Updates in Nursing Management of Multiple

Myeloma Beth Faiman MSN, APRN-BC, AOCN

Nurse Practitioner, Cleveland Clinic

Pre-Doctoral Research Fellow, Case Western Reserve

Cleveland, Ohio

What is Myeloma?• Excess over production of a

normal immunoglobulin• Plasma cells turn malignant• “M” protein (monoclonal), or

“M- Spike”• Types of Myeloma:

– Heavy chains: IgG, IgA, IgD, IgE– Light chains: Kappa or lambda

• Protein in serum, urine, non-secretory

Stem cell

B lymphocyte

Antigens

Plasma cell

GENETICDAMAGE

Malignantplasma cell

(myeloma cell)

DamagedB lymphocyte

PathophysiologyBody System affected Result

Hematologic Anemia, leukopenia

Renal Kidney failure, insufficiency

Orthopedic Bone lesions, osteopenia, fractures

Metabolic Hypercalcemia, hyperuricemia

Infectious Infection risk increased

Neurologic Neuropathy

Epidemiology and Risk Factors• Prevalence

• >100,000 currently are living with MM in the US

• Risk factors• Age• Gender • Race

• Clinical presentation• Back, bone pain • 20% asymptomatic

American Cancer Society. Facts and Figures, 2009.

• Causes: – Benzene– Herbicides– Agent orange? – First degree relatives

• First Case: – Sarah Newbury 1842

• First effective treatment:– Melphalan 1962

Diagnostic EvaluationTest Finding (s) With Myeloma

CBC with differential ↓ Hgb, ↓ WBC, ↓ platelets

Electrolytes ↑ Creat, ↑ Ca+, ↑ Uric acid, ↓ Alb

Serum electrophoresis with quantitative immunoglobulins

↑ M protein in serum, may have ↓ levels of normal antibodies

Immunofixation Identifies light/heavy chain types M protein

β2-microglobulin ↑ Levels (measure of tumor burden)

24-hour urine protein electrophoresis

↑ Monoclonal protein (Bence Jones)

Bone marrow biopsy ≥ 10% plasma cells, FISH and Cytogenetics

Skeletal imaging Osteolytic lesions, osteoporosis

Serum free light chain ↑ Free light chains

MRI Evaluation of involvement of disease

Alb = albumin; CBC = complete blood count; Creat = creatinine; Hgb = hemoglobin; MRI = magnetic resonance imaging; WBC = white blood cell.Abella. Oncology News International. 2007;16:27; Barlogie et al. In: Williams Hematology. 7th ed. 2006:1501; Durie et al. Hematol J. 2003;4:379; MMRF. Multiple Myeloma: Disease Overview. 2006. www.multiplemyeloma.org; Rajkumar et al. Blood. 2005;106(3):812.

Laboratory Findings: CBC

• Anemia (60%)

– Cytokine mediated or from crowded bone marrow

– Blunted erythropoiesis and shortened red cell survival

– Increased blood volume

– Chronic renal disease

– Macrocytic anemia

– MDS

• Leukopenia

• Thrombocytopenia

Baz, R., Alemany, C., Green, R., & Hussein, M. A. (2004). Prevalence of vitamin B12 deficiency in patients with plasma cell dyscrasias. Cancer, 101(4), 790-795.

Laboratory Findings: Renal Failure

• More than 50% of patients will present with renal failure• Tubular capacity for reabsorption exceeded by excess

light chain production• Filtered light chains bind to Tamm-Horsfall glycoprotein • Cast formation and obstruction in the distal nephron • Heavy and light chains can cause tubular damage• Serum free light chain assay more reliable than urine

Laboratory Findings: Renal Failure

• Confounding factors– Hypercalcemia/hyperuricemia– Volume depletion, loop diuretics– Nephrotoxic agents (IV contrast, NSAIDs,

aminoglycosides)– Other comorbidities

Management of Renal Failure

• Supportive therapy – Avoid IV contrast and nephrotoxic agents– Hydration– Correct underlying cause

• ATN, hypovolemia, MM

• Plasmapheresis - 3 prospective trials favor; 1 did not– Dialysis - may reverse renal failure

Durie et al. Hematol J. 2003;4:379-398. [erratum Hematol J. 2004;5:285]; Clark et al. Ann Intern Med. 2005;143;777-784;Hutchinson et al. J Am Soc Nephrol. 2007;18:886-895; Johnson et al. Arch Intern Med. 1990;150:863; Zuchelli et al. Kidney Intl. 1988;33:1175-1180.

