case studies in the proactive management of multiple myeloma

Case Studies in the Proactive Management of Multiple MyelomaCase Studies in the Proactive Management of Multiple Myeloma

ObjectivesObjectives

At the end of this presentation, the participant should be able to:•Discuss the different classes of therapies and the

pharmacology of treatment regimens that might be considered for multiple myeloma (MM)

•Discuss appropriate supportive care and adjunctive measures in patients with MM

•Implement interventions for baseline patient assessment and symptom management for side effects of systemic therapies in patients with MM

Multiple Myeloma:Normal vs. Abnormal Plasma CellsMultiple Myeloma:Normal vs. Abnormal Plasma Cells

Cancer of the plasma cells in bone marrow

Growth of myeloma cells • Disrupts normal

bone marrow function• Reduces normal

immune function• Results in abnormal

production and release of monoclonal protein into blood and/or urine

• Destroys and invades surrounding bone

Barlogie et al. In: Williams Hematology. 7th ed. 2006:1501.Multiple Myeloma Research Foundation. 2009. www.themmrf.org.Illustration adapted from Multiple Myeloma Disease Overview. 2009. www.themmrf.org.

A. Healthy B. Multiple Myeloma

B cell

Antigens

Plasma cell

Genetic Damage

Multiple Myeloma cell

Damaged B cell

Bone Marrow

Multiple Myeloma Prevalence and StatisticsMultiple Myeloma Prevalence and Statistics

2nd most common hematologic malignancy in US

Incidence rises with ageand is more prevalent at ≥65 years of age

Incidence in African Americans is 2 times that of whites

5-year survival rate is about 37% (higher in younger patients)

American Cancer Society. Cancer Facts & Figures 2009. www.cancer.org.Barlogie et al. In: Williams Hematology. 7th ed. 2006:1501.NCI. SEER Cancer Statistics Review 1975-2006. www. seer.cancer.gov/csr/1975_2006/sections.html.

0

5,000

10,000

15,000

20,000

25,000

New Cases Deaths

Female Male Both Genders

Myeloma Can Result in a Broad Spectrum of Clinical Manifestations Myeloma Can Result in a Broad Spectrum of Clinical Manifestations

Renal Compromise (30%)M Protein

Bone pain (75-80%)

Neuropathy (33%)

Hypercalcemia (15-20%)

ImmuneDeficiency

Anemia (~70%)

Lytic lesions (70%)

Infection (15%)

Marrow Infiltration

Destruction of bone

Adapted from: Hoffman R. Hematology: Basic Principles and Practice, 5th Edition 2008.Ropper AH. N Engl J Med. 1998;338(22):1601.Rajkumar SV. Curr Probl Cancer. 2009;33(1):7-64.http://myeloma.org/ArticlePage.action?articleId=1044.

Monoclonal Protein—M SpikeMonoclonal Protein—M Spike

Amount/type of M protein varies among patients (IgG, IgA 80% of cases) Abnormal M protein (immunoglobulin) loses immune function and adheres and

binds to tissues

Normal SPEP Abnormal SPEP

IgA = immunoglobulin A; IgG = immunoglobulin G; SPEP = serum protein electrophoresis.Barlogie et al. In: Williams Hematology, 7th ed. 2006:1501.Durie. International Myeloma Foundation. 2008/2009. http://myeloma.org.Multiple Myeloma Research Foundation. 2009. www.themmrf.org.

Diagnostic EvaluationDiagnostic Evaluation

Test Finding (s) With MyelomaCBC with differential counts ↓ Hgb, ↓ WBC, ↓ platelets

Chemistries ↑ 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)

Serum free light chain ↑ Free light chains

Bone marrow biopsy, cytogenetics−immunohistochemistry

≥10% plasma cellsCD138+, CD20-

Skeletal survey Osteolytic lesions, osteoporosis

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; Multiple Myeloma Research Foundation. Multiple Myeloma: Disease Overview. 2009. www.themmf.org; Rajkumar et al. Blood. 2005;106(3):812.

Myeloma Disease ClassificationsMyeloma Disease Classifications

Name Definition

MGUS

Monoclonal protein present (BMBx < 10% plasma cells)

No underlying disease state

Monitor (Over time risk of progression to MM or related disorder up to 30% or 1%/year)

Asymptomatic myeloma

Higher level of disease than MGUS but still no symptoms or organ damage (BMBx > 10% plasma cells)

Monitor

Symptomatic myeloma

Monoclonal protein (BMBx > 10% plasma cells) and ≥ 1 CRAB features of organ damage present

Begin treatment

MGUS = monoclonal gammopathy of undetermined significance; CRAB = calcium elevation, renal dysfunction, anemia, bone disease.Kyle et al. N Engl J Med. 2002;346:564.Durie. International Myeloma Foundation. 2008/2009. http://myeloma.org.The International Myeloma Working Group. Br J Haematol. 2003;121:749.

Diagnostic Criteria for Symptomatic Multiple Myeloma Diagnostic Criteria for Symptomatic Multiple Myeloma

Monoclonal plasma cells in bone marrow (≥10%)

M protein in serum and/or urine

≥1 CRAB features of organ damage

C: calcium elevation (>11.5 mg/L or ULN)R: renal dysfunction (serum creatinine >2 mg/dL)A: anemia (Hgb <10 g/dL or 2 g <normal)B: bone disease (lytic lesions or osteoporosis)

ULN = upper limit of normal.NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. V.3.2010.

