Drugs Used in the Treatment of Multiple

MyelomaMyeloma Canada National

Conference2011-September-24Toronto, Ontario

Carlo De Angelis, RPh, PharmDClinical Pharmacy Coordinator - Oncology

Objectives

At the end of this educational program,

you will be able to:• Recall common side effects associated with Multiple Myeloma treatment

• Apply the information discussed to help prevent or reduce the severity of side effects of Multiple Myeloma treatment

Improved Survival in Multiple Myeloma Kumar SK et al. Blood 2008

Advances in Multiple MyelomaKyle RA and Rajkumar SV Blood 2008

Thalidomide - Adverse EffectsMateos MV Cancer Treat Rev 2010

• Single agent• Somnolence, asthenia, rash, peripheral edema, dizziness, constipation, dyspnea, leukopenia

• Peripheral neuropathy• Cummulative and dose dependent• Parasthesia, hyperaesthesia, numbness, coldness, pallor

• Symmetrical hands and feet• Caution in patient with predisposition• Early detection critical• Discontinue at first sign of symptoms

Thalidomide - Adverse Effects

• Combination with dexamethasone• Grade 3 (alone versus combination)

• Constipation - 68% versus 55%• Fatigue - 39% versus 55%• Thrombosis - 4% versus 15%• Infection - 14% versus 13%• Neuropathy - 3% versus 5%• Rash - 0% versus 4%

• Overall Grade 4 - 15% versus 31%

Thalidomide - Dose Adjustment for Peripheral NeuropathyMateos MV Cancer Treat Rev 2010

Grade 1• Maintain dose and monitorGrade 2• Reduce dose of thalidomide 50%Grade 3 or 4• Discontinue therapy• Resume at 50% previous dose

Therapeutic Interventions for Peripheral Neuropathy

• Opioids• Morphine, hydromorphone, oxycodone

• Gabapentin• Pregabalin• Duloxetine• Tricyclic antidepressants

ThrombosisMateos MV Cancer Treat Rev 2010

• Single agent - 2% to 4%• In combination - 10% to 35%• Ususllay occurs within the first 3 - 12 months

of therapy• Risk factors

• Previous history of VTE, obesity, presence of central venous catheter, high tumor burden, high dose dexamethsone

• Prevention• ≥ 2 risk factors - anticoagulation

• LMWH or warfarin 1 risk factor - low dose aspirin

Lenalidomide - Adverse EffectsMorgan GJ et al. Lancet Oncol 2006

Lenalidomide and Myelosupression

• Lenalidomide is primarily eliminated through the kidneys

• Thrombocytopenia increased when creatinine clearance was < 50 mL/min 14% versus 5%

• Starting Dosing• Moderate renal impariment

• CrCl ≥ 30 to < 60 mL/min• 10 mg daily

• CrCl < 30 mL/min not on dialysis• 15 mg every 48 hours

• CrCl < 30 mL/min on dialysis• 5 mg daily

Lenalidomide and Myelosupression

Bortezomib - Adverse Effects San Miguel J et al. Oncologist 2006

Bortezomib - Thrombocytopenia

• Transient; Not cumulative• Greater risk if significant bone marrow involvement with MM

• If platelet count < 30,000/L on day 11 of cycle• Repeat count on day 14/15• Transfuse if necessary• Reduce dose 25% next cycle

• Caution in patients with platelet count < 50,000/L at start of Tx

Bortezomib - Peripheral NeuropathyRichardson PG et al. Journal of Clinical Oncology 2006

• Symptoms are primarily sensory• Feet affected more than hands • Symptoms include:

• Pain• Paresthesias or dyesthesias

•Abmornal touch sensations such as wetness, itchiness, creeping, crawling, numbness, tingling

• Burning• Numbness

Bortezomib - Peripheral NeuropathyRichardson PG et al. Journal of Clinical Oncology 2006

• SUMMIT and CREST trial data• 35% patients all grades

• Grade 3 - 13%, Grade 4 - < 1%

• Symptom improvement or reversible 70% patients• Median time to improvement = 47 days (range 1-529)• Dose reductions in 12% patients• Discontinuation 5% patients• Preexisting peripheral neuropathy - 80%• Patients with no pre-existing peripheral neuropathy

- 3% developed Grade 3• In extension study 73% patients reported no

worsening

Bortezomib - Peripheral NeuropathyRichardson PG et al. Journal of Clinical Oncology 2006

• Dose reduction• Grade 1 without pain or loss of function

• No action required

• Grade 1 + pain or Grade 2 - reduce dose•1.0 mg/m2

• Grade 2 + pain or Grade 3 - hold until resolved; resume at dose 0.7 mg/m2 –

once weekly• Grade 4 - Discontinue Tx

Bortezomib Adverse Effects Take Home Messages

• While common, side effects can be managed and are reversible

• Bruising or bleeding may be a sign of low platelets• Contact your care team at the cancer centre

• Peripheral neuropathy• Make sure you inform your care team of any symptoms

Shift in Treatment ParadigmCurrent• Use medications at maximum tolerated doses

Future?• Use optimal effective dose

• Reduced intensity• Improved side effect profile• Prolong duration of therapy• Improved Efficacy

Summary• The availability of new active agents has revolutionized the treatment of Multiple Myeloma

• Standard first line therapy include use of drug combinations of immune modulating drugs (thalidomide, lenalidomide) and/or bortezomib

• Side effects prevention/ management and adherence to treatment are important factor contributing to success of treatment

Multiple Myeloma Word CloudRajkumar SV et al. Blood 2010