Laboratory Findings: Hypercalcemia

• Hypercalcemia in 25% of patients– Widest spread tumor-induced bone destruction– Increased Ca++ levels can lead to decreased renal perfusion,

azotemia– Can cause a decreased GFR secondary to renal

vasoconstriction• Pathobiology: Increased osteoclastic bone resorption mediated by

cytokines – Efflux of calcium into extracellular fluid– Not all patients with bone disease develop hypercalcemia– Osteoclast stimulation can lead to extensive osteolysis, severe

bone pain, and pathologic fractures with or without hypercalcemia

Laboratory Findings: Hypercalcemia

• Consequences of bone loss– Spinal cord compression– Plasmacytoma with significant bone destruction – Painful osteolytic lesions– Vertebral compression fractures

• Most visible aspect of myeloma– 85% of patients develop bone disease

• Treatment: – Pamidronate– Hydration– Treat the disease itself

Laboratory Findings: M Protein

• Immunofixation investigates abnormal bands• Serum and urine are evaluated to improve detection

– SPEP, presence of M protein; could miss 15% of patients with MGUS

– Not performing a urine evaluation could miss 10% of patients with hypogammaglobulinemia where the M spike is undetected

• Serum free light chains – Quantitative marker of disease activity – Especially useful in “nonsecretory” MM patients– Light chain escape

Malpas JS et al. Myeloma Biology and Management. 2nd ed. New York, NY: Oxford University Press; 1998.

Serum Free Light Chains (sFLC)

Normal Abnormal

Kappa light chain - 3.3 to 19.4 mg/L;

Normal ratio for free light-chain kappa:lambda is 0.26 to 1.65

Elevation of kappa:lambda ratio suggests kappa light chain monoclonal gammopathy is present

Lambda light chain- 5.7 to 26.3 mg/L

Kappa:lambda free light-chain ratio less than 0.26 typically defined as having monoclonal lambda free light chain

Reduced kappa:lambda ratio suggests lambda light chain monoclonal gammopathy is present

Drayson et al. Blood. 2001;97:2900-2902; Kühnemund et al. J Can Res Clin Onc. 2009;135(3):477-84.

Radiologic Imaging: Skeletal Survey

Images courtesy of Dr I. Lieberman.

Bone Disease in MM• Malignant cells produce osteoclast-activating

factors that destroy bone cells– Leads to osteolysis, bone pain, and pathologic

fracture– Radiation, balloon kyphoplasty, vertebraplasty

• Bisphosphonates inhibit bone destruction but indicated for bone disease

– Monitor patients for:• Acute-phase reactions• Renal dysfunction• Osteonecrosis of the jaw

Infections in MM

• Leading cause of death in myeloma patients– Risk further increased by cytotoxic therapy, transplant, and

glucocorticoids• Immunoglobulin levels decreased

– Hyporesponsive to antigen stimulation– Deficient antibody production

• Infiltration of bone marrow by plasma cells• Interventions

– Prompt reporting of symptoms– IV Ig prophylaxis– Poor response to pneumococcal and influenza vaccines– H1N1– Herpes zoster oral prophylaxis

Laboratory Findings: Bone Marrow Biopsy

• Suggested at baseline and at end of therapy • As myeloma disease may be assessed with

serum and urine testing, bone marrow does not need to be repeated unless clinically indicated

• Cytogenetics and FISH are helpful with prognosis, especially at baseline

Vescio RA et al. Myeloma, macroglobulinemia, and heavy chain disease. In: Haskell CM, ed. Cancer Treatment. 5th ed. Philadelphia, PA: WB Saunders; 2001:1503-1539.

Signs and Symptoms

• Subjective

– Not all inclusive; everyone is different

• General

– Back/bone pain, #1 presenting symptom

– Generalized weakness and fatigue

– Flu-like symptoms, nausea, and vomiting (electrolytes)

– Easy bruisability, recurrent infections (low platelets)

– Neurologic—headaches, blurred vision, ataxia, vertigo

– 20% of patients will be diagnosed based on routine laboratory examination but are asymptomatic!

Signs and Symptoms

• Objective – Pallor– Tenderness over affected bony areas– Altered mental status– Incontinence, loss of sphincter tone, lower-

extremity weakness with pain may signify an oncologic emergency—spinal cord compression must be ruled out

– Tachycardia/arrhythmias due to electrolyte imbalance and associated renal impairment

Classification Characteristics Management

MGUS

•Serum M protein <3 g/dL and

•Bone marrow plasma cells <10% and

•No evidence of other B-cell disorders

•No related organ or tissue impairment

•Risk of progression to malignancy: 1% per year

• Observation

Asymptomatic, or smoldering myeloma

•Serum M protein ≥3 g/dL and/or

•Bone marrow plasma cells ≥10%

•No related organ or tissue impairment or symptoms

•Risk of progression to malignancy: 10% to 20% per year

•Observation, with treatment beginning at disease progression

•Participation in a clinical trial

Differential Diagnosis

Multiple Myeloma Research Foundation. Available at: http://www.multiplemyeloma.org. Accessed April 3, 2006.

