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Multiple myeloma lenalidomide and dexamethasone oral

Patients with myeloma should be considered for inclusion into clinical trials. Link to ALLG website and ANZCTR website.

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Cycle 1 and further cycles

Drug Dose Route Day
Dexamethasone 40 mg ONCE a day * PO 1, 8, 15, 22
Lenalidomide 25 mg ONCE a day PO 1 to 21

* It is the consensus of the Haematology Reference Committee that 40 mg dexamethasone weekly is to be used as per the Rajkumar et alr and Benboubker et alr trials and clinical practice.

Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity.
Notes:
  • Bisphosphonates should be considered in all patients with symptomatic myeloma requiring treatment. For patients with newly diagnosed symptomatic myeloma, zoledronic acid or pamidronate should be considered for monthly administration (renally adjusted) for up to 2 years. A longer duration of therapy may be appropriate (MRC M IX trial).r
  • In the MM09 and MM010 studies, the main dose limiting toxicities of lenalidomide were neutropenia and thrombocytopenia, manageable with dose adjustment and/or addition of growth factor support; and venous thromboembolic events managed with anticoagulants.rr
Drug status:

Dexamethasone is on the PBS general schedule

Lenalidomide: (PBS authority)

NB: patient registration into the i-access® risk management program is required.

Full prescribing information and Authority Application forms available from the Department of Human Services website

Lenalidomide is available as 5 mg, 10 mg, 15 mg and 25 mg capsules

Dexamethasone is available as 4 mg and 0.5 mg tablets

Cost:
~ $6,610 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes antineoplastic drugs only (not antiemetics or other supportive medications), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many antineoplastic drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 and further cycles

Day 1
Dexamethasone 40 mg (PO) ONCE a day on days 1, 8, 15, and 22. Take in the morning with food.
Lenalidomide 25 mg (PO) ONCE a day on days 1 to 21. Take on an empty stomach, at least one hour before or two hours after food.
Day 2 to 7
Lenalidomide 25 mg (PO) ONCE a day on days 1 to 21. Take on an empty stomach, at least one hour before or two hours after food.
Day 8
Dexamethasone 40 mg (PO) ONCE a day on days 1, 8, 15, and 22. Take in the morning with food.
Lenalidomide 25 mg (PO) ONCE a day on days 1 to 21. Take on an empty stomach, at least one hour before or two hours after food.
Day 9 to 14
Lenalidomide 25 mg (PO) ONCE a day on days 1 to 21. Take on an empty stomach, at least one hour before or two hours after food.
Day 15
Dexamethasone 40 mg (PO) ONCE a day on days 1, 8, 15, and 22. Take in the morning with food.
Lenalidomide 25 mg (PO) ONCE a day on days 1 to 21. Take on an empty stomach, at least one hour before or two hours after food.
Day 16 to 21
Lenalidomide 25 mg (PO) ONCE a day on days 1 to 21. Take on an empty stomach, at least one hour before or two hours after food.
Day 22
Dexamethasone 40 mg (PO) ONCE a day on days 1, 8, 15, and 22. Take in the morning with food.

Note: it is the consensus of the Haematology Reference Committee that 40 mg dexamethasone weekly is to be used as per the Rajkumar et alr and Benboubker et alr trials and clinical practice.

Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity.

Cycle 1 and further cycles

Drug Dose Route Day
Dexamethasone 40 mg ONCE a day * PO 1, 8, 15, 22
Lenalidomide 25 mg ONCE a day PO 1 to 21

* It is the consensus of the Haematology Reference Committee that 40 mg dexamethasone weekly is to be used as per the Rajkumar et alr and Benboubker et alr trials and clinical practice.

Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity.
Notes:
  • Bisphosphonates should be considered in all patients with symptomatic myeloma requiring treatment. For patients with newly diagnosed symptomatic myeloma, zoledronic acid or pamidronate should be considered for monthly administration (renally adjusted) for up to 2 years. A longer duration of therapy may be appropriate (MRC M IX trial).r
  • In the MM09 and MM010 studies, the main dose limiting toxicities of lenalidomide were neutropenia and thrombocytopenia, manageable with dose adjustment and/or addition of growth factor support; and venous thromboembolic events managed with anticoagulants.rr
Drug status:

Dexamethasone is on the PBS general schedule

Lenalidomide: (PBS authority)

NB: patient registration into the i-access® risk management program is required.