International Staging System (ISS):Prognostic GroupingsInternational Staging System (ISS):Prognostic Groupings

Stage Criteria

Median Survival

(mo)

Stage ISerum β2-microglobulin <3.5 mg/L

Serum albumin ≥3.5 g/dL62

Stage II

Not stage I or stage III

2 possibilities:

Serum β2-microglobulin <3.5 mg/L, but serum albumin <3.5 g/dL

Serum β2-microglobulin 3.5 to <5.5 mg/L irrespective of serum albumin level

44

Stage III Serum β2-microglobulin ≥5.5 mg/L 29

Better prognosis

Poorer prognosis

Greipp et al. J Clin Oncol. 2005;23(15):3412.

Cytogenetic Abnormalities Associated with Poor PrognosisCytogenetic Abnormalities Associated with Poor Prognosis

Genomics aids in prognosis and can help guide treatment

Fluorescent in situ hybridization (FISH) analysis identifies genes, chromosomes, and their aberrations

Patients with the abnormalities shown here had statistically significant lower survival

Cytogenetic abnormalityType of cytogenetic

abnormalityt(4;14)* Translocation

t(14;16)* Translocation

del(17p13)* Deletion

del(13) Deletion*International Myeloma Working Group recommends testing for these markers, at a minimum

Dewald et al. Blood. 2005;106:3553. Fonseca R, et al. Blood. 2003;101:4569-4575.Fonseca R, et al. Leukemia. 2009;23:2210-2221.

Challenges of Treating Multiple MyelomaChallenges of Treating Multiple MyelomaM

Pro

tein

s (g

/L)

Therapy

PLATEAUREMISSION

MGUS orSMOLDERING

MYELOMA

ASYMPTOMATIC

10

5

2

SYMPTOMATIC

RELAPSE

ACTIVEMYELOMA

REFRACTORYRELAPSE

Time

Durie. International Myeloma Foundation. 2008/2009. http://myeloma.org.

Primary induction therapy for transplant candidates*

Primary induction therapy for non-transplant candidates

Bortezomib/dexamethasone (category 1)

Bortezomib/cyclophosphamide/dexamethasone

Bortezomib/doxorubicin/dexamethasone (category 1)

Bortezomib/lenalidomide/dexamethasone (category 2B)

Bortezomib/thalidomide/dexamethasone (category 1)

Dexamethasone (category 2B)

Liposomal doxorubicin/vincristine/dexamethasone (DVD) (category 2B)

Lenalidomide/dexamethasone (category 1)

Thalidomide/dexamethasone (category 2B)

Bortezomib/dexamethasone


Lenalidomide/low-dose dexamethasone (category 1)


Melphalan/prednisone (MP)

Melphalan/prednisone/bortezomib (MPB or VMP) (category 1)

Melphalan/prednisone/lenalidomide (MPL)

Melphalan/prednisone/thalidomide (MPT) (category 1)


Vincristine/doxorubicin/dexamethasone (VAD) (category 2B)

* Exposure to myelotoxic agents (including alkylating agents and nitrosoureas) should be limited to avoid compromising stem-cell reserve prior to stem-cell harvest in patients who may be candidates for transplant

NCCN Guidelines in MM - InductionNCCN Guidelines in MM - Induction

NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. V.1.2011.

Salvage Maintenance therapyBendamustine (category 2B)Bortezomib (category 1)Bortezomib/dexamethasoneBortezomib/lenalidomide/dexamethasone (category 2B) Bortezomib/liposomal doxorubicin (category 1)Cyclophosphamide-VADCyclophosphamide/bortezomib/dexamethasoneCyclophosphamide/lenalidomide/dexamethasoneDexamethasoneDexamethasone, cyclophosphamide, etoposide, and

cisplatin (DCEP)Dexamethasone, thalidomide, cisplatin, doxorubicin,

cyclophosphamide, and etoposide (DT-PACE)High-dose cyclophosphamide Lenalidomide/dexamethasone (category 1) LenalidomideRepeat primary induction therapy (if relapse at > 6 mo)ThalidomideThalidomide/dexamethasone

Interferon (category 2B) Lenalidomide (category 2A) Steroids (category 2B)Thalidomide (category 1) ±

prednisone (category 2B)

NCCN Guidelines in MM – Salvage and MaintenanceNCCN Guidelines in MM – Salvage and Maintenance


Case Study #1Proactive Management of Multiple MyelomaCase Study #1Proactive Management of Multiple Myeloma

Case Study #1Case Study #1

72-year-old man•Medical history: diabetes (oral hypoglycemics),

hypertension, hypercholesterolemia, smoking, MI•Surgical history: 3-vessel CABG in 2001; superficial

melanoma L shoulder 2002•Current medications

– Metoprolol 50 mg twice daily– Ramipril 5 mg daily– Potassium 20 mEq daily– Clopidogrel 75 mg daily– Aspirin 81 mg daily – Atorvastatin 5 mg daily – Glipizide ER 2.5 mg daily


Presented in April 2004 to PCP with enlarging mass on left clavicle which was painful

X-ray & CT showed expansile 3 × 4 cm lytic lesion with surrounding soft tissue mass

Fine-needle aspiration showed atypical plasma cells•Positive for CD138•Diffusely positive for kappa, negative for lambda•Negative for pan-melanoma immunohistochemistry panel

Case Study #1: WorkupCase Study #1: Workup

Lab values•WBC 6.8 × 109/L; Hgb 14.3 g/dL; Plts 285 × 109/L•Cr 1.1 mg/dL; Ca 9.5 mg/dL •Albumin 4.4 g/dL•β2 microglobulin 1.5 mg/L•Normal liver enzymes & chemistries•Negative SPEP with IgA, IgG, IgM all within normal range•UPEP-IFE: kappa light chains•24-h urine: 1.49 g/24 h of kappa light chain•KLQnt N/A

Note: Light chain analysis on blood was not yet available at the time of his diagnosis

IFE = immunofixation electrophoresis; Plts = platelets.