Criteria for Diagnosis of MM

 Durie BGM, Kyle RA, Belch A, et al. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation Hematol J. 2003;4:379-398. [erratum Hematol J. 2004;5:285].

• Monoclonal plasma cells in bone marrow (10%/30% if non-secretory)

• Monoclonal protein present in serum and/or urine

• Myeloma-related organ dysfunction – Calcium in serum (>10.5 mg/L) – Renal insufficiency (SCr >2 mg/dL) – Anemia (hemoglobin <10 g/dL or 2g <normal)– Bone lesions or osteoporosis

International Staging SystemStage Criteria

I Serum 2-microglobulin < 3.5 mg/L

Serum albumin ≥ 3.5 g/dL

II Serum 2-microglobulin < 3.5 mg/L

Serum albumin < 3.5 g/dL

or

Serum 2-microglobulin 3.5-< 5.5 mg/L*

III Serum 2-microglobulin ≥ 5.5 mg/L

*Irrespective of serum albumin level.Greipp, P. R., San Miguel, J., Durie, B. G., Crowley, J. J., Barlogie, B., Blade, J., et al. (2005). International staging system for multiple myeloma. Journal of Clinical Oncology, 23(15), 3412-3420.

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Risk Factors for MM• FISH: Looks at genes, chromosomes, and their aberrations

• Chromosomal changes and abnormalities present in 80%–90% patients on FISH analysis

• Transplant candidate or not??

Avet-Loiseau H, Facon T, Grosbois J, et al: Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation. Blood 99:2185-2191, 2003. Fonseca, R. (2007). Multiple myeloma and FISH (but no CHIPS). Blood, 15 April 2007, Vol. 109, No. 8, pp. 3132-3133.

Stewart, A. K., & Fonseca, R. (2005). Prognostic and Therapeutic Significance of Myeloma Genetics and Gene Expression Profiling. J Clin Oncol, 23(26), 6339-6344.

FISH = fluorescence in situ hybridization.

* High risk– t(4;14) or t(14;16) by FISH– Del(17p) by FISH– Del(13) by cytogenetics– Hypodiploidy

– High 2M (≥5.5 mg/L)

– IgA isotype

* Low to intermediate riskt(11;14)HyperdiploidyLow b2M (<3.5 mg/L)

Supportive Therapies and Considerations: Recap

• Anemia: 60% at diagnosis

– ESAs, transfusions, treat underlying cause

• Renal: 25-50%

– plasmapheresis, dialysis, avoid offending agents

• Immune: pneumovax, flu vaccine, HSV? IVIG?

• Bone disease: bisphosphonates, surgical intervention, pain meds, PT

• Palliation of bone pain/Plasmacytoma: radiation therapy (usually 10–30 Gy)

Tariman JD, Estrella EM. Oncol Nurs Forum. 2005;32:E127Faiman, B. (2007). Clinical Updates and Nursing Considerations for Patients With Multiple Myeloma. Clinical Journal of Oncology Nursing, 11(6), 831-840.

Bergsagel DE et al. Cancer Chemother Rep; 1962;21:87; Salmon SE et al. Cancer Chemother Rep. 1967;51:179; Alexanian R et al. Cancer. 1972;30:382; McElwain TJ, Powles RL. Lancet. 1983;2:822; Barlogie B et al. N Engl J Med. 1984;310:1353; Alexanian R et al. Ann Intern Med. 1986;105:8; Berenson JR et al. N Engl J Med. 1996;334:488; Rousselot P et al. Cancer Res. 1999;59:1041

Brief Historical Perspective- Therapies for MM

1962 1984 1986 1996 1999 2000+

Bisphosphonates

Oral melphalan and prednisone

VAD(vincristine,Adriamycin®,

dexamethasone)

High-dose dexamethasone

High-dose therapy with ASCT/

thalidomide/ arsenic trioxide

MAbsMAbsProteasome Proteasome

inhibitorsinhibitorsOther IMiDsOther IMiDs®®

Cure vs. Control?

