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Disclosure of Conflicts of InterestDisclosure of Conflicts of Interest Beth Faiman, PhD(c), RN, APRN, BC, AOCN®, reported a financial

interest/relationship or affiliation in the form of: Consultant, Celgene Corporation, Millennium Pharmaceuticals, Inc.; Speakers' Bureau, Celgene Corporation, Millennium Pharmaceuticals, Inc., Ortho Biotech Products, L.P.

Page Bertolotti, BSN, RN, OCN®, reported a financial interest/relationship or affiliation in the form of: Speakers' Bureau, Celgene Corporation, Millennium Pharmaceuticals, Inc.

Pat Killingsworth, has no real or apparent conflicts of interest to report.

Activity OverviewActivity Overview

Beth Faiman, PhD(c), RN, APRN, BC, AOCN®

Cleveland Clinic Taussig Cancer Institute

Learning ObjectivesLearning ObjectivesUpon completion of this activity, Upon completion of this activity,

participants should be better able to:participants should be better able to:

Discuss the risk factors, staging, prognostic factors, and cytogenetics of MM

Describe recent research in the treatment of patients with newly diagnosed MM

Identify new combination therapies for patients who are not candidates for transplant

Assess new options for treating patients with relapsed/refractory MM

Identify the role and timing of stem cell transplant in MM

Outline an evidence-based nursing care plan for MM patients based on common disease and treatment-related symptoms

Describe potential side effects from MM treatment with patients and the recommendations for their management

Introduction to Faculty PanelIntroduction to Faculty Panel Beth Faiman, PhD(c), RN, APRN, BC, AOCN® (Chairperson)

– Nurse Practitioner– Cleveland Clinic Taussig Cancer Institute

Page Bertolotti, BSN, RN, OCN®

– Oncology Nurse Coordinator– Samuel Oschin Cancer Center at Cedars-Sinai Medical Center

Sundar Jagannath, MD– Multiple Myeloma Program Director– Mount Sinai School of Medicine

Pat Killingsworth (Patient Speaker)– Columnist for the Myeloma Beacon

Activity AgendaActivity Agenda

6:00 – 6:05 AM Welcome and Activity Overview

6:05 – 6:20 AM Diagnosing Multiple Myeloma

6:20 – 6:40 AM The Evolving Landscape of Myeloma Treatment: First-Line

6:40 – 6:50 AM The Evolving Landscape of Myeloma Treatment: Maintenance Therapy

6:50 – 7:10 AM The Evolving Landscape of Myeloma Treatment: Relapsed/Refractory Disease

7:10 – 7:25 AM Patient Perspective

7:25 – 7:30 AM Questions and Answers

Diagnosing Multiple MyelomaDiagnosing Multiple Myeloma

Page Bertolotti, BSN, RN, OCN®

The Samuel Oschin Cancer Center

at Cedars-Sinai Medical Center

Multiple Myeloma (MM) OverviewMultiple Myeloma (MM) Overview

A malignant proliferation of a single clone of plasma cells that arise from B cells in the bone marrow

Extensive skeletal destruction results in bone pain, fractures, spinal cord compression and hypercalcemia

End organ damage best remembered by the mnemonic CRAB

– Calcium

– Renal

– Anemia

– Bone impairment

Kyle et al, 2009; Nau et al, 2008.

Clinical PresentationClinical Presentation

Disease Process Clinical PresentationM protein in serum or urine (97%) Hyperviscocity with excessive M protein

in the blood (common in IgA myeloma)

Clonal plasma cells (96%) > 10% plasma cells in bone marrow

Skeletal involvement (80%) Pain, reduced height, lytic lesions, pathologic fractures, osteoporosis, hypercalcemia

Anemia: Hgb < 12 g/dL (40%–73%) Weakness, fatigue

Hgb = hemoglobin.Dispenzieri et al, 2009; Nau et al, 2008; Rajkumar, 2011.

Clinical Presentation (cont.)Clinical Presentation (cont.)

Disease Process Clinical Presentation

Renal insufficiency (20%–25%): light chain cast nephropathy (myeloma kidney) and hypercalcemia

Serum creatinine 2 mg/dL or greater

Hypercalcemia: Calcium > 11 mg/dL (13%–30%)

Anorexia, nausea, lethargy, polydipsia (excessive thirst), constipation, confusion

Neuropathy (20%) Numbness, tingling, carpal tunnel syndrome (consider amyloidosis)

Immune function deficiency (0.8–1.4 infections per patient-year)

Recurrent infections, bacteremia, pneumonia; “tumor fever” in < 1%

Dispenzieri et al, 2009; Nau et al, 2008; Rajkumar, 2011.

Risk FactorsRisk Factors

Age Median 65–70 years

Race Twice as likely in African Americans than Caucasians

Gender Slightly more common in men than women

Genetics Higher risk in those with a first-degree relative with MM

Exposures Ionizing radiation, pesticides, herbicides, fungicides, benzene, petroleum, hair dyes, engine exhaust, furniture worker products

Other Factors Obesity and chronic immune stimulation such as systemic lupus erythematosus

Kyle et al, 2012; Rajkumar, 2011; Tariman, 2010; Okali et al, 2009.

Diagnostic EvaluationDiagnostic Evaluation Complete history and physical

Laboratory tests

BMB and aspirate

– Immunophenotyping: Flow cytometry and protein expression

– Conventional cytogenetics: Chromosome analysis, deletions, and karyotype

– FISH: Genetic mapping and translocations

– PCLI if available

Imaging

BMB = bone marrow biopsy; FISH = fluorescent in situ hybridization; PCLI = plasma cell labeling index. Kyle et al, 2012; Dispenzieri et al, 2009; NCCN, 2012.

mSMART Risk Stratification of MMmSMART Risk Stratification of MM

High Risk Intermediate Risk Standard Risk

FISH

del(17p)

t(14;16)

t(14;20)

GEP

High-risk signature

FISH

t(4;14)

Cytogenetic del(13) or hypodiploidy

PCLI > 3%

All other including:

Hyperdiploidy

t(11;14)

t(6;14)

mSMART = Mayo Stratification of Myeloma and Risk-Adapted Therapy; GEP = gene-expression profiling.Dispenzieri-Kumar et al, 2011.

Laboratory TestsLaboratory Tests

Lab Tests Common Findings

CBC with differential Anemia (80%)

Complete metabolic panel, phosphorus, uric acid

Elevated creatinine (19%), hypercalcemia (13%), low albumin

LDH Tumor burden

β2m Tumor burden

CBC = complete blood count; LDH = lactate dehydrogenase; β2m = beta-2-microglobulin. Kyle et al, 2012; Tariman et al, 2010; Dispenzieri et al, 2009.

Laboratory Tests (cont.)Laboratory Tests (cont.)Lab Tests Common Findings

SPEP M spike in the beta or gamma region; 97% monoclonal heavy or light-chain protein; < 3% nonsecretory

Quantitative immunoglobulins (Igs) IgG (52%), IgA (21%), IgM (< 1%),

IgD (2%)

SIFE Identifies light/heavy chain types of the M protein

Serum FLC Lambda, kappa, and ratio (20% only light chain disease)

24-hour urine: Total protein, UPEP, UIFE Urinary M protein (Bence-Jones proteinuria); 20% lack serum M protein but have urinary M protein; involves renal impairment

SPEP = serum protein electrophoresis; SIFE = serum immunofixation electrophoresis; FLC = free light chain assay;

UPEP = urine protein electrophoresis; UIFE = urine immunofixation.