Case Study #1: Workup Case Study #1: Workup

BMBx• Normocellular with sheets and clusters of atypical plasma cells

representing 60% of marrow cellularity• CD138 positive with kappa light chain restriction and rare lambda

positive cells• FISH positive for del(13) in 48% cells

Bone survey• Numerous 5-mm skull lesions, known lesion in clavicle, 3-cm right

femoral lesion (no risk of fracture)• Degenerative changes in spine, shoulders, & hips

Based on the results of this work-up, what diagnosis would you expect?

BMBx = bone marrow biopsy.

Case Study #1: DiagnosisCase Study #1: Diagnosis

Pt with diagnosis of multiple myeloma• Plasmacytosis• Presence of Kappa light chain in urine• Lytic bone lesions

What stage is he?• ISS Stage I

Does he need treatment of his disease?• By CRAB criteria he has symptomatic disease• Positive lytic lesions

Primary induction therapy for transplant candidates*

Primary induction therapy for non-transplant candidates

Bortezomib/dexamethasone (category 1)

Bortezomib/cyclophosphamide/dexamethasone

Bortezomib/doxorubicin/dexamethasone (category 1)

Bortezomib/lenalidomide/dexamethasone (category 2B)

Bortezomib/thalidomide/dexamethasone (category 1)



Lenalidomide/dexamethasone (category 1)


Bortezomib/dexamethasone


Lenalidomide/low-dose dexamethasone (category 1)


Melphalan/prednisone (MP)

Melphalan/prednisone/bortezomib (MPB or VMP) (category 1)

Melphalan/prednisone/lenalidomide (MPL)

Melphalan/prednisone/thalidomide (MPT) (category 1)


Vincristine/doxorubicin/dexamethasone (VAD) (category 2B)

* Exposure to myelotoxic agents (including alkylating agents and nitrosoureas) should be limited to avoid compromising stem-cell reserve prior to stem-cell harvest in patients who may be candidates for transplant

Based on the NCCN Guidelines, how would you treat this patient?Based on the NCCN Guidelines, how would you treat this patient?


Case Study #1: Initial TreatmentCase Study #1: Initial Treatment

Wanted to be considered for bone marrow transplant•VAD (vincristine/doxorubicin/dexamethasone)

versus thalidomide-dexamethasone

He was started on•Thalidomide 200 mg daily•Dexamethasone 40 mg, days 1-4, 9-12, 17-20•Monthly zoledronic acid

Treatment of Myeloma: High-Dose Chemotherapy and Stem Cell TransplantTreatment of Myeloma: High-Dose Chemotherapy and Stem Cell Transplant

No prior use of stem cell toxins in transplant candidates

Autologous transplant• Immediate ASCT after high-dose chemo increases PFS but not OS• In high-risk myeloma, no OS or PFS advantage when ASCT followed by mini-allo transplant

Tandem transplant (2 within 6 months)

Decreased disease burden before ASCT associated with CR and longer TTP

Patients <65 years of age generally have better response/outcomes

Allogeneic and mini-allo transplants• Need compatible donor• Greater risk for complications• In newly diagnosed, stem cell allograft superior to tandem stem cell autografts

ASCT = autologous stem cell transplant; CR = complete response; OS = overall survival; PFS = progression-free survival. Bruno et al. N Engl J Med. 2007;356(1):1110; Dingli et al. Cancer Sci. 2007;98(7):1035; Durie. International Myeloma Foundation. 20078/2009 http.myeloma.org; NCCN. Multiple Myeloma Clinical Practice Guidelines. V.3.2010. www.nccn.org; Garban et al, Blood 2006;107:3474.

Thalidomide Thalidomide

Immunomodulatory agent with anti-inflammatory and antiangiogenic properties

FDA approved for first-line therapy when combined with Dex • Dosing: Thal 200 mg/day po and Dex 40 mg po on days 1-4, 9-12,

and 17-20 given every 28 days• Response rate: ≥50% decrease in serum / urine M protein significantly

higher with Thal + Dex vs. Dex alone

Known teratogen

DVT prophylaxis is recommended with Thal + Dex

No dose adjustment necessary for renal dysfunction

Dex = dexamethasone; FDA = Food and Drug Administration; po = oral; Thal = thalidomide.Barlogie et al. In: Williams Hematology. 7th ed. 2006:1501; NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. V.3.2010.Rajkumar et al. J Clin Oncol. 2006;24:431-436; Richardson et al. The Oncologist. 2007;12:664; Thalomid® (thalidomide) [package insert]. Celgene Corporation; 2007.

Alters the production and activity of cytokines

in bone marrow microenvironment (IL-6,

IL-10, Il-1β, TNF-α)ACTIONS

Stimulates the immune system by promoting the growth of

stimulated T cells

Synergistic antimyeloma effect with steroids

Inhibits the growth and survival of myeloma cells

Inhibits the growth of new blood vessels by inhibiting VEGF and bFGF (angiogenesis)

Alters adhesion molecules

IL = interleukin; II-1β = interleukin-1-beta; TNF-α = tumor necrosis factor-alpha.

Richardson P, Anderson K. J Clin Oncol. 2004;22:3212.

Thalidomide and Lenalidomide Mechanism of ActionThalidomide and Lenalidomide Mechanism of Action

Thalidomide Side EffectsThalidomide Side Effects

Toxicity Incidence Intervention

Peripheral neuropathy

Mild: 85%Severe: 3%-5%

Patient education/early detection Monitor at each visit Dose adjustment Symptom control with pharmacologic interventions

SomnolenceMild: 75%Severe: 5%-10%

PM dosing Avoid concurrent meds causing drowsiness Dose adjustment

Skin rash Mild: 45% Moisturizing lotion; antihistamines; low-dose prednisone Stop Thal for systemic symptoms

Thromboembolic complications (DVT/PE)

Monotherapy: 1%-3%With Dex: 10%-12%

Escalate dose gradually Anticoagulation recommended Monitor coagulation assays

Myelosuppression(neutropenia)

15%-25% Do not initiate if ANC <750/mm3

If ANC <500/mm3, withhold Thal until ANC >500/mm3 and restart at 50% lower dose

Gastrointestinal (constipation)

Mild: 80%-90%Severe: 5%

Bowel regimen (call office if no BM in 3 days) Increase fluid and fiber intake

Incidences 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. J Support Oncol. 2003;1(3):194; Thalomid® (thalidomide) [package insert]. Celgene; 2007.