Full prescribing information and Authority Application forms available from the Department of Human Services website

Lenalidomide is available as 5 mg, 10 mg, 15 mg and 25 mg capsules

Dexamethasone is available as 4 mg and 0.5 mg tablets

Cost:
~ $6,610 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes antineoplastic drugs only (not antiemetics or other supportive medications), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many antineoplastic drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 and further cycles

Day 1
Dexamethasone 40 mg (PO) ONCE a day on days 1, 8, 15, and 22. Take in the morning with food.
Lenalidomide 25 mg (PO) ONCE a day on days 1 to 21. Take on an empty stomach, at least one hour before or two hours after food.
Day 2 to 7
Lenalidomide 25 mg (PO) ONCE a day on days 1 to 21. Take on an empty stomach, at least one hour before or two hours after food.
Day 8
Dexamethasone 40 mg (PO) ONCE a day on days 1, 8, 15, and 22. Take in the morning with food.
Lenalidomide 25 mg (PO) ONCE a day on days 1 to 21. Take on an empty stomach, at least one hour before or two hours after food.
Day 9 to 14
Lenalidomide 25 mg (PO) ONCE a day on days 1 to 21. Take on an empty stomach, at least one hour before or two hours after food.
Day 15
Dexamethasone 40 mg (PO) ONCE a day on days 1, 8, 15, and 22. Take in the morning with food.
Lenalidomide 25 mg (PO) ONCE a day on days 1 to 21. Take on an empty stomach, at least one hour before or two hours after food.
Day 16 to 21
Lenalidomide 25 mg (PO) ONCE a day on days 1 to 21. Take on an empty stomach, at least one hour before or two hours after food.
Day 22
Dexamethasone 40 mg (PO) ONCE a day on days 1, 8, 15, and 22. Take in the morning with food.

Note: it is the consensus of the Haematology Reference Committee that 40 mg dexamethasone weekly is to be used as per the Rajkumar et alr and Benboubker et alr trials and clinical practice.

Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity.
  • Relapsed/refractory multiple myeloma (after failure of at least one prior therapy)
  • Newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation.
Caution with oral antineoplastic agents

Select link for information on the safe prescribing, dispensing and administration of orally administered antineoplastic agents (cytotoxic and non-cytotoxic chemotherapy).

Read more about oral chemotherapy for cancer
Emetogenicity LOW

Antiemetics are not routinely required; however should a patient experience emesis:

Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR

Prochlorperazine 10 mg PO or 12.5 mg IV every 6 hours when necessary may be administered.

Read more about preventing chemotherapy induced nausea and vomiting
Teratogenic effects

Lenalidomide is structurally related to thalidomide and may cause severe birth defects or death to an unborn baby.

Female patients of childbearing potential must use effective contraception for 4 weeks before therapy, during therapy and until 4 weeks after lenalidomide therapy even in case of dose interruption.

Male patients should also use a condom when having sexual intercourse with a woman of childbearing potential during therapy and for 1 week after therapy is discontinued.

Read more about the i-access® program.
Thromboembolism

Patients are at an increased risk of venous thrombosis with this treatment. 

Risk assessment for VTE should be performed prior to and during treatment. 

It is the consensus opinion of the Haematology Reference Committee that concomitant thromboprophylaxis is recommended: consider using low dose aspirin for patients without pre-existing risk factors, while patients with pre-existing risk factors should receive enoxaparin 40 mg subcut daily for the duration of treatment (unless contraindicated; reduce dose in renal impairment)

Read more about the prophylaxis of venous thromboembolism (VTE) in multiple myeloma
Bisphosphonates and dental review

Caution should be taken with prolonged use of bisphosphonates due to the risk of osteonecrosis of the jaw (ONJ). A dental review prior to treatment is recommended, and all dental issues treated before the initiation of bisphosphonates. Dental review 6 to 12 monthly during treatment is advisable to minimise risk of ONJ. Concurrent daily oral supplements of calcium 500 mg and vitamin D 400 International Units are recommended.

Read more about medication-related osteonecrosis of the jaw (MRONJ)
Corticosteroids

Diabetic patients should monitor their blood glucose levels closely. To minimise gastric irritation, advise patient to take immediately after food. Consider the use of a H2 antagonist or proton pump inhibitor if appropriate.

Read more about acute short term effects from corticosteroids
Tumour lysis risk

Assess patient for risk of developing tumour lysis syndrome.

