Managing Side Effects of Multiple Myeloma and its Treatments

Multiple Myeloma :Managing Side EffectsPatricia Mangan, CRNP

Clinical Presentationand Common Symptoms• Pain from bone disease is most commonpresenting symptom• Anemia and fatigue• Recurrent infection• Renal dysfunction• Hypercalcemia• Often no symptoms in the early stagesBarlogie B, et al. In: Williams Hematology. 7th ed. 2006:chap 100.Rajkumar SV, Kyle RA. Mayo Clin Proc. 2005;80:1371-1382.

Bone Disease - Pain• Accumulation of myeloma cells in bone inhibitsnormal bone formation• Increased osteoclast activity (bone resorption)• Multiple osteolytic lesions in bones• Supportive therapy– Physical therapy, bisphosphonates, radiation,bed rest, pain medication, kyphoplasty orvertebroplastyBarlogie B, et al. In: Williams Hematology. 7th ed. 2006:chap 100.Durie BG, et al. Hematol J. 2003;4:379-398.NCCN Clinical Practice Guidelines. www.nccn.org.

Myeloma Bone Pathology

Bisphosphonates InhibitBone Destruction• For all myeloma patientswith bone disease• Pamidronate (Aredia ® )• Zoledronic acid (Zometa ® )• Monitor for– Osteonecrosis of the jaw– Renal dysfunction– Acute phase reactionsBisphosphonates coat the surface,inhibiting bone resorptionAdapted from: Durie BGM. International Myeloma Foundation. 2006. www.myeloma.org.Durie BG, et al. Hematol J. 2003;4:379-398.NCCN Clinical Practice Guidelines. www.nccn.org.

Bisphosphonates andOsteonecrosis• Uncommon complicationcausing avascular necrosisof maxilla or mandible• Suspect with tooth or jawpain or exposed bone• May be related to durationof therapy• 2004 IMF web-basedsurvey:– 10% incidence withzoledronic acid– 4% incidence withpamidronateDurie BG, et al. New Engl J Med. 2005;353(1):99-102.

ASCO 2007 Clinical Practice Guideline:The Role of Bisphosphonates in MM• Suggest monthly bisphosphonates for 2 y• After 2 y– Consider stopping therapy in patients withresponsive or stable disease– Further use is at the discretion of thetreating physician– Resume treatment on relapse with new onset ofskeletal events• While on therapy– Excellent dental hygiene and avoidance ofinvasive dental proceduresASCO = American Society of Clinical Oncology; y = years.Kyle et al. J Clin Oncol. 2007;25(17):2464.

Balloon KyphoplastyTreatment for tumor-related vertebralcompression fractures (VCFs)Stabilizes the fracture and correctsspinal deformity caused by VCFsKyphon. www.kyphon.com.

Anemia and Fatigue• ↑ Malignant plasma cells in bone marrow• Myeloma cells displace marrow cell precursors• ↓ Red cell production• Fatigue associated with anemia• Supportive therapy– Treatment of myeloma; epoetin alfa(recombinant human erythropoietin) (Procrit ® )or darbepoetin alfa (Aranesp ® ); red celltransfusion if neededDurie BG, et al. Hematol J. 2003;4:379-398.NCCN Clinical Practice Guidelines. www.nccn.org.

Recurrent Infection• May have 15-fold increased risk• With increased myeloma cells, WBCproduction ↓• Normal immune role of plasma cell is lost• Supportive therapy– Antibiotics, Ig therapy– Consider pneumonia and influenza vaccines,and prophylaxis for Pneumocystis carinii,herpes zoster, fungal infectionsDurie BG, et al. Hematol J. 2003;4:379-398.Multiple Myeloma Research Foundation. 2007. www.multiplemyeloma.org.NCCN Clinical Practice Guidelines. www.nccn.org.

Renal Dysfunction• Myeloma proteins filtered by kidneys• Accumulated proteins can cause tubulardamage (Bence Jones proteins in particular)• Not all patients develop renal insufficiency• Hypercalcemia contributes to renal damage• Supportive therapy– Hydration, avoid nonsteroidal antiinflammatorydrugs (NSAIDs), avoidintravenous (IV) contrastDurie BG, et al. Hematol J. 2003;4:379-398.NCCN Clinical Practice Guidelines. www.nccn.org.