Thalidomide and Lenalidomide: Thromboembolic Event ManagementThalidomide and Lenalidomide: Thromboembolic Event Management

Symptom assessment and patient education at baseline and at each visit

Thromboprophylaxis• Full-dose warfarin• LMWH or full-dose heparin for high-dose Dex, doxorubicin, or multi-agent

chemotherapy independent of risk factors• LMWH or full-dose heparin for patients with ≥2 risk factors• Aspirin for low-risk patients only (anecdotal evidence)

Risk factors include• Drugs (epoetin alfa, birth control)• History of thromboembolic event • Concurrent cardiac or renal disease, diabetes, acute infection• Obesity• Surgery

LMWH = low molecular weight heparin.Palumbo et al. Leukemia. December 2007 [Epub]; Revlimid® [package insert]. Celgene; 2009; Thalomid® [package insert]. Celgene; 2007; Wiley. Clin J Oncol Nurs. 2007;11(6):847.

Case Study #1: TreatmentCase Study #1: Treatment

After 4 months of therapy (June 2004 – September 2004) he experienced an excellent response with negative UPEP-IFE

Was evaluated by the transplant center in September 2004• BMBx: 2% scattered, mature plasma cells, no evidence of

monoclonality• PFTs: mildly restrictive lung disease and severely reduced diffusing

capacity; • MUGA: 43% EF • Not good candidate for transplant

Began thalidomide maintenance 9/04 but after 18 months needed to discontinue in 2/06 due to increasing neuropathy

Peripheral Neuropathy Peripheral Neuropathy

Associated with multiple myeloma• Found in 33% of newly diagnosed patients• Present in ~80% of previously treated patients

Nerve-root pain due to direct compression by plasmacytomas

Patient education, baseline assessment by patient inquiry, and symptom assessment at each visit is crucial

Symptom control • Vitamins/minerals (B, folic acid, E, magnesium, potassium)• Amino acids , acetyl-L-carnitine and alpha lipoic acid) • Miscellaneous (topical creams [capsaicin], tonic water, curcumin)• 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 Cancer Res. 2003;9:5756; Richardson et al. J Clin Oncol. 2006;24(19):3113.

Case Study #1: First RelapseCase Study #1: First Relapse

9 months after stopping thalidomide (10/06), urine protein rose dramatically (75 y)• 24-h urine: 2.89 g/24 h of kappa light chain• WBC 6.2 × 109/L; Hgb 9.6 g/dL; Plts 252 × 109/L;

Cr 1.54 mg/dL; Ca 8.7 mg/dL• Asymptomatic

Offered the following treatment options:• Bortezomib• Thalidomide + dexamethasone• Lenalidomide + dexamethasone

What treatment would you select?

Thal-Dex

Evaluate for BMTx

Stop Dex Stop Thal

Total Urine Protein

Date

Case Study #1: First RelapseCase Study #1: First Relapse

Opted for lenalidomide (Len) + Dex• On 12/06 started Len 25 mg days 1-21 & Dex 40 mg weekly• Stopped Dex after 10 months (11/07) but continued lenalidomide

Start Len-Dex

Stop Dex

LenalidomideLenalidomide

Thalidomide analogue with different toxicity profile FDA approved for second-line therapy when combined with

Dex• Len 25 mg, days 1-21 + Dex 40 mg, days 1-4, 9-12, 17-20 for each 28-day cycle• Efficacy based on significant improvement in TTP in 2 large studies (Len + Dex,

11.1 and 13.3 mo vs. Dex, 4.7 and 5.1 mo; P <.000001)

Potential teratogen Excreted by kidneys – requires dose adjustments for

renal dysfunction as follows:• Moderate impairment (30 ≤CLcr <60mL/min), 10 mg q 24 h• Severe impairment (CLcr <30 mL/min not requiring dialysis), 15 mg q 48 h• ESRD (CLcr <30 mL/min requiring dialysis), 5 mg once daily (after dialysis)

Len = lenalidomide; TTP = time to progression.Revlimid® (lenalidomide) [package insert]. Celgene Corporation; 2009.; Richardson et al. The Oncologist. 2007;12:664.; Wang et al. J Clin Oncol. 2006;24(18S):Abstract 7522.

Lenalidomide Side EffectsLenalidomide Side Effects

Toxicity Intervention

Asthenia Counsel patient

Avoid concurrent meds causing asthenia

Hyperglycemia Monitor blood sugar

Counsel patient regarding diet

Thromboembolic complications (DVT/PE)

Anticoagulation recommended

Monitor coagulation assays

Myelosuppression(neutropenia and thrombocytopenia)

Interrupt therapy if platelets fall to <30,000/μL or ANC falls to <1000/μL

Resume therapy at lower (thrombocytopenia) or same dose (neutropenia) on first recovery

Drop dose by 5 mg on subsequent recoveries

These are general guidelines; see complete PI for details (slide 75)

Gastrointestinal (constipation) Bowel regimen (call office if no BM in 3 days)

Increase fluid and fiber intake

Incidences 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® (lenalidomide) [package insert]. Celgene Corporation; 2009.