Current Treatment Options

• Clinical challenges– Renal failure, age, comorbidities

• Transplant candidate: (Based on age, desire)– Bortezomib + dexamethasone – Lenalidomide + dexamethasone (+ bortezomib?)– Thalidomide + dexamethasone (+ bortezomib or PLD?)– Steroids alone (dexamethasone/prednisone)

• Nontransplant candidate: – Any of the novel agents but avoid dexamethasone – Melphalan + any of the above

• Maintenance – Controversial; many ongoing studies

Myeloma Response Criteria Response subcategory Response criteria

Complete remission

CR

Negative immunofixation on the serum and urine and

Disappearance of any soft tissue plasmacytomas and

<5% plasma cells in bone marrow

Very good partial remission

VGPR

Serum and urine M-protein detectable by immunofixation but not on electrophoresis or

90% or greater reduction in serum M-protein plus urine M-protein level <100 mg per 24 h

Partial remission

PR

>50% reduction of serum M-protein and reduction in 24 h urinary M-protein by ≥90% or to <200 mg per 24 h

Durie et al, on behalf of the International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467–1473.

Thalidomide (Thalomid®)• Oral agent; doses range from 50 mg to 200 mg PO/d Mechanisms

of action

– Antiangiogenesis, inhibition of cytokines

– Interference with cell adhesion to stroma

– Stimulation of T cells

– Induces apoptosis

• Currently used in all settings through STEPS® Program

• Thalidomide/dexamethasone median time to progression 22.4 months vs placebo/dexamethasone 6.5 months

Rajkumar SV, Kyle RA. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc. 2005;80(10):1371-1382.Tariman, J. D. (2003). Thalidomide: Current therapeutic uses and management of its toxicities. Clinical Journal of Oncology Nursing, 7, 143-147.

Management of Thalidomide ToxicityToxicity Incidence Intervention

Peripheral neuropathy(tingling/numb-ness, burning sensation, coldness in feet)

Mild: 85%Severe: 3%–5%

• Early detection and appropriate dose/schedule modification may result in resolution or improvement of neuropathy

• Instruct patients to contact physician if new or worsening symptoms of peripheral neuropathy occur

• Use neuropathy questionnaire• Symptom control with medication (sertraline, gabapentin)

SedationMild: 75%Severe: 5%–10%

• Dose at night• Gradually increase dose over 2 wk• Patients usually acclimate within 2–4 wk• Divided doses for elderly

ConstipationMild: 80%–90%Severe: 5%

Bowel regimen (call MD if no bowel movement in 3 days)

Skin rash Mild: 45%• Antihistamine; low-dose prednisone; discontinue thalidomide if any

systemic symptoms

Peripheral edema

Mild: 15%Anasarca: 3%

• Limb elevation, elastic stockings, gentle diuretics

Thromboembolic events (DVT, PE)

Thal alone: 1-3%Thal + Dex: 15%

• Anticoagulation recommended • Monitor coagulation assays

WeaknessMild: 60%Severe: 3%–5%

• Steroids; increase hydration

Lenalidomide (Revlimid®)• More “potent” oral immunomodulator than thalidomide

• Approved for treatment of patients with relapsed myeloma who have received one prior therapy

• Only available through restricted distribution program “RevAssistSM” because of potential for human birth defects.

• Different toxicity profile than thalidomide

– Greater myelosuppression

– Fatigue, Asthenia

Revlimid® (lenalidomide) prescribing information.

Randomized multicenter Phase III ECOG E4A03 study– RD arm (223 patients)

• Revlimid 25 mg (days 1-21)

• Dexamethasone 40 mg (days 1-4,9-12,17-20)

– Rd arm (222 patients)• Revlimid 25 mg (days 1-21)

• Dexamethasone 40 mg (days 1,8,15,22)

– Primary end point: response rate at 4 months

Rev/Dex (RD) vs Rev/Low-dose Dex (Rd) in Transplant Ineligible Patients

Rajkumar et al, Blood 2007 110: Abstract 74

Results from Rev/Dex (RD) vs Rev/Low-dose Dex (Rd)

Efficacy RD Rd

1-year survival 88% 96%

2-year survival 75% 87%

OS in pts<65 (1 year) 92% 97%

OS in pts>65 (1 year) 83% 94%

Deaths 42 16

Rajkumar et al, Blood 2007 110: Abstract 74; Jacobus et al., Blood 2008 112: Abstract 1740

Toxicity (Grade >3) RD (N=223) Rd (N=222)

Neutropenia 2.7% 3.2%

Thrombocytopenia 1.8% 1.4%

DVT/PE 25.6% 11.4%

Atrial fibrillation/flutter 3.1% 0.0%

Infection/Pneumonia 16.1% 9.0%

Fatigue 11.7% 4.1%

Hyperglycemia 5.8% 2.3%

Neuropathy 0.4% 1.4%

A Phase III Study to Determine the Efficacy and Safety of Lenalidomide in Combination with Melphalan and Prednisone (MPR) in Elderly Patients

with Newly Diagnosed Multiple Myeloma

Palumbo, A., Dimopoulos, M. A., Delforge, M. et al. (2009). A Phase III Study to Determine the Efficacy and Safety of Lenalidomide in Combination with Melphalan and Prednisone (MPR) in Elderly Patients with Newly Diagnosed Multiple Myeloma [Abstract No. 613].