Nursing Implications forSelected Therapy-Related Side EffectsThalidomide Lenalidomide BortezomibPegylatedLiposomalDoxorubicin/BortezomibBortezomib/Melphalan/PrednisonePeripheralneuropathy√ √ √ √DVT√√More withDexMore with DexMyelosuppression√√√√√NeutropeniaNeutropenia,thrombocytopenia,anemiaThrombocytopeniaNeutropenia,thrombocytopenia,anemiaNeutropenia,thrombocytopeniaHypotension√Fatigue, weakness √ √ √ √ √Sedation√Rash √ √ √ √GI disturbance√Constipation√Constipation,diarrhea√Nausea andvomiting, diarrhea√Nausea andvomiting, diarrhea,constipation,mucositis/stomatitis√Nausea, diarrhea,constipation,vomitingGI = gastrointestinal.Doxil ® [package insert]. Ortho Biotech; revised December 2007; Revlimid ® [package insert]. Celgene; 2006; Thalomid ® [package insert].Celgene; 2007; Velcade ® [package insert]. Millennium Pharmaceuticals, Inc; 2008.

Thalidomide Side EffectsToxicity Incidence InterventionPeripheralneuropathyMild: 85%Severe: 3%-5%• Patient education/early detection• Monitor at each visit• Dose adjustment• Symptom control with pharmacologicinterventionsSomnolence Mild: 75%Severe: 5%-10%• PM dosing• Avoid concurrent meds causing drowsiness• Dose adjustmentSkin rash Mild: 45% • Moisturizing lotion; antihistamines; low-doseprednisone• Stop Thal for systemic symptomsThromboemboliccomplications(DVT/PE)Monotherapy: 1%-3%With Dex: 10%-12%• Escalate dose gradually• Anticoagulation recommended• Monitor coagulation assaysMyelosuppression(neutropenia)15%-25% • Do not initiate if ANC < 750/mm 3• If ANC < 500/mm 3 , withhold Thal untilANC > 500/mm 3 and restart at 50% lower doseGastrointestinal(constipation)Mild: 80-90%Severe: 5%• Bowel regimen (call office if no BM in 3 days)• Increase fluid and fiber intakeIncidences of toxicities are approximate estimates based on clinical trials in myeloma and other conditions (malignant and nonmalignant).ANC = absolute neutrophil count; BM = bowel movement; DVT = deep vein thrombosis; PE = pulmonary embolism; Ghobrial & Rajkumar. JSupport Oncol. 2003;1(3):194; Thalomid ® [package insert]. Celgene; 2007.

Lenalidomide Side EffectsToxicityAstheniaHyperglycemiaThromboembolic complications(DVT/PE)Intervention• Counsel patient• Avoid concurrent meds causing asthenia• Monitor blood sugar• Counsel patient regarding diet• Anticoagulation recommended• Monitor coagulation assaysMyelosuppression(neutropenia andthrombocytopenia)• Interrupt therapy if platelets fall to< 30,000/mcL or ANC falls to < 1,000/mcL• Resume therapy at lower or same dose on first recovery• Drop dose by 5 mg on subsequent recoveriesGastrointestinal (constipation)•Bowel regimen (call office if no BM in 3 days)•Increase fluid and fiber intakeIncidences of toxicities are from 2 clinical trials of multiple myeloma patients (N = 346) with lenalidomide + dexamethasone.Miceli et al. Clin J Oncol Nurs. 2008:12(3 suppl):13-20; Revlimid ® [package insert]. Celgene; 2006.

Bortezomib Side EffectsToxicityPeripheralneuropathyIncidence:Single agent vs (VMP)Overall: 37% (47%)Grade ≥ 3: 11% (13%)Intervention• Patient education/early detection• Baseline assessment and monitor at each visit• Dose adjustment• Symptom control with pharmacologic interventionsHypotension Overall: 12% (12%)Grade ≥ 3: 3% (2%)• Counsel patient• Avoid concurrent meds causing hypotensionAsthenia(fatigue, malaise,weakness)MyelosuppressionOverall: 62% (21%)Grade ≥ 3: 16% (6%)Thrombocytopenia:Overall: 38% (52%)Grade ≥ 3: 32% (37%)Neutropenia:Overall: 18% (49%)Grade ≥ 3: 14% (40%)• Counsel patient (rest, nutrition, hydration, exercise)• Avoid concurrent meds causing asthenia• Cyclical with lowest levels on Day 11 of cycle• Consistent pattern that is not cumulative• Hold if platelets < 25,000/µL and reintroduce ata 25% lower dose with recoveryDiarrhea Overall: 53% (46%)Grade ≥ 3: 8% (7%)•Bulk forming laxatives such as Metamucil ® , loperamide•with caution•Adequate fluid intakeSingle-agent incidences of toxicities are based on an integrated analyses of relapsed multiple myeloma studies (N = 1008) while VMPincidences are based on the VISTA study. Colson et al. Cancer Nurs. 2008;31:239-249; Velcade ® [package insert]. MillenniumPharmaceuticals, Inc; 2008.

