyclophosphamide Other side-effects of steroids gastric irritation / peptic ulcers, psychosis, hypertension, insomnia, fluid retention, increased risk of osteoporosis, muscle weakness / wasting, Cushingoid syndrome, earlier development of cataracts. References 1. MRC Myeloma IX Trial 2005 2. Rajkumar SV et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trails coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006; 24:431-436. [Dex 40mg was given on days 1-4, 9-12, 17-20 of a 28 day cycle, thal 200mg daily] 3. Kyriakou C et al. Low dose thalidomide in combination with oral weekly cyclophosphamide and pulsed dexamethasone is a well tolerated and effective regimen in patients with relapsed and refractory multiple myeloma. Br J Haematol. 2005; 129:763-770. [Dex 40mg day 1-4 only of a 28 day cycle]

Written by: Approved by: Review Date:

R Salim, Ian Hincks B Woodcock 1st June 2010 24th June 2008

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