Trial stopped: 50% increase in progression free survivalMPR-R (median NR) compared to MP-P (median 13 mo.)

MPR-R reduces risk for progression by 75% compared to MPR-P

FIRST TRIAL TO DOCUMENT VALUE OF SINGLE AGENT LEN MAINTENANCE!!!

Thalidomide and Lenalidomide: Thromboembolic Event Management

LMWH = low molecular weight heparin.Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2007;December 20 [Epub; doi:10.1038/sj.jeu.2405062]. Rome, S., Doss, D., Miller, K., & Westphal, J. (2008). Thromboembolic Events Associated With Novel Therapies in Patients With Multiple Myeloma: Consensus Statement of the IMF Nurse Leadership Board. Clinical Journal of Oncology Nursing, 12(0), 21-28.

• Symptom assessment at baseline and each visit• Risk factors include

– Drugs (erythropoietin [EPO])– History of thromboembolic event – Obesity– Concurrent cardiac or renal disease, diabetes, acute infection– Surgery

• Thromboprophylaxis– Full-dose warfarin– LMWH or full-dose heparin for high-dose dexamethasone,

doxorubicin, or multiagent chemotherapy independent of risk factors

– LMWH or full-dose heparin for patients with ≥ 2 risk factors– Aspirin for low-risk patients only (81-100mg/d)

A Prospective, Multicenter, Randomized, Trial of Bortezomib/Melphalan/Prednisone (VMP) Versus Bortezomib/Thalidomide/Prednisone (VTP) as Induction Therapy Followed by Maintenance Treatment with Bortezomib/Thalidomide (VT) Versus

Bortezomib/Prednisone (VP) in Elderly Untreated Patients with Multiple Myeloma Older Than 65 Years

• 260 patients >65yrs received VMP vs VTP followed by maintenance• Both modified induction schedules (VMP and VTP) are highly

effective with similar ORR and CR rates, but a clear different toxicity profile (more neutropenia, but less cardiac toxicity and PN with VMP)

• After a median duration of maintenance of 13 m a trend in favour of VT vs VP :1-y TTP (84% vs 71%; p=0.05), without differences in 1-y OS (92% for VT vs 89% for VP).

• Long and tolerated therapy improves CR rates to the transplant range in older people

Mateos, M-V., Oriol, V., Martinez, J. et al., (2009). [Abstract No. 613]. Retrieved http://ash.confex.com/ash/2009/webprogram/Paper22787.html .

Retrospective Early vs late ASCT after initial IMiD

• In newly diagnosed patients treated with thalidomide or lenalidomide as initial therapy, an approach of continued initial therapy and delayed transplant at the time of first relapse appears comparable to upfront transplant

• Median OS similar between the Early and Delayed group in the TD group (86 vs. 64 months respectively) as well as in the LD group (NR for either group; 82% vs. 86% at 4 years respectively).

Kumar, S., Lacy, M.Q., Dispenzieri,A. (2009). [Abstract No. 956] http://ash.confex.com/ash/2009/webprogram/Paper17095.html

Renal Dosing of Lenalidomide

• Category Renal

function Dose: Multiple Myeloma

Moderate Renal Impairment

< 60 mL/min/ 30 ≤ CLcr

10 mg Every 24 hours

Severe Renal Impairment (not requiring dialysis)

CLcr < 30 mL/min 15 mg Every 48 hours

End Stage Renal Disease (requiring dialysis)

CLcr < 30 mL/min 5 mgOnce daily. On dialysis days the dose should be administered followingdialysis

Celgene Corporation. (2008). Lenalidomide (Revlimid) package insert. Summit, NJ: Author.