Peripheral Neuropathy• Associated with multiple myeloma (found in 3%-13%of patients)– Present in ~80% of previously treated patients• Nerve root pain due to direct compression byplasmacytomas• Patient education, baseline assessment by patientinquiry, and symptom assessment at each visit is crucial• Symptom control– Vitamins/minerals (B, folic acid, E, magnesium, potassium)– Amino acids (acetyl-L-carnitine, alpha lipoic acid)– Miscellaneous (topical creams [capsaicin], tonic water)– Prescription drugs (gabapentin, pregabalin, amitriptyline,sertraline, lidocaine patch)Colson et al. Clin J Oncol Nurs. 2004;8(5):473; Kwan. Neurol Clin. 2007;25:47; Maestri et al. Tumori. 2005;91:135; Pisano et al. Clin CancerRes. 2003;9:5756; Richardson et al. J Clin Oncol. 2006;24(19):3113.

Neuropathy-Assessment ToolI have numbness or tingling in myhandsI have numbness or tingling in myfeetNot at all A little bit Somewhat Quite a bitVerymuch0 1 2 3 40 1 2 3 4I feel discomfort in my hands 0 1 2 3 4I feel discomfort in my feet 0 1 2 3 4I have joint pain or muscle cramps 0 1 2 3 4I feel weak all over 0 1 2 3 4I have trouble hearing 0 1 2 3 4I get a ringing or buzzing in myears0 1 2 3 4I have trouble buttoning buttons 0 1 2 3 4I have trouble feeling the shape ofsmall objects when they are in myhand0 1 2 3 4I have trouble walking 0 1 2 3 4Cella D, et al. Cancer. 2003;98:822-831.

Hematologic Management• Thalidomide—neutropenia– Do not initiate therapy with absolute neutrophil count (ANC)

Sedation and Rash• Sedation (thalidomide)– Take total dose at night– Avoid hazardous tasks– Gradual dose titration may allow for acclimation– Review concurrent contributing medications• Rash (thalidomide,lenalidomide)– Diphenhydramine, cortisone creams,acetaminophen– Discontinue thalidomide if any systemicsymptomsColson K, et al. Clin J Oncol Nurs. 2004;8:473-480; Ghobrial IM, Rajkumar SV. J Support Oncol.2003;1:194-205; Revlimid [package insert]. Summit, NJ: Celgene Corporation; 2006; Thalomid [packageinsert]. Summit, NJ: Celgene Corporation; 2006.

Herpes Zoster Eruption

Herpes Zoster/Shingles

DVT Risk Reduction withLenalidomideThromboembolic Events Among 445 PatientsEnrolled in ECOG 4A03% of Patients2018161412108642022.16.1High Dose Dex(n=223)Low Dose Dex(n=222)Rajkumar SV et al. Abstract # 8025. Presented at: ASCO Annual Meeting; June 1–5, 2007; Chicago

Patient Resources• American Cancer Society– 1-800-227-2345; www.cancer.org• Association of Cancer Online Resources– 1-212-226-5525; www.acor.org• Cancer Care, Inc.– 1-800-813-4673; www.cancercare.org• Chronic Disease Fund– 1-877-968-7233; www.cdfund.org• International Myeloma Foundation (IMF)– 1-800-452-2873; www.myeloma.org• The Leukemia & Lymphoma Society– 1-800-955-4572; www.leukemia-lymphoma.org• Multiple Myeloma Research Foundation (MMRF)– 1-203-972-1250; www.multiplemyeloma.org• National Cancer Institute– 1-800-4-CANCER; www.nci.nih.gov