Kyle et al, 2012; Tariman et al, 2010; Dispenzieri et al, 2009; Reece et al, 2012.

ImagingImaging

Test Finding

Skeletal survey Extent of bone involvement (head-to-toe X rays of axial bones), osteolytic lesions, osteopenia, osteoporosis

Bone density Bone loss

MRI Location and size of plasmacytomas, fractures, R/O cord compression

PET Extent of disease and response to treatment; useful in nonsecretory disease

MRI = magnetic resonance imaging; PET = positron emission tomography; R/O = rule out.

Kyle et al, 2012; Dispenzieri et al, 2009; Durie, 2011.

IMWG Diagnostic CriteriaIMWG Diagnostic CriteriaDiagnosis Criteria (all 3 required)

MGUS < 3 g/dL M protein; < 10% clonal plasma cells; no end organ damage

Smoldering (asymptomatic) myeloma

≥ 3 g/dL M protein; ≥ 10% clonal plasma cells; no end organ damage

Active (symptomatic) myeloma > 10% clonal plasma cells

M protein in serum and/or urine (unless nonsecretory);

At least 1 of the following CRAB features:

C - Calcium > 11.5 mg/L

R - Renal dysfunction, serum creatinine > 2 mg/dL

A - Anemia with Hgb < 10 g/dL

B - Bone involvement with lytic lesions or osteoporosis

Solitary plasmacytoma of bone Single plasmacytoma (biopsy proven), no plasma cells in bone marrow and no end organ damage

IMWG = International Myeloma Working Group; MGUS = monoclonal gammopathy of undetermined significance.

IMWG, 2009; Kyle et al, 2009; Rajkumar, 2011.

International Staging System (ISS)International Staging System (ISS)

Stage Criteria Median Survival (months)

I Serum β2m < 3.5 mg/L

Serum albumin ≥ 3.5 g/dL

62

II Neither stage I nor III 44

III Serum β2m ≥ 5.5 mg/L 29

Greipp et al, 2005.

The Durie and Salmon Staging SystemThe Durie and Salmon Staging System

Stage ILow Cell Mass

Stage IIIntermediate Cell Mass

Stage IIIHigh Cell Mass, Subclass A or B

All of the Following:

• Hgb value > 10 g/dL

• Serum calcium value normal or < 10.5 mg/dL

• Bone X ray, normal bone structure (scale 0), or solitary bone plasmacytoma only

• Low M component production rates: IgG value < 5 g/dL; IgA value < 3 g/dL

• Urine light chain M component on electrophoresis (Bence-Jones protein) < 4 g/24 hours

Fitting Neither Stage I

nor Stage III

1 or More of the Following:

• Hgb value < 8.5 g/dL

• Serum calcium value > 12 mg/dL

• Advanced lytic bone lesions (scale 3)

• High M component production rates IgG value > 7 g/dL IgA value > 5 g/dL

• Bence-Jones protein > 12 g/24 hours

• A: Relatively normal renal function (serum creatinine value) < 2.0 mg/dL

• B: Abnormal renal function (serum creatinine value) > 2.0 mg/dL

Examples: Stage IA (low cell mass with normal renal function) Stage IIIB (high cell mass with abnormal renal function)

Durie et al, 1975.

Key TakeawaysKey Takeaways

MM is a malignant proliferation of a single clone of plasma cells that arise from B cells in the bone marrow

Most patients present with bone pain and anemia

Cytogenetic evaluation of the bone marrow is important for risk stratification and management of the disease

The myeloma panel should be monitored closely to evaluate response to therapy or relapse disease

Diagnosing MM at an early stage prevents organ damage such as renal failure and fractures

The Evolving Landscape of The Evolving Landscape of Myeloma Treatment: First-Line Myeloma Treatment: First-Line

Page Bertolotti, BSN, RN, OCN®

The Samuel Oschin Cancer Center

at Cedars-Sinai Medical Center

Case StudyCase Study

60-year-old man

July: Chest pain, dyspnea. A stent was placed for coronary artery disease. Placed on an antiplatelet agent.

August: Developed hematuria and proteinuria. Treated for UTI.

November: Severe mid and lower back pain without trauma. Fatigue “no better since stent.” UA/C&S: 2+ proteinuria, hematuria; no bacteria.

UPEP: Immunofixation positive for kappa light chains

UTI = urinary tract infection; UA = urinalysis; C&S = culture & sensitivity.

Case Study: Case Study: Baseline CBC and Chemistry Baseline CBC and Chemistry

WBC3.70–11.00 k/uL 15.80 (H)

RBC4.20–6.00 m/uL 3.79 (L)

Hgb13.0–17.0 g/dL 7.7(L)

Hematocrit 21.2 (L)

Platelets150–400 k/uL 262

Neut %39.5%–74.0% 93.0 (H)

ANC1.45–7.50 k/uL 14.80 (H)

Lymph %15.9–47.3% 5.3 (L)

Abs Lymph1.00–4.00 k/uL 0.80 (L)

Sodium, Whole Blood135–146 mmol/L 131 (L)

Potassium, Whole Blood3.5–5.0 mmol/L 5.1 (H)

Chloride, Whole Blood98–110 mmol/L 101

Glucose, Whole Blood65–100 mg/dL 260 (H)

BUN, Whole Blood (iSTAT)10–25 mg/dL 37 (H)

Creatinine, Whole Blood (iSTAT)0.70–1.40 mg/dL 3.1 (H)

Calcium8.5–10.5 mg/dL 14.3

Protein, Total6.0–8.4 g/dL 6.4

Albumin3.5–5.0 g/dL 4.0

Sodium, Whole Blood135–146 mmol/L 131 (L)

Potassium, Whole Blood3.5–5.0 mmol/L 5.1 (H)

Chloride, Whole Blood98–110 mmol/L 101

Glucose, Whole Blood65–100 mg/dL 260 (H)

BUN, Whole Blood (iSTAT)10–25 mg/dL 37 (H)

Creatinine, Whole Blood (iSTAT)0.70–1.40 mg/dL 3.1 (H)

Calcium8.5–10.5 mg/dL 14.3

Protein, Total6.0–8.4 g/dL 6.4

Albumin3.5–5.0 g/dL 4.0

Liver Function Normal

Case Study: CRAB Criteria?Case Study: CRAB Criteria? Related organ or tissue involvement (CRAB)

– Calcium > 11.5 mg/dL, actual value: 14.3 mg/dL

– Renal (creatinine > 2 mg/dL), actual value: 3.1 mg/dL

– Anemia (Hgb < 10 g/dL or 2 g/dL below LLN), actual: 7.7 g/dL

– Bone/skeletal survey: Diffuse abnormal appearance of the pelvis. 2 large lytic lesions right femur. Calvarial lesions.

Additional testing?

– BMB cytogenetics, FISH

– “Myeloma labs”

(SPEP, UPEP, sFLC)

FemurFemurFemurFemur CalvariumCalvarium

LLN = lower limit of normal.