Management of Common Lenalidomide Toxicities

Symptom Description InterventionsMyelosuppression(neutropenia, thrombocytopenia)

Predominant toxicity. Occurs most often with higher doses. More common in combination with dexamethasone

• Monitor CBCs bi-weekly for first

12 wk of treatment and monthly thereafter

• Hold drug or reduce dose• Transfusions, growth factors

Thromboembolic events (DVT, PE)

More common in combination with dexamethasone

• Anticoagulation recommended

• Monitor coagulation assays

Rash Usually resolves within 1 wk

• Antihistamine q 4–6 hr• Discontinue if any signs of toxic

epidermal necrosis

GI complaints Usually mild/intermittentCramping and/or diarrheaDecreased appetite

• Diet control• Dose reduction

Revlimid® (lenalidomide) prescribing information. Available at: http://www.celgene.com/PDF/RevlimidPI.pdf

Bortezomib (Velcade®)

• FDA-approved indication first-line (with MP) – Relapsed myeloma who have received at least 1

prior therapy– Ongoing frontline and combination studies

• Combination therapy with doxil, lenalidomide and thalidomide

• Maintenance therapy• Can be used with renal dysfunction, failure

.Chanan-Khan AA, Kaufman JL, Mehta J, et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood. Mar 15 2007;109(6):2604-2606 Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc; 2008.

Frequent Side Effects of Bortezomib

• No black box warnings• Thrombocytopenia- cyclic, predictable• Asthenia

– Fatigue, weakness• GI effects

– Nausea, vomiting, diarrhea• Peripheral neuropathy• Hypotension

Dicato M, et al, for the Multiple Myeloma Experts Debate Group. Oncology. 2006;70:474-482.Kyle RA, Rajkumar SV. N Engl J Med. 2004;351:1860-1873. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc; 2007.

VISTA Trial: VMP vs. MP in NDMM Results(>65 yrs)

CR = complete response; DOR = duration of response; HDT-ASCT = high-dose therapy plus autologous stem cell transplantation; IDMC = Independent Data Monitoring Committee; M = melphalan; MM = multiple myeloma; ORR = overall response rate; OS = overall survival; P = prednisone; PFS = progression-free survival; QoL = quality of life; TNT = time to next therapy; TTP = time to progression; TTR = time to response; V = bortezomibSan Miguel, J. F., Schlag, R., Khuageva, N. K., Dimopoulos, M. A., Shpilberg, O., Kropff, M., et al. (2008). Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma. N Engl J Med, 359(9), 906-917.

ARM A (VMP)VMP: Four 6-week cycles: Cycles 1-4Bortezomib 1.3mg/m2 days 1, 4, 8, 11, 22, 25, 29, 32; Melphalan 9mg/m2 and prednisone 60mg/m2 days 1-4

Followed by five 6-week cycles: Cycles 5-9 Bortezomib 1.3mg/m2 days 1, 8, 22, 29; Melphalan 9mg/m2 and prednisone 60mg/m2 once daily on days 1–4

ARM B (MP)MP: Nine 6-week cycles:

Cycles 1-9Melphalan 9mg/m2 and prednisone 60mg/m2 days 1-4

N=682 RANDOMIZED

San Miguel, J. F., Schlag, R., Khuageva, N. K., Dimopoulos, M. A., Shpilberg, O., Kropff, M., et al. (2008). Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma. N Engl J Med, 359(9), 906-917.

• Safety and tolerability consistent with VMP profiles• Results consistent across all prognostic subgroups

VISTA Trial Results: VMP vs MP in Newly Diagnosed MM

ResponseVMP

(n = 344)MP

(n = 338) P Value

EBMT EBMT

3-y OS, % 72 59 0.0032

Median time to next therapy Not reached 20.8 0.000009

Median TTP 24 16.6 0.0000001

ORR 71% 35% < 0.000001

Lenalidomide/bortezomib/Dexamethasone in Transplant Eligible Patients

• First line Phase II study assesses safety and efficacy (35 patients)– Lenalidomide 25 mg (days 1-14)– Bortezomib 1.3 mg/m2 (days 1,4,8,11)– Dexamethasone 40/20 mg (cycles 1-4/5-8) (days 1,2,4,5,8,9,11,12)– Up to 8- 21-day cycles

• Manageable toxicities– All G3/4 hematological (3-15%)– G3 hypophosphatemia (8%)– DVT/pulmonary embolism

(5% with daily aspirin)– No treatment related mortality

• Overall response rate was 100%

The combination was efficacious and well

tolerated in NDMM patients

Richardson et al, Blood 2008 112: Abstract 92

But will the 3 drug regimen =

improved overall

survival?