Case Study #1: Second RelapseCase Study #1: Second Relapse

In April of 2009, at age 77 after 28 months of Len therapy he showed evidence of mild progression of his urine protein • UPEP = 1.43 g/24 of kappa light chain• WBC 7.3 × 109/L; Hgb 12.8 g/dL; Plts 201 × 109/L;

Cr 1.9 mg/dL• Asymptomatic

Lenalidomide stopped

Offered the following treatment options• Add back dexamethasone to his regimen• Bortezomib• Bortezomib-melphalan-prednisone• Clinical trial with bortezomib + vorinostat

What would you select?• Began bortezomib with excellent response

BortezomibBortezomib

FDA approved for patients with MM• In newly diagnosed, nontransplant-eligible patients (VISTA trial)• As a single agent or in combination with pegylated liposomal doxorubicin in any

patient who has received at least 1 prior therapy

IV administration

No dose adjustment necessary for renal dysfunction• Administer after dialysis• 44% of myeloma patients with renal impairment had renal impairment reversal when

treated with VMP

Dose adjustment for hepatic impairment• For mild impairment: no starting dose adjustment needed• For moderate or severe impairment: lower starting dose required

No adverse impact on stem-cell mobilization and engraftment with bortezomib-based induction

Dimopoulos M et al. J Clin Oncol. 2009;27:6086-6093.Richardson et al. Expert Rev Anticancer Ther. 2008;8:1053; Velcade® (bortezomib) [package insert]. Millennium Pharmaceuticals, Inc; 2009.

Bortezomib Proteasome InhibitionBortezomib Proteasome Inhibition

Proteasome inhibitors blockthe proteasome from functioning, interfering with, and producing conflicting regulatory signals

Cancer cells cannot process this overload of conflicting cellular regulatory signals

Normal cells are less sensitive than cancer cells to the proapoptotic effects of proteasome inhibition

Cancer cells undergo apoptosis

Normal cells can recover from the effects of proteasome inhibition

Proteasome Intracelllularproteins(signals)

tagged fordegradation

Degraded proteins

Bortezomib

Bortezomib Side EffectsBortezomib Side Effects

Toxicity Incidence: Single agent vs. (VMP) Intervention

Peripheral neuropathyOverall: 37% (47%)Grade ≥ 3: 11% (13%)

Patient education/early detection Baseline assessment and monitor at each visit Dose adjustment Symptom control with pharmacologic interventions

HypotensionOverall: 12% (12%)Grade ≥ 3: 3% (2%)

Counsel patientAvoid concurrent meds causing hypotension

Asthenia (fatigue, malaise, weakness)

Overall: 62% (21%)Grade ≥ 3: 16% (6%)

Counsel patient (rest, nutrition, hydration, exercise) Avoid concurrent meds causing asthenia

Myelosuppression

Thrombocytopenia:Overall: 38% (52%)Grade ≥ 3: 32% (37%)Neutropenia:Overall: 18% (49%)Grade ≥ 3: 14% (40%)

Cyclical with lowest levels on day 11 of cycleConsistent pattern that is not cumulativeHold if platelets <25,000/µL and reintroduce at a 25% lower

dose with recovery

DiarrheaOverall: 53% (46%)Grade ≥ 3: 8% (7%)

Bulk forming laxatives such as Metamucil®, loperamide with caution

Adequate fluid intake

Reactivation of herpes virus

Herpes zoster (vs. Dex)Overall: 13% (5%)Grade 3/4: 1.8% (1.5%)

Antiviral prophylaxis (usually acyclovir)

VMP = bortezomib/melphalan/prednisone. Single-agent incidences of toxicities are based on an integrated analyses of relapsed multiple myeloma studies (n = 1008) while VMP incidences are based on the VISTA study. Chanan-Khan et al. J Clin Oncol. 2008;26:4784-4790.Colson et al. Cancer Nurs. 2008;31:239-249; Velcade® (bortezomib) [package insert]. Millennium Pharmaceuticals, Inc; 2009.

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sCase Study #1: Second RelapseCase Study #1: Second Relapse

Received 7 cycles of bortezomib but required discontinuation of agent 8/09 due to severe orthostatic hypotension requiring hospitalization, a mineral-corticosteroid (fludrocortisone), and rehabilitation

4 mo later, performance status & hypotension improved, disease stable

StartBortezomib

StopBortezomib

Thal-Dex

Evaluate for BMTx

Stop Dex

Stop Thal

Start Len-Dex

Stop Dex

Total Urine Protein

Date

SummarySummary

Current options?•Observation•Bortezomib maintenance at a lower dose

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Total Urine Protein

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Case Study #2Proactive Management of Multiple MyelomaCase Study #2Proactive Management of Multiple Myeloma

Case Study #2:Presentation and WorkupCase Study #2:Presentation and Workup

A 71-year-old retired teacher with a history of CAD, MI with stent placement, and type 2 diabetes who was flying home from vacation when she suddenly developed back pain while placing luggage in the airplane overhead bin

Evaluated by her PCP for persistent low back pain, which she rated at a +9/10, along with increasing fatigue

Workup revealed IgG kappa myeloma as evidenced by bone marrow plasmacytosis, anemia, monoclonal protein in serum and urine; skeletal involvement with lytic lesions in spine, ribs, and skull; pathologic fracture of right 6th rib; and a soft tissue mass and compression fracture of L3 and L4

Due to her advanced age, extensive cardiac disease, and diabetes, did not wish to pursue ASCT and opted to initiate VMP

VMP = bortezomib, melphalan, prednisone.