Case Study: Case Study: Bone Marrow and MM StudiesBone Marrow and MM Studies

Bone marrow plasma cell infiltration: 20%

Myeloma FISH panel: Not performed; Cytogenetics: 46,XY

ISS stage: Albumin: 3.6 g/dL, β2m: 6.0 mg/L (III)

Salmon Durie Stage: Stage III (Hgb < 8.5g/dL, Ca ≥ 12 mg/dL, ≥ 3 lytic bone lesions, total IgG > 7 g/dL, IgA > 5 g/dL, or Bence-Jones protein > 12 g/24 hrs) B (creatinine ≥ 2 mg/dL)

Monoclonal proteins at diagnosis

– Serum M spike: Negative

– Serum kappa free light chains: 3014.0 mg/L

– Urinary M protein: 2.81 g/24 hrs

Diagnosis: Symptomatic MM kappa light chain type

Does this patient require treatmennt for MM? Does this patient require treatmennt for MM?

Considerations: Considerations: Initial or Initial or InductionInduction Therapy Therapy

Induction chemotherapy

– Treatment given to “induce” a response

The ideal initial or induction therapy should

– Rapidly and effectively control disease

– Reverse disease-related complications

– Decrease the risk of early death

– Be easily tolerated with minimal/manageable toxicity

– Not interfere with the ability to collect stem cells for transplantation (if a transplant candidate based on age, desire, health status)

Kumar et al, 2009.

Should All Patients Receive Should All Patients Receive Induction Chemotherapy?Induction Chemotherapy?

Only patients with symptomatic MM (CRAB) require treatment

Evidence that patients with “smoldering” MM can benefit from early treatment with lenalidomide + dexamethasone

– This should only be recommended in the context of a clinical trial

A percentage of patients with MGUS may never require treatment

– Increased sFLC ratio, higher M protein may indicate a group more likely to progress to symptomatic MM

3 key agents given today: Bortezomib, lenalidomide, and thalidomide in combination with corticosteroids

Spectrum of Plasma Cell Dyscrasias

Low M component, no CRAB High M component, no CRAB CRAB

Spectrum of Plasma Cell Dyscrasias

Low M component, no CRAB High M component, no CRAB CRABSmoldering MM MMMGUS

Mateos et al, 2011; Khoriaty et al, 2010; Rajkumar et al, 2005.

Initial or Induction Therapy for MM:Initial or Induction Therapy for MM:Transplant Eligible and IneligibleTransplant Eligible and Ineligible

Melphalan +/- • Bortezomib• Lenalidomide• Thalidomide• Other

Transplant Eligible

Induction TherapyNon-Alkylator Based

Early Autologous Transplant

Delayed Autologous Transplant

Transplant Ineligible

Supportive care should be considered at diagnosis and throughout

NCCN, 2012; Kumar et al, 2009.

How Do You Treat MM: Specific DosesHow Do You Treat MM: Specific Doses

NCCN, 2012; Rajkumar et al, 2007; San Miguel et al, 2008; Kumar et al, 2008; Ludwig et al, 2009; Jagannath et al, 2004; Thalomid® prescribing information, 2012.

PO = oral; MPV = melphalan, prednisone, bortezomib; PLD = pegylated liposomal doxorubicin; PFS = progression-free survival.

Transplant CandidateBortezomib +dexamethasone (+ cyclophosphamide, lenalidomide, or thalidomide)

Bortezomib 1.3 mg/m2 SC/IV Days 1, 4, 8, 11 + Dexamethasone 20 mg PO Day 1, 2, 4, 5, 8, 9, 11, 12

Lenalidomide +dexamethasone (+/- bortezomib?)

Lenalidomide 25 mg PO Days 1–21, q28d + Dexamethasone 40 mg PO wkly (+ bortezomib 1.3 mg/m2 wkly or BID?)

Thalidomide +dexamethasone (+ bortezomib or PLD?)

Thalidomide 200 mg PO Days 1–28 + Dexamethasone 40 mg PO Days 1–4, 9–12, 17–20 x 4 28-day cycles (+ bortezomib or PLD?) – LESS COMMON TO GIVE THAL UPFRONT

Non-Transplant CandidateAny of the novel agents

Prednisone is often substituted for dexamethasone (elderly poor tolerance)

Melphalan + any of the above

MPV: 9 6-wk cycles of melphalan 9 mg/m2 PO + prednisone 60 mg/m2 PO Days 1–4 and/ or bortezomib 1.3 mg/m2 on Days 1, 4, 8, 11, 22, 25, 29, 32 during Cycles 1–4 and Days 1, 8, 22, 29 during Cycles 5–9

Maintenance May improve PFS; ongoing studies

Can Induction Therapy Be Individualized? Can Induction Therapy Be Individualized? The Mayo Clinic ApproachThe Mayo Clinic Approach

High Risk Intermediate Risk

Standard Risk

FISH

del(17p)

t(14;16)

t(14;20)

GEP

• High-risk signature

FISH

t(4;14)

Cytogenetic del(13) or hypodiploidy

PCLI ≥ 3%

All other including:

Hyperdiploidy

t(11;14)

t(6;14)

Approx. 25% of patients Approx. 75% of patients

High Risk Standard Risk

Newly Diagnosed Myeloma Eligible for Transplantation

4–6 cycles of CyBorD or VRd

4 cycles of Rd

Collect Stem Cells Collect Stem Cells

Autologous stem cell transplant

Autologous stem cell transplant

ORContinue Rd

Consider Lenalidomide maintenance

Bortezomib-based maintenance

Newly Diagnosed Myeloma Not Eligible for Transplantation

High Risk Standard Risk

VMP or CyBorD Rd

mSMART 2.0: Classification of active MM

Rd = lenalidomide, dexamethasone; VRd = bortezomib plus Rd; CyBorD = cyclophosphamide, bortezomib, dexamethasone;VMP = bortezomib, melphalan, prednisone.Dispenzieri-Kumar, 2011.

Side Effects of Common Therapies: SnapshotSide Effects of Common Therapies: Snapshot

Oral Thalidomide Oral Lenalidomide IV/SC Bortezomib

PN

DVT

Myelosuppression

Neutropenia

Neutropenia, thrombocytopenia,

anemia

Thrombocytopenia

Hypotension

Fatigue, weakness

Sedation

Rash

GI disturbance

Constipation

Constipation, diarrhea

Nausea and vomiting, diarrhea

Dose modifications to address side effects can optimize adherence, allow patients to remain on regimen longer!

Dose modifications to address side effects can optimize adherence, allow patients to remain on regimen longer!

DVT = deep vein thrombosisThalomid® prescribing information, 2012; Velcade® prescribing information, 2012; Revlimid® prescribing information, 2011; Palumbo et al, 2011.