Bortezomib ToxicitiesSymptom Description Intervention

Asthenic conditions (fatigue, malaise, weakness)

Most often reported during cycles 1/2; most patients areable to continue therapy

General supportive care at discretion of physician

GI events (nausea, diarrhea, vomiting, constipation)

Majority of events are mild to moderate

• Antiemetics and antidiarrheals • Fluid and electrolyte replacement• Hold bortezomib treatment at onset for any

Grade 3 AEs; therapy may be reinitiated at 25% reduced dose when symptoms resolve

Hypotension Mild to moderate; may occur throughout therapy

• Adjustment of antihypertensive medications, hydration, or administration of mineralocorticoids

Thrombocytopenia Transient thrombocytopenia generally occurs during dosing period (days 1–11), with return to baseline during rest period (days 12–21)

• Monitor platelet count prior to each dose • Platelet transfusions at discretion of physician • Hold bortezomib treatment at onset if platelet

count <25,000/mL; therapy may be reinitiated at 25% reduced dose with acceptable platelet recovery

Peripheral neuropathy New onset or worsening of existing neuropathy may occur throughout cycles of treatment

• Early detection and appropriate dose/schedule modification may result in symptom resolution

• Instruct patients to contact physician if new or worsening symptoms occur

• Use neuropathy questionnaire• Symptom control with medication (sertraline,

gabapentin)

Conclusion• Multiple Myeloma is an incurable but treatable

disorder of the plasma cells • Cutting – edge treatments have shown improved

survival but more side effects • Nurses are in the unique position to educate

patients in regard to side effects and disease management so patients can adhere to therapy

.

Bibliography

• Abella HA. MR tops x-ray and scintigraphy for detecting bone mets. Oncology News International. 2007;16(12):27.

• Avet-Loiseau H, Facon T, Grosbois J, et al: Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation. Blood 99:2185-2191, 2003.

• Barlogie B, Shaughnessy J, Epstein J, et al. Plasma cell myeloma. In: Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, Kaushansky K, Prchal JT, eds. Williams Hematology. 7th ed. New York, NY: McGraw-Hill; 2006:1501-1533.

• Baz, R., Alemany, C., Green, R., & Hussein, M. A. (2004). Prevalence of vitamin B12 deficiency in patients with plasma cell dyscrasias. Cancer, 101(4), 790-795.

• Celgene Corporation. (2008). Lenalidomide (Revlimid) package insert. Summit, NJ: Author.

• Chanan-Khan AA, Kaufman JL, Mehta J, et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood. Mar 15 2007;109(6):2604-2606

• Clark, WF, Stewart, AK and the Canadian Apheresis Group (2005). Plasma exchange when myeloma presents as acute renal failure: a randomized controlled trial. Ann Intern Med, 143, 777-84.

• Dispenzieri A, Kyle RA, Katzmann JA, et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood. 2007.

Cont.• Drayson M, Tang LX, Drew R, Mead GP, Carr-Smith H, Bradwell AR. Serum free light-chain

measurements for identifying and monitoring patients with nonsecretory multiple myeloma. Blood. 2001; 97:2900-2902

• Durie BGM, Kyle RA, Belch A, et al. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation Hematol J. 2003;4:379-398. [erratum Hematol J. 2004;5:285].

• Durie, B. G. M., Harousseau, J. L., Miguel, J. S., Blade, J., Barlogie, B., Anderson, K., et al. (2006). International uniform response criteria for multiple myeloma. Leukemia, 20(9), 1467-1473.

• Faiman, B. (2007). Clinical Updates and Nursing Considerations for Patients With Multiple Myeloma. Clinical Journal of Oncology Nursing, 11(6), 831-840.

• Fonseca, R. (2007). Multiple myeloma and FISH (but no CHIPS). Blood, 15 April 2007, Vol. 109, No. 8, pp. 3132-3133.

• Greipp, P. R., San Miguel, J., Durie, B. G., Crowley, J. J., Barlogie, B., Blade, J., et al. (2005). International staging system for multiple myeloma. Journal of Clinical Oncology, 23(15), 3412-3420.

• Hutchinson, CA, Cockwell, P, Reid, S, Chandler, et al (2007). Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: In Vitro and In Vivo Studies. J Am Soc Nephrol, 18: 886-895.

• Johnson, WJ et al. Treatment of renal failure associated with multiple myeloma. Plasmapheresis, hemodialysis, and chemotherapy. Arch Intern Med 1990, 150:863.

• Kühnemund A; Liebisch P; Bauchmüller K; zur Hausen A; Veelken H; Wäsch R; Engelhardt M. 'Light-chain escape-multiple myeloma'-an escape phenomenon from plateau phase: report of the largest patient series using LC-monitoring. Journal of cancer research and clinical oncology, 2009;135(3):477-84.