Read more about prevention and management of tumour lysis syndrome.
Pneumocystis jiroveci pneumonia (PJP) prophylaxis

PJP prophylaxis is recommended e.g. trimethoprim/sulfamethoxazole 160/800 mg PO one tablet twice daily, twice weekly (e.g. on Mondays and Thursdays) OR one tablet three times weekly (e.g. on Mondays, Wednesdays and Fridays).

Read more about prophylaxis of pneumocystis jiroveci (carinii) in cancer patients
Antiviral prophylaxis

­

Read more about antiviral prophylaxis drugs and doses
Growth factor support

G-CSF (filgrastim, lipegfilgrastim or pegfilgrastim) is available on the PBS for the secondary prevention of neutropenia. Note: lenograstim is available but not PBS reimbursed.

Access the PBS website
Blood tests

FBC, EUC, LFTs, calcium, magnesium, phosphate and BSL at baseline and prior to each treatment. 
Patients with normal pre-treatment FBC: repeat FBC fortnightly for the first cycle then monthly thereafter.
Patients with pre-treatment cytopenias: repeat FBC 1 to 2 weekly for the first cycle then monthly thereafter.

Consider monitoring thyroid function tests (reported cases of hypothyroidism).
Hepatitis B screening and prophylaxis

Routine screening for HBsAg and anti-HBc is recommended prior to initiation of treatment. Prophylaxis should be determined according to individual institutional policy.

Read more about hepatitis B screening and prophylaxis in cancer patients requiring cytotoxic and/or immunosuppressive therapy
Vaccinations

Live vaccines, including BCG, MMR, zoster and varicella vaccines, are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease.

Refer to the recommended schedule of vaccination for immunocompromised patients, as outlined in the Australian Immunisation Handbook.
Effects of cancer treatment on fertility

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive age prior to commencing treatment.

Read more about the effect of cancer treatment on fertility
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the antineoplastic regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences. Suggested dose modifications are based on clinical trial findings, product information and reference committee consensus. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Initial treatment with lenalidomide should not be started if ANC less than 1.0 x 109/L and/or platelets less than 75 x 109/L (or platelets less than 30 x 109/L if heavy bone marrow involvement) unless prescribing Haematologist believes treatment is of benefit despite cytopenias.

Dose reduction steps for lenalidomide to manage haematological toxicities
Starting dose 25 mg
Dose level 1 15 mg
Dose level 2 10 mg
Dose level 3 5 mg
Haematological toxicity
ANC x 109/L
First fall to less than 0.5 Interrupt lenalidomide treatment
Return to greater than or equal to 0.5 when neutropenia is only observed toxicity Resume lenalidomide at starting dose
Return to greater than or equal to 0.5 when dose-dependent haematological toxicities other than neutropenia are observed Resume lenalidomide at dose level 1
For each subsequent drop less then 0.5 Interrupt lenalidomide treatment
Return to greater than or equal to 0.5 Resume lenalidomide at next lower dose level (dose level 2 or 3)
Do not dose below 5 mg
Consider using G-CSF (filgrastim, lenograstim, lipegfilgrastim or pegfilgrastim) for neutropenia
Platelets x 109/L  
First fall to less than 30 Interrupt lenalidomide treatment
Return to greater than or equal to 30 Resume lenalidomide at dose level 1
For each subsequent drop less then 30 Interrupt lenalidomide treatment
Return to greater than or equal to 30 Resume lenalidomide at next lower dose level (dose level 2 or 3)
Do not dose below 5 mg
Renal impairment
Lenalidomide is substantially excreted by the kidneys. Monitoring of renal function is advised in all patients with renal impairment. The following dose adjustments are recommended at the start of therapy for patients with moderate or severe impaired renal function or endstage renal disease.
Creatinine clearance (mL/min)  
30 to 50 Reduce lenalidomide dose to 10 mg once daily*
less than 30 (not requiring dialysis) Reduce lenalidomide dose to 15 mg on alternate days (every 48 hours)
less than 30 (requiring dialysis) Reduce lenalidomide dose to 5 mg once daily. On dialysis, the dose should be administered following dialysis

* The dose may be escalated to 15 mg after 2 cycles if the patient is not responding to treatment and is tolerating treatment

Hepatic impairment
No formal studies of lenalidomide in patients with hepatic impairment, therefore no specific dose recommendations.
Dermatological reactions
Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. These may be potentially fatal.
Rash maculo-papular  
Greater than or equal to Grade 2; exfoliative or bullous; suspected Stevens-Johnson syndrome and toxic epidermal necrolysis

Cease lenalidomide and do not resume
Dexamethasone and lenalidomide
The reference committee recommend that the dexamethasone and lenalidomide dose be individualised or dose reduced where the high dose regimen is not well tolerated (i.e. in older patients or those that develop severe steroid related side effects).