Important Considerations in MM: Important Considerations in MM: Bone Disease Bone Disease

Malignant cells produce osteoclast-activating factors (hormones, cytokines) that destroy bone cells

– Leads to osteolysis, bone pain, and pathologic fracture

BP (pamidronate, zoledronic acid) inhibit bone destruction

– Monitor patients for

• Acute phase reactions (flulike sxs, chills)

• Renal dysfunction

– Dose reduce BP for decreased CrCl, longer infusion time

– Monitor for albuminuria, a sign of tubular damage

• Osteonecrosis of the jaw (ONJ)

– Baseline and ongoing dental exams

– Hold BP if jaw pain

BP = bisphosphonates; CrCl = creatinine clearance; ONJ = osteonecrosis of the jaw.Tariman et al, 2010; Kyle et al, 2007; Morgan et al, 2010a.

Important Considerations in MM: Important Considerations in MM: InfectionsInfections

A leading cause of death in myeloma patients

Ig levels decreased (hypogammaglobulinemia)

Infiltration of bone marrow by plasma cells

Cytotoxic therapy, transplant and glucocorticoids

Interventions

– Prompt reporting of symptoms

– Intravenous immunoglobulin (IVIG) prophylaxis for frequent infections

– Poor response to pneumococcal and influenza vaccines

– Herpes zoster oral prophylaxis (bortezomib)

Barlogie et al, 2006; Durie at al, 2003; Malpas et al, 2004; NCCN, 2012.

Important Considerations in MM: Important Considerations in MM: Peripheral NeuropathyPeripheral Neuropathy

Damage to the peripheral nervous system caused by injury, inflammation, or degeneration of peripheral nerve fibers (sensory, motor, autonomic)

Incidence of CIPN is increasing

– More neurotoxic drugs have been developed, patients are living longer

Thalidomide and bortezomib (vincristine, cisplatin less commonly used)

Sensory, motor, autonomic

Signs and symptoms: Numbness, tingling, pain

Monitoring: Symptom assessment, test sensation, DTRs, gait, proprioception

ADLs = activities of daily life; CIPN = chemotherapy-induced peripheral neuropathy; DTR = deep tendon reflexes. Tariman et al, 2008; Wickham, 2007; Thalomid® prescribing information, 2012; Velcade® prescribing information, 2012; NCI.v4.0 (CT-CAE), 2009; Richardson et al, 2011.

Grade 1 Grade 2 Grade 3 Grade 4

Peripheral Sensory Neuropathy

Asymptomatic; loss of reflexes

If pain: Reduce 1 level or change to wkly

Moderate symptoms; limiting instrumental ADLs

Hold and/or reduce

Severe symptoms; limiting selfcare ADLs

Life-threatening; urgent intervention indicated

STOP

Venous Thromboembolic Events Venous Thromboembolic Events (VTEs) in MM(VTEs) in MM

MM is an intrinsically hypercoagulable disease associated with a higher risk of thromboembolic events

Higher risk for DVT/PE in patients treated with conventional chemotherapies plus novel therapies (thalidomide, lenalidomide)

– Prior VTEs, surgery, immobility, obesity require LMWH/warfarin

– All patients should receive ASA unless contraindicated

Dx: Duplex ultrasound, spiral CT if PE suspected

Prevent: Ambulate, SCDs, antiembolism stockings (questionable benefit), exercise

Prophylaxis if high risk as abovePE = pulmonary embolism; SCD = sequential compression device; LMWH = low molecular weight heparin;ASA = acetylsalicylic acid.Rome et al, 2008; Musallam et al, 2010; Menon et al, 2008.

Side-Effect Assessment and ManagementSide-Effect Assessment and ManagementIndividualized for Each Patient

IMiDs = immunomodulatory drugs.IMF, 2011; Kyle et al, 2007; NCCN, 2012; Smith et al, 2008.

What is the risk of VTE? Increased if prior VTE, receiving IMiDs, etc.

Bone health Are bisphosphonates indicated?

Infectious diseases Is your patient at high risk for infection? (myelosuppression from disease/treatment)

– Wkly CBC, differential for 8 wks with lenalidomide– Acyclovir prophylaxis with

bortezomib– IV Ig for recurrent infections (a result of hypogammaglobulinemia)

GI Antiemetic prior to bortezomib, doxorubicin

Assess for diarrhea, constipation

PNPN Review increased risk of PN with bortezomib and thalidomide

Prompt intervention can prevent irreversible PN symptoms

Monthly monitoring of disease parameters

SPEP, UPEP, 24-hr urine, sFLC

Bortezomib: Bortezomib: New Data on Survival, Dosing New Data on Survival, Dosing

VISTA trial: 655 patients ineligible for transplant

US, transplant eligibility

– Age, desire, social, financial

Patients randomized to 9 6-wk cycles of MP plus bortezomib (VMP) or to MP alone

VMP (mos) MP (mos)

Median OS 56.4 43.1

Median time to next treatment

27 19.2

MP = melphalan, prednisone; OS = overall survival; TTP = time to progression.

San Miguel et al, 2011; Moreau et al, 2011.

MP = melphalan, prednisone; OS = overall survival; TTP = time to progression.

San Miguel et al, 2011; Moreau et al, 2011.

New evidence for dosing of bortezomib – Once-wkly IV

– SC

Wkly bortezomib: Significantly less severe PN (3%)

compared with twice-wkly IV without a change in

response

Bortezomib SC is not inferior to IV by overall

response rate

Bortezomib SC not different from IV by

TTP; p = .387

1-yr OS; p = .504

Wkly bortezomib: Significantly less severe PN (3%)

compared with twice-wkly IV without a change in

response

Bortezomib SC is not inferior to IV by overall

response rate

Bortezomib SC not different from IV by

TTP; p = .387

1-yr OS; p = .504

Lenalidomide: Lenalidomide: New Data on Safety, EfficacyNew Data on Safety, Efficacy

Similar to bortezomib, oral lenalidomide remains a common treatment for patients with newly diagnosed MM (transplant eligible or ineligible)

Tumoricidal and immunomodulatory

Non-transplant: MPR-R vs. MPR vs. MP

– Continuous MPR-R reduced risk of progression, maintenance improved PFS 31 mos

Lenalidomide post-transplant maintenance improves PFS (compared to placebo)

MPR = melphalan, prednisone, lenalidomide; MPR-R = MPR plus lenalidomide maintenance.

Palumbo et al, 2010, 2011; McCarthy et al, 2011; Attal et al, 2011.

MPR = melphalan, prednisone, lenalidomide; MPR-R = MPR plus lenalidomide maintenance.

Palumbo et al, 2010, 2011; McCarthy et al, 2011; Attal et al, 2011.

Is My Patient Responding to Treatment? Is My Patient Responding to Treatment? Response Assessment* Response Assessment*

Response IMWG

sCR CR as below plus normal FLC ratio + absence of clonal cells in bone marrow by IHC

CR Neg IFE on the serum + urine, disappearance of any soft tissue plasmacytomas and < 5% BM PCs

VGPR Serum and urine M protein detectable by IFE but not on electrophoresis or ≥ 90% reduction in serum M protein + urine M protein level < 100 mg/24 hrs

PR Serum and urine M protein detectable by immunofixation but not on electrophoresis or ≥ 50% reduction in serum M protein

IHC = immunohistochemistry; CR = complete response; sCR = stringent CR; PR = partial response;

VGPR = very good partial response; PD = progression disease.

Durie et al, 2006; Kyle et al, 2008

IHC = immunohistochemistry; CR = complete response; sCR = stringent CR; PR = partial response;

VGPR = very good partial response; PD = progression disease.