What supportive care measures would you consider with this patient?• Bisphosphonate therapy• Radiation therapy• Erythropoietin therapy• Physical therapy • Pain medication

Along with VMP, she initiated zoledronic acid infusions and long- and short-acting pain medication

After 3 cycles of therapy she achieved a near CR

Case Study #2: Herpes ZosterCase Study #2: Herpes Zoster

While on therapy she developed a painful vesicular rash at left waist

Felt to be herpes zoster reactivation and initiated acyclovir 800 mg - 5 x day

Netter Anatomy Illustration Collection, used with permission of Elsevier, Inc. All rights reserved. Poncelet AN. Am Fam Phys 1998;57:755-64.

What Is the Risk of Viral Reactivation in this Patient? What Is the Risk of Viral Reactivation in this Patient?

Prophylaxis for herpes zoster reactivation• Antiviral prophylaxis should be considered for patients

being treated with bortezomib• In the phase 3 studies of patients with MM, herpes zoster

reactivation was more common in patients treated with bortezomib (13%) than in the control groups (4%–5%)

• In the phase 3 study of patients with previously untreated MM, herpes zoster virus reactivation in the VMP arm was less common in patients receiving prophylactic antiviral therapy (3%) than in patients who did not receive such therapy (13%)

Chanan-Khan et al. J Clin Oncol. 2008;26:4784-4790; San Miguel JF et al. N Engl J Med. 2008;359:906-917; Velcade® (bortezomib) [package insert]. Millennium Pharmaceuticals, Inc; 2009.


Should therapy be discontinued?

What is the role of maintenance therapy for this patient?


She continued on VMP × 8 cycles with a continued excellent PR and went on to bortezomib maintenance (schedule of 1.3 mg/m2 weekly × 4 weeks then 1 week off)

She continued monthly zoledronic acid

Due to chronic low back pain, she also continued her pain medications

Palumbo A et al. Blood. ASH Annual Meeting 2009;114(22):Abstract 128.Mateos MV et al. LanOnc.2010 Aug 24; early online pub.


During her recent visit, 9 mo after initiation of therapy, she described new onset of pain in the lower left jaw

Physical exam revealed a visible area of exposed bone

She was evaluated by her dentist who found evidence of osteonecrosis of the jaw (ONJ)

Bisphosphonates and OsteonecrosisBisphosphonates and Osteonecrosis

Uncommon complication causing avascular necrosis of maxilla or mandible

Suspect with tooth or jaw pain or exposed bone

May be related to duration of therapy

Incidence unknown but 2004 IMF web-based survey: •10% incidence with

zoledronic acid•4% incidence with

pamidronateDurie BG, et al. New Engl J Med. 2005;353(1):99-102.

Bone DestructionBone Destruction

Malignant cells produce osteoclast-activating factors that destroy bone cells•Leads to osteolysis,

bone pain, and pathologic fracture

Bisphosphonates inhibit bone destruction•Monitor patients for:

– Acute-phase reactions– Renal dysfunction– Osteonecrosis of the jaw

Plasma cell stimulates osteoclast

Osteoclasts take up bisphosphonates triggering apoptosis

Bisphosphonates bind to bone surface inhibiting resorption

Diel et al. J Support Oncol. 2007;5(10):475; Durie. International Myeloma Foundation. 2008/2009. http://myeloma.org; Durie et al. Hematol J. 2003;4:379; NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. V.3.2010.

ASCO 2007 Clinical Practice Guidelines:The Role of Bisphosphonates in MMASCO 2007 Clinical Practice Guidelines:The Role of Bisphosphonates in MM

Suggest monthly bisphosphonates for 2 years

After 2 years •Consider stopping therapy in patients with responsive or

stable disease•Further use is at the discretion of the treating physician •Resume treatment on relapse with new onset of

skeletal events

While on therapy•Excellent dental hygiene and avoidance of invasive

dental procedures

ASCO = American Society of Clinical Oncology.Kyle et al. J Clin Oncol. 2007;25(17):2464.


Decision was made to discontinue bisphosphonate therapy

Feeling well on bortezomib maintenance therapy with minimal peripheral neuropathy in toes

She is still experiencing persistent back pain in the L 3-4 area which is impacting her function and QoL

Case Study #2 Case Study #2

What strategies would you use to help with her symptoms?•Peripheral neuropathy

–Evaluate closely with each treatment for change or progression

•Low back pain–Repeat imaging studies to evaluate new or worsening

disease including MRI– Insure adequate pain management–Referral to orthopedics for possible mechanical support –Referral for evaluation of kyphoplasty

Balloon KyphoplastyTreatment for tumor-related vertebral compression fractures (VCFs)Balloon KyphoplastyTreatment for tumor-related vertebral compression fractures (VCFs)

Stabilizes the fracture and correctsspinal deformity caused by VCFs

Kyphon. www.kyphon.com.


She underwent kyphoplasty of her L3 and L4 with significant improvement in low back pain

She remained in VGPR for 7 months on weekly maintenance therapy but developed anemia and new bone pain in the mid back

Lab evaluation confirmed progression of myeloma and decreasing hemoglobin


What therapy would you now consider initiating for this patient?• Len + Dex• Bortezomib• VMP• Len + Bortezomib + Dex• Clinical trial

Lenalidomide + Bortezomib + Dexamethasone (RVD) in Relapsed DiseaseLenalidomide + Bortezomib + Dexamethasone (RVD) in Relapsed Disease

Based on preclinical data, lenalidomide added to bortezomib might induce synergistic killing of myeloma cells

Phase 1 trial of MTD in relapsed/refractory MM started• Results showed RVD well tolerated, with 58% ≥MR

Phase 2 study of safety and efficacy started in 64 patients with relapsed/refractory MM• Up to eight 21-d cycles of RVD• After cycle 8 maintenance RVD

Results: ORR, 84%; PR or better, 68%; CR or near CR, 21%

MR = minimal response; MTD = maximum tolerated dose.Anderson KC et al. J Clin Oncol. Abstract 8536. Video presentation available at: http://myeloma.org/ArticlePage.action?articleId=2664. Accessed March 10, 2010.