References & Disclaimer

Dexamethasone
  Interaction Clinical management
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of dexamethasone possible due to increased clearance Avoid combination or monitor for decreased clinical response to dexamethasone
CYP3A4 and P-gp inhibitors (e.g. amiodarone, aprepitant, azole-antifungals, ritonavir, lapatinib, nilotinib, sorafenib, macrolides, ciclosporin, grapefruit juice etc.) Increased effect/toxicity of dexamethasone possible due to reduced clearance Monitor for dexamethasone toxicity; consider dose reduction if the protocol being used does not already take the interaction into account
Drugs metabolised by CYP3A4 (e.g. atorvastatin, benzodiazepines, calcineurin inhibitors, clarithromycin, dihydroergotamine, simvastatin, etc.) Reduced efficacy of these drugs possible due to induction of CYP3A4 by dexamethasone resulting in increased clearance Avoid combination or monitor for decreased clinical response to the interacting drugs (esp. anticoagulants, antimicrobials, antineoplastics, antivirals, antiparasitics)
Lenalidomide
  Interaction Clinical management
Digoxin Increased digoxin plasma levels possible when combined with lenalidomide; mechanism unknown Monitor digoxin levels during treatment with lenalidomide
Itraconazole Increased lenalidomide exposure and toxicity possible due to inhibition of P-gp by itraconazole (resulting in reduced clearance of lenalidomide) Avoid combination or monitor for lenalidomide toxicity (e.g. neutropenia and recurrent infections)

Caution advised if other P-gp inhibitors are to be used (e.g. amiodarone, azole-antifungals, macrolides etc.)
Hormonal therapy (combined oral contraceptive, HRT), erythropoietic agents Additive risk of thromboembolic events Avoid combination
General
  Interaction Clinical management
Warfarin Antineoplastic agents may alter the anticoagulant effect of warfarin Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant (e.g. LMWH or unfractionated heparin)
Digoxin Antineoplastic agents can damage the lining of the intestine; affecting the absorption of digoxin Monitor digoxin serum levels; adjust digoxin dosage as appropriate
Antiepileptics Both altered antiepileptic and antineoplastic levels may occur, possibly leading to loss of efficacy or toxicity Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the antineoplastic therapy
Antiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia Avoid or minimise combination.
If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.
If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).
For more information link to TGA Medicines Safety Update
Vaccines Diminished response to vaccines and increased risk of infection with live vaccines Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

Days 1, 8, 15 and 22 (dexamethasone)

This is an oral treatment

Dexamethasone

  • administer orally ONCE a day in the morning, on days 1, 8, 15 and 22 
  • to be taken with or immediately after food.

Note: if a dose is forgotten or vomited, contact treating team.

Days 1 to 21 (lenalidomide)

This is an oral treatment

Safe handling and waste management (reproductive risk only)

Safe administration (reproductive risk only)

General patient assessment prior to each day of treatment.

Any toxicity grade 2 or greater may require delay of treatment and review by medical officer before commencing treatment.

Peripheral neuropathy assessment tool.

Any toxicity grade 1 or greater may require dose reduction or delay of treatment and review by medical officer before commencing treatment.

Lenalidomide

  • administer orally ONCE a day, at the same time each day, on days 1 to 21 every 28 days
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • to be taken on an empty stomach, one hour before or two hours after food

Note: missed doses should not be taken if it is less than 12 hours until the next dose.

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Discharge information

Dexamethasone tablets and lenalidomide capsules
  • Dexamethasone tablets and lenalidomide capsules with written instructions on how to take them.
Antiemetics
  • Antiemetics as prescribed.
Thromboprophylaxis
  • Low dose aspirin OR enoxaparin 40 mg subcut daily for the duration of treatment if prescribed.
Growth factor support
  • Arrangements for administration if prescribed.
Prophylaxis medications

Prophylaxis medications (if prescribed) i.e.  antivirals, tumour lysis prophylaxis, PJP prophylaxis and medication for constipation.

Patient information
  • Ensure patient receives patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)
Taste and smell alteration

Read more about taste and smell changes

Early (onset days to weeks)
Skin rash

Antineoplastic agents can cause a number of changes in the skin with maculo-papular rash the most common type of drug-induced skin reaction. 