Durie et al, 2006; Kyle et al, 2008

Response IMWGPD Increase of ≥ 25% from

lowest response value: Serum ≥ 0.5 g/dL;

Urine ≥ 200 mg/24 hrs;

Bone marrow plasma cell (BMPCs) ≥ 10%

Relapse See above and/or CRAB

*Note: This is not inclusive of all response categories. *Note: This is not inclusive of all response categories.

Case Study (cont.)Case Study (cont.)

Remember our case study?

Does not want to pursue up-front transplant

Induction regimen (clinical trial)

– Bortezomib 1.3 mg/m2 IV Day 1, 4, 8, 11 q21days

– Dexamethasone 40 mg Day 1, 2, 4, 5, 8, 9, 11, 12 q21days

– Cyclophosphamide 500 mg absolute po on Day 1, 8, 15 q28days

Side effects

– Mild PN after Cycle 3 (discomfort feet)

– Mild steroid induced hyperglycemia, managed with diet, glipizide

Decided to withdraw consent for clinical trial

Case Study (cont.)Case Study (cont.)

After Cycle 5, he was changed to bortezomib SC (reconstitute at 2.5 mg/mL NS and rotate injection sites) based on new data

After 8 cycles: Continues on bortezomib Days 1, 8, 15, 22 q28days; neuropathy has improved from Grade 2 to Grade 1 PN with pain

Switched from cyclophosphamide to lenalidomide 5 mg Days 1–21 in September to deepen response

Now has achieved a complete remission which remains sustained

KAPPA, FREE, SERUM K/L RATIO, Mo/Ref Rng 3.3 - 19.4 mg/L 0.26 - 1.65January 3014.0 (H) >1255.83 (H)February 911.9 (H) >379.96 (H)March 939.4 (H) 391.42 (H)April 550.0 (H) 110.00 (H)May 419.1 (H) 83.82 (H)Sept* 93.7 (H) >39.04 (H)November 5.8 (H) >23.25 (H)January 7.4 1.48February 5.4 1.08

KAPPA, FREE, SERUM K/L RATIO, Mo/Ref Rng 3.3 - 19.4 mg/L 0.26 - 1.65January 3014.0 (H) >1255.83 (H)February 911.9 (H) >379.96 (H)March 939.4 (H) 391.42 (H)April 550.0 (H) 110.00 (H)May 419.1 (H) 83.82 (H)Sept* 93.7 (H) >39.04 (H)November 5.8 (H) >23.25 (H)January 7.4 1.48February 5.4 1.08

Component M Spike Quant 24 HrMo/ Ref Rng Low: 0.00 gm/24 HrJanuary 1.391March 1)0.074 2)0.215April 0.193Sept <0.093November 0.134January 0.00 No M Spike DetectedFebruary 0.00 No M Spike Detected

Component M Spike Quant 24 HrMo/ Ref Rng Low: 0.00 gm/24 HrJanuary 1.391March 1)0.074 2)0.215April 0.193Sept <0.093November 0.134January 0.00 No M Spike DetectedFebruary 0.00 No M Spike Detected

NS = normal saline.

You are the nurse caring for this patient. Recall his baseline laboratory studies. He has anemia, renal insufficiency, hypercalcemia, and lesions on his bone survey. He will start Cycle 1 of treatment.

What supportive care therapy would you consider to be important?

1) Granulocyte stimulating factor (GCSF)

2) Platelet transfusions

3) Bone marrow transplant

4) Bisphosphonates, acyclovir

5) None of the above

Case Study: Question 1Case Study: Question 1

Key TakeawaysKey Takeaways

There is no‘gold standard’treatment for MM

Newer agents provide improved response rates, improved survival

Nurses play an important role in side-effect recognition, management

Newer dosing strategies can decrease side effects

Personalized care plans are necessary for all patients

The Evolving Landscape of Myeloma The Evolving Landscape of Myeloma Treatment: Maintenance TherapyTreatment: Maintenance Therapy

Beth Faiman, PhD(c), MSN, APRN, BC, AOCN®

Cleveland Clinic Taussig Cancer Institute

Case Study: MaintenanceCase Study: Maintenance

Mr. P is a 48-year-old with newly diagnosed IgG Kappa multiple myeloma

M spike at diagnosis: 5.2 g/dL

CRAB features at presentation

– Renal insufficiency (creatinine 2.8 mg/dL)

– Anemia (Hgb 8.8 g/dL)

Receives 4 cycles of induction chemotherapy with bortezomib and dexamethasone and undergoes ASCT

Would he be a candidate for maintenance therapy?

ASCT = autologous stem cell transplant.

MaintenanceMaintenance Therapy Therapy

Maintenance therapy is the use of ongoing low intensity chemotherapy to eliminate or suppress the minimal residual tumor clone over a prolonged period of time

Maintenance therapy is administered when the disease is in remission, either undetectable or at a low level

The purpose of maintenance therapy is to prolong remission duration and thereby, life expectancy

Immunomodulatory molecules are well suited for maintenance therapy, as they can be administered orally at low doses for a prolonged period of time

Thalidomide Maintenance After ASCTThalidomide Maintenance After ASCT

Author/Year N Thalidomide Dose (mg)/ Duration

PFS / EFS

OS

Attal et al, 2006 597 Thalidomide 200 (median dose) vs. observation / progression

+ +

Spencer et al, 2006 243 Thalidomide 200 + prednisone vs. prednisone / 12 months

+ +

Maiolino et al, 2008 212 Thalidomide 200 + dexamethasone vs. dexamethasone / 12 months

+ NS

Barlogie et al, 2006* 668 Thalidomide 400 / progression + NS(+ in high-risk)

Morgan et al, 2010a* 820 Thalidomide 100 / progression + / - NS(if optimal

relapse Rx)

Lokhorst et al, 2010* 550 Thalidomide 50 / progression + -

Stewart et al, 2010 332 Thalidomide 200 + prednisone vs. observation / 48 months

+ NS

*Thalidomide also given as part of induction therapy.PFS = progression-free survival; EFS = event-free survival; OS = overall survival; NS = not significant.

Thalidomide Maintenance: MRC TrialThalidomide Maintenance: MRC Trial

At Median Follow-Up From Randomization of 38 Months

HR [95% CI] = 1.45 [1.22, 1.73], p = .0003

Maintenance, N = 407

No maintenance, N = 410

20

40

60

80

100

12 24 36 48 60 72

Pat

ien

ts (

%)

PFS (months)

HR [95% CI] = 0.91 [0.72, 1.17], p = 0.40

Maintenance, N = 408

No maintenance, N = 410

20

40

60

80

100

12 24 36 48 60 72

Pat

ien

ts (

%)

OS (months)

Thalidomide maintenance improves PFS with no OS advantage

0 0

HR = hazard ratio; CI = confidence interval.Morgan et al, 2010b.