Lenalidomide +

Bortezomib

Apoptosis

Emerging New AgentsEmerging New Agents

Carfilzomib• 2nd-generation proteosome inhibitor binds irreversibly to proteasome;

less neuropathy than bortezomib

Pomalidomide• Immunomodulatory agent; better AE profile than thalidomide or

lenalidomide

Vorinostat/bortezomib Elotuzumab

• Human monoclonal IgG1 antibody

Perifosine• Oral Akt inhibitor

Anti-IL-6 monoclonal antibody (CNTO 328)

Key TakeawaysKey Takeaways

Exciting new agents in the treatment of multiple myeloma have been introduced in the past 5 years

New treatment options, including combinations of novel therapies, are available for patients with multiple myeloma

The potential for longer survival exists• Clinical trials are in progress to assess novel combination

therapies and SCT

Side effects of therapies are manageable

Several new potential therapies are being investigated

Patient Resources Patient Resources

American Cancer Society• 1-800-ACS-2345 (1-800-227-2345); www.cancer.org

Association of Cancer Online Resources• 1-212-226-5525; www.acor.org

CancerCare, Inc• 1-800-813-4673; www.cancercare.org

Chronic Disease Fund• 1-877-968-7233; www.cdfund.org

International Myeloma Foundation • 1-800-452-2873; http://myeloma.org

The Leukemia & Lymphoma Society• 1-800-955-4572; www.leukemia-lymphoma.org

Multiple Myeloma Research Foundation • 1-203-229-0464; www.themmrf.org

Cancer Information Service (NCI)• 1-800-4-CANCER (1-800-422-6237); www.nci.nih.gov

Cytogenetic Testing MethodologiesCytogenetic Testing Methodologies

Methodology Advantages Disadvantages

Karyotype analysisHighly sensitive for the detection of

chromosomal abnormalities

Low yield of karyotype abnormalities from MM bone marrow samples

Some aberrations not detected by karyotype

Cannot describe possible heterogeneity within a population of clonal cells

FISH

Can be performed in non-dividing cells

Can detect translocationsValidation with positive and

negative controls is standard

Variable scoring criteriaSome aberrations are technically

difficult to detect

MicroarraySimultaneously detect expression

of thousands of genes

Currently no clinical implications associated with gene expression profiling

Fonseca R, et al. Cancer Res. 2004;64:1546-1558.

Neuropathy Assessment Tool Neuropathy Assessment Tool

Not at All

A Little Bit Somewhat Quite a

BitVery Much

I have numbness or tingling in my hands 0 1 2 3 4

I have numbness or tingling in my feet 0 1 2 3 4

I feel discomfort in my hands 0 1 2 3 4

I feel discomfort in my feet 0 1 2 3 4

I have joint pain or muscle cramps 0 1 2 3 4

I feel weak all over 0 1 2 3 4

I have trouble hearing 0 1 2 3 4

I get a ringing or buzzing in my ears 0 1 2 3 4

I have trouble buttoning buttons 0 1 2 3 4

I have trouble feeling the shape of small objects when they are in my hand 0 1 2 3 4

I have trouble walking 0 1 2 3 4

Cella et al. Cancer. 2003;98:822-831.

Thalidomide/IMiDs® Target MM Cells inBone Marrow MicroenvironmentThalidomide/IMiDs® Target MM Cells inBone Marrow Microenvironment

MM cells

BM stromal cells

PBMC

IL-6

TNF

IL-1A. Thalidomide/IMiDs

IL-2

IFN

CD8+ T-cells

C. Thalidomide/IMiDs

F. Thalidomide/IMiDs

BM vessels

ICAM-1

VEGFbFGF

E. Thalidomide/IMiDs

B. Thalidomide/IMiDs

NK cells

D. Thalidomide/IMiDs

Richardson PG et al. Blood. 2002;100:3063 Hideshima T et al. Blood. 2000;96:2943

Thalidomide Dose-ModificationGuidelines for Peripheral NeuropathyThalidomide Dose-ModificationGuidelines for Peripheral Neuropathy

Grade and Severity of Peripheral Neuropathy Signs / Symptoms Incidence Modification of Dose

and Regimen

Grade 1: Subjective weakness with no objective findings/loss of deep tendon reflexes or paresthesia not interfering with function

≥80%(Grades 1-2)

Reduce dose by 50%

Grade 2: Symptomatic weakness/ paresthesia interfering with function but not with ADL

Withhold until toxicity resolves to baseline or decreases to < Grade 1 Restart at a 50% lower dose

Grade 3: Weakness/paresthesia interfering with ADL Grade 4: Disabling/life threatening 3%-5% Discontinue permanently

Benefit-Risk Assessment: Apply more stringent dose reductions/discontinuation strategies with newly diagnosed patients than with relapsed/refractory patients

ADL = activities of daily living.Ghobrial & Rajkumar. J Support Oncol. 2003;1(3):194.NCI. Common Terminology Criteria for Adverse Events. v 3.0. October 2003. http://ctep.cancer.gov.

Lenalidomide Dose Adjustments During TreatmentLenalidomide Dose Adjustments During Treatment

Thrombocytopenia Recommended Course

When platelets

Fall to <30,000/μL

Return to ≥30,000/μL

For each subsequent drop <30,000/μL

Return to ≥30,000/μL

Interrupt lenalidomide treatment, follow CBC weekly

Restart lenalidomide at 15 mg daily

Interrupt lenalidomide treatment

Resume lenalidomide at 5 mg less than the previous dose; do not dose below 5 mg daily

Neutropenia Recommended Course

When neutrophils

Fall to <1000 μL

Return to ≥1000 μL and neutropenia is the only toxicity

Return to ≥1000 μL and if other toxicity

For each subsequent drop <1000/μL

Return to ≥1000 μL

Interrupt lenalidomide treatment, add G-CSF, follow CBC weekly



Interrupt lenalidomide

Resume lenalidomide at 5 mg less than the previous dose; do not dose below 5 mg daily

Revlimid® (lenalidomide) [package insert]. Celgene Corporation; 2009.