Read more about skin rash
Neutropenia

Abnormally low levels of neutrophils in the blood. This increases the risk of infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively. 

Read more about neutropenia
Thrombocytopenia

A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding.  

Read more about thrombocytopenia
Side effects of corticosteroids

Insomnia, oedema, increased risk of infection e.g. oral thrush, gastric irritation, worsening of peptic ulcer disease, increased blood sugar levels, loss of diabetic control, mood and behavioural changes - including anxiety, euphoria, depression, mood swings, increased appetite and weight gain, osteoporosis and fractures (long term use), bruising and skin fragility are associated with corticosteroid use.
Constipation
Diarrhoea

Read more about treatment induced diarrhoea
Fatigue

Read more about fatigue
Thromboembolism

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) is significantly increased in multiple myeloma patients treated with thalidomide in combination with other therapies including doxorubicin, melphalan and prednisolone or dexamethasone; and lenalidomide and pomalidomide in combination with dexamethasone.

Read more about management of thromboembolism (VTE) in multiple myeloma
Arthralgia and myalgia

Generalised joint pain or and/or stiffness and muscle aches, often worse upon waking or after long periods of inactivity. Can improve with movement. May be mild or severe, intermittent or constant and accompanied by inflammation. 

Read more about arthralgia and myalgia

Late (onset weeks to months)
Anaemia

Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. 

Read more about anaemia
Hypothyroidism
Muscle cramps

Cramping in the hands, calves and/or thighs associated with hypomagnesaemia (low magnesium) and/or hypocalcaemia (low calcium). 
Stevens-johnson syndrome (SJS)

Steven-johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is characterised by fever, malaise, a painful rash, erythematous macules, targetoid lesions, or diffuse erythema progressing to vesicles and bullae, and oral, ocular and/or genital mucositis with painful mucosal erosion.   Patients who develop SJS/TEN should never be re-exposed to the causative agent.

This regimen has a role in both the upfront and relapsed/refractory settings.

The FIRST trial (MM-020) provided support evidence for the use of lenalidomide/dexamethasone (LenDex) in the upfront setting, for transplant-ineligible patients.r Between 2008 and 2011 across 18 countries and multiple treatment centres, a total of 1,623 patients were assigned in 1:1:1 randomisation to receive either LenDex in 28-day cycles till disease progression (Rd continuous), LenDex for 18 cycles then stop (Rd18), or Melphalan/Prednisone/Thalidomide in 42-day cycles for 12 cycles (MPT). Continuous Rd was found to achieve better median progression-free survival and trend towards better overall survival compared to the other two comparator regimens. Among the previously treated patients, the studies supporting the use of this regimen were published as MM-009 4 and MM-0105, with longer term follow-up published in 2009.r

In paired randomised studies recruiting in USA (MM-009) and Europe, Israel and Australia (MM-010), lenalidomide with dexamethasone was compared to dexamethasone alone. These studies were double blind, placebo controlled, multicentre studies. Eligible patients had progressive myeloma after at least 1 line of therapy, and had measurable disease not progressing on a regimen including high-dose dexamethasone. Other important eligibility criteria included ECOG =2, ALT/AST <3 x ULN, total bilirubin <2 x ULN, creatinine <221 micromol/L, ANC >1.0 x 109/L, and platelet count >75 x 109/L (>30 x 109/L if heavy marrow infiltration). Treatment assignment was stratified according to B-2 microglobulin, prior SCT, and number of prior therapies. The primary endpoint was time to disease progression.rr

Efficacy

The following table depicts the results from the FIRST trial (MM-020), excerpted from the product information of lenalidomide (Revlimid®).r Progression free survival was statistically superior compared to Rd18 and MPT arms; overall survival showed trend in favour of Continuous Rd but did not reach the threshold for significance.