D-S Stage 1-3, ≤ 70 years≥ 2 cycles of induction Attained SD or better 1 yr from start of therapy≥ 2 x 106 CD34 cells/kg

Placebo

Lenalidomide*10 mg/d with ↑↓ (5–15 mg)

Lenalidomide*10 mg/d with ↑↓ (5–15 mg)

RestagingDays 90–100

Registration

CRPRSD

Patient stratification based on diagnostic 2m level and prior thalidomide and lenalidomide use during induction

Mel 200

ASCT

Randomization

CALGB = Cancer and Leukemia Group B; ECOG = Eastern Cooperative Oncology Group; BMT-CTN = Blood and Marrow Transplant-Clinical Trials Network; CR = complete response; PR = partial response; SD = stable disease;2m = beta-2-microglobulin. McCarthy et al, 2011.

CALGB, ECOG, BMT-CTNCALGB, ECOG, BMT-CTN

Lenalidomide Maintenance: Lenalidomide Maintenance: CALGB 100104 SchemaCALGB 100104 Schema

CALGB 100104, Follow-Up 10/31/11

Median TTP: 27 mos

Survival at 3 years is 88% for the lenalidomide and 80% for placebo arm patients, HR = 0.62 (95%CI = 0.40–0.95)

PFS and OS at Median Follow-Up of 34 MonthsPFS and OS at Median Follow-Up of 34 Months

Median TTP: 46 mos

p < .0001

p = .027

35 deaths in the lenalidomide arm and 53 deaths in the placebo arm

TTP = time to progression.McCarthy et al, 2011.

Lenalidomide Maintenance Lenalidomide Maintenance Post-TransplantPost-Transplant: : IFM 2005-02: IFM 2005-02: Study DesignStudy Design

Arm A

Placebo

(n = 307)

until relapse

Arm A

Placebo

(n = 307)

until relapse

Patients < 65 Years, With Non-Progressive Disease,

6 Months After ASCT in First-Line

Arm B

Lenalidomide

(n = 307)

10–15 mg/d

until relapse

Arm B

Lenalidomide

(n = 307)

10–15 mg/d

until relapse Primary end point: PFS Secondary end points: CR rate, TTP, OS, feasibility of long-term lenalidomide

Phase III Randomized, Placebo-Controlled TrialN = 614 Patients, From 78 Centers, Enrolled Between 7/2006 and 8/2008

IFM = Intergroupe Francophone du Myelome; del(13) = deletion 13; VGPR = very good partial response;

Attal et al, 2011.

Consolidation:Lenalidomide alone 25 mg/day po Days 1–21 q28days for 2 months

Consolidation:Lenalidomide alone 25 mg/day po Days 1–21 q28days for 2 months

Randomization: Stratified According to β2m, del(13), VGPRRandomization: Stratified According to β2m, del(13), VGPR

0.0

00.2

50.5

00.7

51.0

0

0 6 12 18 24 30 36 42 48 54

Placebo Revlimid

Lenalidomide Maintenance Post-Transplant: Lenalidomide Maintenance Post-Transplant: IFM 2005-02: PFS and OS From Randomization (4/2011)IFM 2005-02: PFS and OS From Randomization (4/2011)

p < 10 -9

Rev (n = 307)

Placebo (n = 307)

Median F/U: 36 months post-random, 46 months post-diagnosisMedian F/U: 36 months post-random, 46 months post-diagnosis

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36 42 48

Placebo Revlimid

p = .79

Attal et al, 2011.

Lenalidomide Lenalidomide

PFS OS

Stratified by age (< 75 vs. > 75 years) and stage (ISS I/II vs. III) Primary comparison: MPR-R vs. MP

MPM: 0.18 mg/kg, days 1-4P: 2 mg/kg, days 1-4PBO: days 1-21

MPRM: 0.18 mg/kg, days 1-4P: 2 mg/kg, days 1-4R: 10 mg/day po, days 1-21

Placebo

Placebo

MPR-RM: 0.18 mg/kg, days 1-4P: 2 mg/kg, days 1-4R: 10 mg/day po, days 1-21

RA

ND

OM

IZA

TIO

N

Double- Blind Treatment Phase

DiseaseProgression

Maintenance

Lenalidomide(25 mg/day)

+/-Dexamethasone

Open-Label Extension Phase

Lenalidomide10 mg/daydays 1-21

Cycles (28-day) 1-9 Cycles 10+

N = 459, 82 centers in Europe, Australia, and Israel

Palumbo et al, 2011b.

MM-015: Study DesignMM-015: Study Design

0

HR, hazard ratio; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone, lenalidomide with lenalidomide maintenance; OS, overall survival; PFS, progression-free survival; TTP, time to progression.

ProgressionProgression--Free and Overall SurvivalFree and Overall SurvivalAll PatientsAll Patients

• TTP HR advantages were similar: MPR-R vs MP = 0.337; MPR vs MP = 0.826

Time (Months)

Pa

tie

nts

(%

)

HR 0.395 P < .001

HR 0.796P = .135

0 10 20 30 400

25

50

75

100

Median PFS

MPR-R 31 months

MPR 14 months

MP 13 months

Median PFS

MPR-R 31 months

MPR 14 months

MP 13 months

0 20 30 40 50 60

4-year OS

MPR-R 59%

MPR 58%

MP 58%

4-year OS

MPR-R 59%

MPR 58%

MP 58%

Pa

tie

nts

(%

)

25

50

75

10

100

HR 0.898 P = .579

HR 1.089P = .648

Time (Months)

MP = melphalan; P = prednisone; R = lenalidomide. Palumbo et al, 2011b.

MM-015: PFS and OS for All PatientsMM-015: PFS and OS for All Patients

TTP HR advantages were similar: MPR-R vs. MP = 0.337; MPR vs. MP = 0.826

Bortezomib 1.3 mg/m2

Doxorubicin 9 mg/m2

Dexameth 40 mg

Randomization

CAD + GCSF

3 x VAD

CAD + GCSF

3 x PAD

Mel 200 + PBSCT

In GMMG 2nd Mel 200 + PBSCT

Mel 200 + PBSCT

In GMMG 2nd Mel 200 + PBSCT

Thalidomidemaintenance 50 mg/day for 2 years

Allogeneic Tx

Bortezomib Maintenance1.3 mg/m2 / 2 weeks for 2 years

HOVON Trial: Bortezomib Induction HOVON Trial: Bortezomib Induction and Maintenanceand Maintenance

CAD = coronary artery disease; GCSF = granulocyte colony-stimulating factor; PBSCT = peripheral blood stem cell transplant. Sonneveld et al, 2010.

Bortezomib Maintenance: OutcomesBortezomib Maintenance: Outcomes

A: VADB: PAD

N373371

F243215

A: VADB: PAD

10 Nov 2010-15:14:01

At risk:373371

289321

199237

110118

3039

A: VAD

B: PAD

0

25

50

75

100

months0 12 24 36 48

Cum

ulat

ive

perc

enta

ge

Progression free survival

A: VADB: PAD

N373371

D12093

A: VADB: PAD

10 Nov 2010-15:14:34

At risk:373371

320336

290306

174191

6379

A: VAD

B: PAD

0

25

50

75

100

months0 12 24 36 48

Cum

ulat

ive

perc

enta

ge

Overall survival

VAD PAD

CR/nCR 34 49 < .001

≥ VGPR 55 76 .001

≥ PR 83 91 .003

p = .005p = .02

3-year PFS 48% vs. 42% 3-year OS 78% vs. 71%

nCR = near complete response.Sonneveld et al, 2010.