Cont.• Kumar, S., Lacy, M.Q., Dispenzieri,A. (2009). Novel Agents for Initial Therapy of Multiple Myeloma:

Comparable Results with Continued Initial Therapy and Delayed Transplantation at Relapse Versus Early Transplantation [Abstract No. 956] http://ash.confex.com/ash/2009/webprogram/Paper17095.html

• Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. Mar 1 2008;111(5):2516-2520.

• Mateos, M-V., Oriol, V., Martinez, J. et al., (2009). A Prospective, Multicenter, Randomized, Trial of Bortezomib/Melphalan/Prednisone (VMP) Versus Bortezomib/Thalidomide/Prednisone (VTP) as Induction Therapy Followed by Maintenance Treatment with Bortezomib/Thalidomide (VT) Versus Bortezomib/Prednisone (VP) in Elderly Untreated Patients with Multiple Myeloma Older Than 65 Years. [Abstract No. 613]. Retrieved http://ash.confex.com/ash/2009/webprogram/Paper22787.html

• Multiple Myeloma Research Foundation (MMRF). Multiple Myeloma: Disease Overview. Norwalk, CT: Multiple Myeloma Research Foundation; 2006. Available at: www.multiplemyeloma.org/about_myeloma/index.html. Accessed January 8, 2008.

• Oyajobi, BO. (2007). Multiple myeloma/hypercalcemia. Arth Res Ther, 9(Suppl 1): 54.

• Palumbo, A., Dimopoulos, M. A., Delforge, M. et al. (2009). A Phase III Study to Determine the Efficacy and Safety of Lenalidomide in Combination with Melphalan and Prednisone (MPR) in Elderly Patients with Newly Diagnosed Multiple Myeloma [Abstract No. 613].

• Palumbo, A., Rajkumar, S. V., Dimopoulos, M. A., Richardson, P. G., San Miguel, J., Barlogie, B., et al. (2008). Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia, 22(2), 414-423.

Cont. • Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an independent risk

factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005;106(3):812-817.

• Rajkumar SV, Kyle RA. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc. 2005;80(10):1371-1382.

• Rajkumar SV, Jacobus S, Callander N, et al. A randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2008;26[Abstract 8504].

• Rome, S., Doss, D., Miller, K., & Westphal, J. (2008). Thromboembolic Events Associated With Novel Therapies in Patients With Multiple Myeloma: Consensus Statement of the IMF Nurse Leadership Board. Clinical Journal of Oncology Nursing, 12(0), 21-28.Roodman, G. D. (2008). Skeletal imaging and management of bone disease. Retrieved June 4, 2009, from http://asheducationbook.hematologylibrary.org/cgi/content/full/2008/1/313

• Sanders, PW et al. Pathobiology of cast nephropathy from human Bence Jones proteins. J Clin Invest 1992; 89:630

• San Miguel, J. F., Schlag, R., Khuageva, N. K., Dimopoulos, M. A., Shpilberg, O., Kropff, M., et al. (2008). Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma. N Engl J Med, 359(9), 906-917.

• Stewart, A. K., & Fonseca, R. (2005). Prognostic and Therapeutic Significance of Myeloma Genetics and Gene Expression Profiling. J Clin Oncol, 23(26), 6339-6344.

Cont.• Tariman, J. D. (2003). Thalidomide: Current therapeutic uses and management of its toxicities.

Clinical Journal of Oncology Nursing, 7, 143-147.

• Tariman, J. D., & Faiman, B. (2009). Multiple Myeloma. In C. H. Yarbro, D. Wujcik & B. Holmes-Gobel (Eds.), Cancer Nursing Principles and Practice (7th ed., pp. In Press). Sadbury, MA: Jones and Bartlett Publishers.

• Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc; 2008. Vescio RA et al. Myeloma, macroglobulinemia, and heavy chain disease. In: Haskell CM, ed. Cancer Treatment. 5th ed. Philadelphia, PA: WB Saunders; 2001:1503-1539.Weininger M, Lauterbach B, Knop S, et al. Whole-body MRI of multiple myeloma: comparison of different MRI sequences in assessment of different growth patterns. Eur J Radiol. December 2007 [Epub ahead of print; Doi: 10.1016/j.ejrad.2007.10.025].

• Yeh, H. S., & Berenson, J. R. (2006). Treatment for Myeloma Bone Disease. Clinical Cancer Research, 12(20), 6279s-6284s.

• Zuchelli, P., Pasquali, S., Cagnoli, L., and Ferrari, G. (1988). Controlled plasma exchange trial in acute renal failure due to multiple myeloma. Kidney international, 33, 1175-1180.