Effects of Bortezomib in MMEffects of Bortezomib in MM

MM Cell Growth

a Bortezomib c Bortezomib

b Bortezomib

d BortezomibVEGFbFGF

Bone MarrowVessels

ICAM-1VCAM-1

TNFαVEGF

IL-6

Myeloma Cells

Bone MarrowStromal Cells

Cavo M. Leukemia. 2006;20:1341-1352.

Bortezomib Dose-ModificationGuidelines for Peripheral NeuropathyBortezomib Dose-ModificationGuidelines for Peripheral Neuropathy

Severity of Peripheral Neuropathy Signs/Symptoms Modification of Dose and Regimen

Grade 1 (paresthesia, weakness and/or loss of reflexes) without pain or loss of function

No action

Grade 1 with pain or grade 2 (interfering with function but not with ADL Reduce bortezomib to 1.0 mg/m2

Grade 2 with pain or grade 3 (interfering with ADL)

Withhold bortezomib until toxicity resolves. When toxicity resolves, reinitiate therapy with a reduced dose (0.7 mg/m2) and change treatment schedule to once per week

Grade 4 (sensory neuropathy that is disabling or motor neuropathy that is life threatening or leads to paralysis)

Discontinue bortezomib

Velcade® (bortezomib) [package insert]. Millennium Pharmaceuticals, Inc; 2009.Grading based on NCI. Common Terminology Criteria for Adverse Events. v 3.0. October 2003. http://ctep.cancer.gov.

Randomized, international trial in previously untreated patients with symptomatic MM who were not candidates for HDT-ASCT due to age (≥ 65 yrs) or comorbid conditions

Max of 9 cycles (total 54 weeks) in both arms

RANDOMIZE

IDMC = Independent Data Monitoring Committee; M = melphalan; ORR = overall response rate; P = prednisone; PFS = progression-free survival;QoL = quality of life; TNT = time to next therapy; TTR = time to response; V = bortezomib. San Miguel et al. EHA 2008:Abstract 473; San Miguel et al. N Engl J Med. 2008;359(9):906.

VISTA Phase 3 Trial: VMP vs. MP VISTA Phase 3 Trial: VMP vs. MP

Primary endpoint: TTP Study schema:

• 682 patients randomized – 151 centers – 22 countries

• IDMC recommended study stop in September 2007 based on protocol-specified interim analysis

• VMP was significantly superior for all efficacy endpointsARM B (MP)

MP: Nine 6-week cycles: Cycles 1-9Melphalan 9 mg/m2 and prednisone 60 mg/m2 Days 1-4

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

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

VISTA: Response VMP vs. MP*ASH 2009 UpdateVISTA: Response VMP vs. MP*ASH 2009 Update

ResponseVMP

(n = 344)MP

(n = 338) P Value

EBMT EBMT

3 yr OS (%) 68.5 54 —

Median TTNT (mo) 28.1 19.2 <.0001

Median TFI (mo) 17.6 8.4 <.0001

*Median time to follow up = 36.7 mo

EBMT = European Group for Blood and Marrow Transplant criteria. TTNT = time to next treatment; TFI = treatment free interval.Mateos M-V et al. Blood. (ASH Annual Meeting Abstracts). 2009;114(22):Abstract 3859.

VISTA: Response VMP vs. MPVISTA: Response VMP vs. MP

ResponseVMP

(n = 337)MP

(n = 331) P ValueEBMT EBMT

CRIF- 30% 4% <0.000001

PR 40% 31%

VGPR N/A N/A

ORR (CR+PR) 71% 35% <0.000001

Time to Response*

All responders 1.4 mo 4.2 mo <10-10

Time to CR* 4.2 mo 5.3 mo <10-10

Duration of Response

All responders 20 mo 13 mo

CR 24 mo 13 mo*Medians shown for responding patients; P values based on total study population

EBMT = European Group for Blood and Marrow Transplant; IF- = immunofixation negative. Criteria for evaluating disease progression and response per Bladé et al. Br J Haematol 1998;102:1115-23; San Miguel et al. EHA 2008:Abstract 473; San Miguel et al. N Engl J Med. 2008;359(9):906.

Nursing Implications for Selected Therapy-Related Side EffectsNursing Implications for Selected Therapy-Related Side Effects

Thalidomide Lenalidomide Bortezomib

Pegylated Liposomal

Doxorubicin/ Bortezomib

Bortezomib/Melphalan/Prednisone

Peripheral neuropathy

DVT

More with Dex

More with Dex

Myelosuppression

Neutropenia

Neutropenia,

thrombocytopenia, anemia

Thrombocytopenia

Neutropenia,

thrombocytopenia, anemia

Neutropenia,

thrombocytopenia

Hypotension

Fatigue, weakness

Sedation

Rash

Viral reactivation of herpes zoster

GI disturbance

Constipation

Constipation,

diarrhea

Nausea and

vomiting, diarrhea

Nausea and

vomiting, diarrhea, constipation,

mucositis/stomatitis

Nausea, diarrhea,

constipation, vomiting

GI = gastrointestinal.Doxil® [package insert]. Ortho Biotech; revised December 2007; Revlimid® [package insert]. Celgene; 2009; Thalomid® [package insert]. Celgene; 2007; Velcade® (bortezomib) [package insert]. Millennium Pharmaceuticals, Inc; 2009.

case studies in the proactive management of multiple myeloma

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