VAD/HDM/Thalidomide

PAD/HDM/Bortezomib

N PFS at 36 mos

(%)

OS at 36 mos

(%)

N PFS at 36 mos

(%)

OS at 36 mos

(%)

All 373 40 70 371 48 78

ISS 1 ISS 2 ISS 3

16865

101

503229

817050

1679373

554537

867168

Creatinine 0–2 mg/dL> 2 mg/dL

32844

4412

7532

33634

4849

7872

Subgroup Analysis (1)Subgroup Analysis (1)

p < .01 in univariate analysisp < .01 in univariate analysis

ISS = International Staging System.Sonneveld et al, 2010.

VAD/HDM/Thalidomide

PAD/HDM/Bortezomib

N PFS at 36 mos

(%)

OS at 36 mos

(%)

N PFS at 36 mos

(%)

OS at 36 mos

(%)

All 373 40 70 371 48 78

-13/13q- 155 29 58 134 40 79

t(4;14)

33 20 40 31 28 60

17p-

39 16 17 19 22 61

Subgroup Analysis (2)Subgroup Analysis (2)

p < .01 in univariate analysisAll data FISH, -13/13q- also karyotype if available

FISH = fluorescent in situ hybridization. Sonneveld et al, 2010.

Case Study: Maintenance Case Study: Maintenance ConclusionConclusion

3 months following ASCT, Mr. P achieved a PR (80% reduction in serum m protein)

– M spike 0.49 g/dL

Renal insufficiency and anemia resolved

– Creatinine normal 0.8 g/dL

– Hbg 13.4 g/dL

Would he be a candidate for maintenance therapy?

ANSWER: Yes (based on data presented)

Began maintenance with lenalidomide 10 mg po daily

Key TakeawaysKey Takeaways

Maintenance therapy delays recurrence of myeloma and prolongs PFS

Chronic low dose oral agents are preferable for maintenance strategy

Bortezomib and lenalidomide are better suited for high-risk disease

There is a slight increase in incidence of second malignancy after lenalidomide maintenance following melphalan

New agents may be appropriate for maintenance studies

– Carfilzomib, pomalidomide, oral proteasome inhibitors (MLN9708, ONX0912)

The Evolving Landscape of The Evolving Landscape of Myeloma Treatment: Myeloma Treatment:

Relapsed/Refractory DiseaseRelapsed/Refractory DiseaseBeth Faiman, PhD(c), MSN, APRN, BC, AOCN®

Cleveland Clinic Taussig Cancer Institute

Case Study: Mr. P (cont.)Case Study: Mr. P (cont.) Mr. P remains on lenalidomide 10 mg po daily for 3 years Develops lower back pain and worsening anemia Bone survey

– L2 vertebral compression fracture and calvarial lesions consistent with disease progression

Labs

– M spike February 2012: 0.95 g/dL

– M spike March 2012: 1.32 g/dL (confirms disease progression)

– Hgb 9.2 g/dL, creatinine 1.3 mg/dL

Mr. P has relapsed myeloma What are his treatment options?

How Is Relapse Defined?How Is Relapse Defined? Relapse is defined as reappearance of signs and

symptoms of the disease or signs of increasing disease and/or end organ dysfunction (MDE) that are felt related to the underlying myeloma

1) Reappearance or increase in paraprotein serum and/or urine – serum M spike, sFLC or BJP in urine

2) Development of new soft tissue plasmacytomas or bone lesions or increase in the size of existing lesion on imaging

3) Hypercalcemia

4) Development of anemia

5) New or worsening kidney function

6) Hyperviscosity requiring therapeutic intervention

MDE = myeloma-defining event; sFLC = serum free light chain; BJP = Bence Jones protein.Lonial, 2010; Bird et al, 2011; Anderson et al, 2008.

When Do You Treat Relapsed When Do You Treat Relapsed Myeloma?Myeloma?

Symptomatic relapse

– CRAB symptoms: HyperCalcemia, Renal impairment, Anemia, Bone lesion, new plasmacytoma, bone lesions

Clinically significant relapse

– Doubling of paraprotein

• (M spike > 1 g/dL, BJP > 500 mg/day, sFLC level > 200 mg/L)

Asymptomatic biochemical relapse should not be treated

Goals: Control of disease, decrease morbidity

Nurses can ensure ongoing evaluation for risk of VTE, skeletal events, infections, neuropathy

Bird et al, 2011; Anderson et al, 2008.

How Is Refractory Disease Defined?How Is Refractory Disease Defined? Refractory disease should fulfill all of the following

criteria

– Should have failed > 2 lines of therapy

– Should have PD after treatment with all 4 classes of drugs

• Cytotoxic agents (melphalan, cyclophosphamide, anthracyclines, bendamustine)

• Immunomodulatory agents (thalidomide, lenalidomide)

• Proteasome inhibitor (bortezomib)

• Glucocorticoids (prednisone, dexamethasone)

– Should be progressing on the last line of therapy or within 60 days of discontinuing treatment

PD = progressive disease.Lonial, 2010; Anderson et al, 2008.

Considerations in Relapsed MMConsiderations in Relapsed MM Disease related

– Indolent, slow, or single site relapse

– Rapid and multiple sites of relapse

– Extramedullary disease, CNS, plasma cell leukemia

– Additional genetic changes

Patient related

– Poor performance

– Poor renal function

– Poor hematopoietic reserve

Treatment related

– Prior drug exposure (relapsed or PD on therapy)

– Ongoing toxicity from prior therapy

CNS = central nervous system.Mohty et al, 2012; Richardson et al, 2010; Lonial, 2010.

Treatment of Relapsed Myeloma:Treatment of Relapsed Myeloma:How Do We Decide?How Do We Decide?

Existing novel agents

– Thalidomide, bortezomib, lenalidomide

Existing older agents

– Dexamethasone, prednisone, cyclophosphamide, melphalan, anthracyclines

Clinical trial options

Single agent vs. combination

NCCN, 2012; Laubach et al, 2009; Blade et al, 2009.

Indolent, Slow, or First RelapseIndolent, Slow, or First Relapse

Initial Tx with Bz Underlying PN Good risk

Lenalidomide Based Salvage

High-Dose Melphalan and Stem Cell TransplantHigh-Dose Melphalan and Stem Cell TransplantIf Deferred During First-Line of TherapyIf Deferred During First-Line of Therapy

Bortezomib Based Salvage

Thalidomide Based Salvage

Initial Tx with IMiD Renal dysfunction High-risk genetics;

1q+, del(17p), t(4;14)

Prior bortezomib/lenalidomide

Cytopenia Severe renal

impairmentClinical Trial Options

Tx = therapy; Bz = bortezomib; PN = peripheral neuropathy; IMiD = immunomodulatory drugs.Lonial et al, 2011.

Aggressive, Rapid, Multiple RelapseAggressive, Rapid, Multiple Relapse

DCEP vs. DT-PACE

Chemotherapy Based Salvage

Likely Combination TherapyLikely Combination TherapyDo Not Wait for Symptomatic RelapseDo Not Wait for Symptomatic Relapse

Chemotherapy + Novel Agent

Transplant Based Salvage

Combinations of Len/Bz and other chemo agents

Additional stem cells in storage

Long remission after first transplant

Cytopenia

Clinical Trial Options

DCEP vs. DT-PACE = dexamethasone/cyclophosphamide/etoposide/cisplatin vs. dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophos/phanide/etoposide; Len = lenalidomide.Lonial et al, 2011.