In MM-009,r 177 patients were assigned to the lenalidomide/dexamethasone group and 176 to the dexamethasone group. Complete, near-complete, or partial responses occurred in 108 patients (61.0%) in the lenalidomide group and in 35 patients (19.9%) in the placebo group (P<0.001); complete responses occurred in 14.1% and 0.6%, respectively (P<0.001). The median time to progression was 11.1 months in the lenalidomide group and 4.7 months in the placebo group (P<0.001). Median overall survival times in the two groups were 29.6 months and 20.2 months, respectively (P<0.001). In MM-010,r 176 patients were assigned to the lenalidomide/dexamethasone group and 175 to the dexamethasone group. Complete, near-complete, or partial responses occurred in 106 patients (60.2%) in the lenalidomide group and in 42 patients (24%) in the placebo group (P<0.001); complete responses occurred in 15.9% and 3.4%, respectively (P<0.001). The median time to progression was 11.3 months in the lenalidomide group and 4.7 months in the placebo group (P<0.001). Overall survival was significantly improved in the lenalidomide group (hazard ratio for death, 0.66; P = 0.03). A pooled analysis with longer follow-up (median 48 months) confirmed lenalidomide/dexamethasone significantly improved overall response (60.6 vs. 21.9%, p<0.001), complete response rate (15.0 vs. 2.0%, p<0.001), time to progression (median 13.4 vs. 4.6 months, p<0.001), duration of response (median of 15.8 vs. 7 months, p<0.001), and overall survival (median 38.0 vs. 31.6 months, p=0.045).r A further analysis suggests this efficacy is maintained in patients aged over 65 years.r A small non randomised study of 45 patients aged over 75 years with relapsed myeloma found 62% overall response rate and median progression free survival of 14 months, similar to the MM-009 and MM-010 studies.r

Lastly most studies have utilised a high-dose dexamethasone regimen of 40 mg on days 1 to 4, 9 to 12 and 17-20 in the first four 28 days cycles with 40 mg on days 1 to 4 in subsequent cycles. Rajkumar et alr compared this high-dose dexamethasone regimen with 40 mg on days 1, 8, 15 and 22 of every 28 days cycle during the first 4 cycles in patients with newly diagnosed myeloma prior to ASCT. The study was stopped after the second interim analysis with 50% of patients completing the study and a median follow-up of 1 year as overall survival (a secondary endpoint) was significantly greater in the low-dose dexamethasone cohort (96% vs 87% overall survival, p=0·0002). Grade 3 or higher toxicity (52% vs 35% p=0.0001), deaths (12 vs 1, p=0.003), venous thromboembolism (26% vs 12% p=0.0003) and infection (16% vs 9% p=0.04) were significantly more frequent in the high-dose dexamethasone cohort. Given this and other experience with the high-dose dexamethasone regimens the reference committee recommend that the dexamethasone dose be individualised or dose reduced where the high dose regimen is not well tolerated (i.e. in older patients or those that develop severe steroid related side effects).

Response rates, TTP, PFS and OS: Pooled Analysis of MM-009 and MM-010 Trials:r

© Leukemia 2009

Toxicity

In the combined analysis,r grade 3 or 4 adverse events were reported in 83.3% of the lenalidomide/dexamethasone group and in 69.7% of the dexamethasone group. The grade 3 or 4 events resulted in study discontinuation in 19.8% and 10.2% or patients. Grade 3 or 4 adverse events occurring in >5% of patients are summarised in the table below. The main differences were increased bone marrow suppression (neutropenia, thrombocytopenia and anaemia) and thromboembolism with the combination of lenalidomide and dexamethasone compared with dexamethasone alone. Hyperglycaemia was seen in almost 8% of patients. The most frequently reported non-haematologic adverse effects included fatigue, insomnia, dizziness, diarrhoea, constipation, muscle cramps and infection. Infection was observed twice as often in the lenalidomide/dexamethasone cohort (Grade 3 or 4 ~21% vs 12%, p=0.14). The reference committee recommends routine antimicrobial and thromboprophylaxis.

A retrospective analysis of phase III data has shown that lenalidomide/dexamethasone remains effective and well-tolerated in patients with moderate or severe renal impairment (RI), albeit with an increase in myelosuppression.r Lenalidomide has a predominantly renal route of excretion and in patients with RI the plasma concentration and half-life of the drug are significantly increased. As a consequence, lower starting doses are required in patients with RI to avoid over-exposure and an increased risk of adverse events, while maintaining good therapeutic index.

After > 60 months’ follow up of the FIRST trial cohort of patients, there were no new safety signals compared to earlier studies. The rate of grade 3-4 infections were observed in a greater proportion of Rd continuous patients (32%), compared to Rd18 (22%) or MPT (17%). The rate of second primary solid tumours were equivalent in the subgroups, with slightly higher haematological malignancies in the MPT cohort (3%, compared to Rd continuous 1% and Rd18 <1%).r

Grade 3 and 4 Adverse Events: 'First' Trialr

© NEJM 2014

Grade 3 and 4 Adverse Events: Pooled Analysis of MM-009 and MM-010 Trials:r

© Leukemia 2009

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14 Nov 2018