Courtesy of US NIH, 2012.

Agents in Phase III StudiesAgents in Phase III Studies

Target Combination Partner(s)

Pomalidomide Dexamethasone

Carfilzomib Lenalidomide, Dexamethsone

Vorinostat Bortezomib

Panobinostat Bortezomib

Elotuzumab Lenalidomide, Dexamethsone

Perifosine Bortezomib

Structurally similar, but functionally different both qualitatively and quantitatively

Molecular Structure of Thalidomide, Molecular Structure of Thalidomide, Lenalidomide, and PomalidomideLenalidomide, and Pomalidomide

DVT = deep vein thrombosis.Kotla et al, 2009; Thalomid® prescribing information, 2010; Revlimid® prescribing information, 2010.

Discrepancies in totals are due to rounding.

Disease control (≥ SD) observed in 81% of overall patients

POM (n = 108)

POM + LoDEX (n = 113)

ORR (≥ PR) % 13 34

≥ MR % 29 45

CR % 1 1

PR % 12 33

VGPR % 2 9

MR % 16 12

SD % 50 37

PD % 10 6

NE % 11 12

Median time to response, months 2.9 1.9

Median DOR, months 8.5 7.9

Relapsed and Refractory MyelomaRelapsed and Refractory MyelomaSingle Agent: PomalidomideSingle Agent: Pomalidomide

POM = pomalidomide; ORR = overall response rate; PR = partial response; MR = minor response; CR = complete response; VGPR = very good partial response; SD = stable disease; NE = non-event; DOR = duration of response.Richardson et al, 2011.

Relapsed and Refractory MyelomaRelapsed and Refractory MyelomaSingle Agent: Pomalidomide (cont.)Single Agent: Pomalidomide (cont.)

Median PFS: POM + LoDEX 4.7 months; POM alone 2.7 months Median OS: POM + LoDEX 16.9 months; POM alone 14 months

~ Median OS for patients with PD as best response; 5.4 months

PFS = progression-free survival; OS = overall survival.

100

80

60

40

20

00 5 10 15 20

PFS (months)

Pa

tie

nts

(%

)

POM + LoDEXPOM

100

80

60

40

20

00 5 10 15 20

OS (months)P

ati

en

ts (

%)

POM + LoDEXPOM

Richardson et al, 2011.

Relapsed and Refractory MyelomaRelapsed and Refractory MyelomaSingle Agent: Carfilzomib PX171-003 A1Single Agent: Carfilzomib PX171-003 A1

ORR CBR DOR

All patients (N = 257) 24 34 8.3

PD on or within 60 days (N = 227) 24 34 8.3

Median PFS: 3.7 months Median OS: 15.5 months

CBR = clinical benefit response; ORR = overall response rate.Siegel, Martin, et al, 2010.

Months Since Study Entry Months Since Study Entry

Pro

po

rtio

n o

f P

atie

nts

Su

rviv

ing

Pro

po

rtio

n o

f P

atie

nts

With

ou

t P

rog

ress

ion

0 5 10 15 20 25

Time (months)

0

10

20

30

40

50

60

70

80

90

100

PF

S (

%)

BTZ + Placebo

BTZ + Vorinostat

Vantage 095: PFS (IAC)Vantage 095: PFS (IAC)

IAC = independent adjudication committee; CI = confidence interval; HR = hazard ratio.

BTZ + Vorinostat

BTZ + Placebo

Events 201/317 216/320

Median PFS (95% CI)

7.63 months (6.9–8.4)

6.83 months (5.7–7.7)

HR (95% CI) 0.774 (0.64–0.94)

p Value 0.01

VGPR 28 21

PR 28 19

ORR 56 41

Siegel et al, 2011.

Elotuzumab 10 mg/kg

Elotuzumab 20 mg/kg Total

Patients, n 36 37 73

ORR (≥ PR), n (%) 33 (92) 27 (73) 60 (82)

CR/stringent CR, n (%) 5 (14) 4 (11) 9 (12)

VGPR, n (%) 14 (39) 12 (32) 26 (36)

PR, n (%) 14 (39) 11 (30) 25 (34)

< PR, n (%) 3 (8) 10 (27) 13 (18)

Elotuzumab With Lenalidomide Elotuzumab With Lenalidomide and Weekly Dexamethasoneand Weekly Dexamethasone

Best Response (IMWG Criteria)Best Response (IMWG Criteria)

IMWG = International Myeloma Working Group.

At a median follow-up of 14.1 months, the median PFS was not reached

Lonial et al, 2011.

Phase I/II Trial of Perifosine/Bortezomib ± Phase I/II Trial of Perifosine/Bortezomib ± Dexamethasone in Relapsed/Refractory Dexamethasone in Relapsed/Refractory

Myeloma (N = 73)Myeloma (N = 73)

Median prior Rx in Bz refractory patients: 6

Median prior Bz in Bz refractory patients: 2

Median prior Rx in Bz relapsed patients: 4

Median prior Bz in Bz relapsed patients: 1

Median No. of Treatment Cycles Received: 8

45/84 patients (54%) had Dex added to Peri/Vel 39/84 (46%) patients had Peri/Vel only

MR = minimal response; Bz = bortezomib. Richardson et al, 2011.

Case Study (cont.)Case Study (cont.)

Mr. P is enrolled in a clinical trial with Lenalidomide, Elotuzumab and Dexamethasone

He achieves a VGPR (> 90% reduction in serum M-protein) after 3 months of therapy

Side effects of myelosuppression were mild and controlled with appropriate dose adjustments

He continues on therapy per clinical trial protocol until relapse

Key TakeawaysKey Takeaways The overall survival of patients with MM has increased

within the last decade

Many new treatments have become available

The diagnosis of MM has transitioned to a chronic disease thus supportive care must be ongoing

Future research is directed at newer targets using a more “novel” approach

Patient PerspectivePatient Perspective

Pat KillingsworthColumnist for the Myeloma Beacon

Oncology Nurses Rock!Oncology Nurses Rock!

A Long, 5-Year Rollercoaster RideA Long, 5-Year Rollercoaster Ride

How to Help Newly Diagnosed How to Help Newly Diagnosed Patients Cope: Take a TIME-OUT!Patients Cope: Take a TIME-OUT!

Ignore Median Expectancy NumbersIgnore Median Expectancy Numbers

Help Patients Build A Healthcare TeamHelp Patients Build A Healthcare Team

DonDon’’t Rush to Transplant – Do Your t Rush to Transplant – Do Your Homework FirstHomework First

Multiple Myeloma Patient ResourcesMultiple Myeloma Patient Resources

International Myeloma Foundation (IMF) - www.myeloma.orgThe Myeloma Beacon – www.myelomabeacon.com

www.multiplemyelomablog.comwww.mymultiplemyeloma.com

Books by Pat KillingsworthLiving with Multiple MyelomaStem Cell Transplants from a Patient’s Perspective

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