Overview of Multiple Myeloma. The Basics of Multiple Myeloma This program is supported by educational grants from Celgene Corporation, Millennium:, and

Overview of Multiple Myeloma

The Basics of Multiple Myeloma

This program is supported by educational grants from Celgene Corporation, Millennium: , and Onyx Pharmaceuticals.

clinicaloptions.com/oncologyNursing Considerations for Patients With Multiple Myeloma

What Is Multiple Myeloma?

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 B, et al. In: Williams Hematology; 2006. Durie BG. IMF 2007.


Multiple Myeloma Epidemiology

Death rates

– Decreased during 1991-2005

– 11.3% decrease for women, 7.25% decrease for men

Risk factors

– Unknown in the majority of cases

– Increased with age, male sex, obesity, and black race

Variable response to treatment and variation in survival

– From a few mos to > 10 yrs

– High-risk attributes are thought to play a primary role

– 20% of patients survive > 10 yrs, regardless of therapy

– Novel agents may neutralize the effects of some high-risk features

New Cases, n(US, 2014)

Deaths, n(US, 2014)

Mean Age at Diagnosis, Yrs

5-Yr Relative Survival Rates 2004-2010, %

24,050 11,090 62 44.9

Badros AZ. J Natl Compr Canc Netw. 2010;8:S28-S34. Kurtin S. Oncology Nurse Ed. 2011;25. Siegel R, et al. CA Cancer J Clin. 2014;64:9-29. SEER Stat Fact Sheets: Myeloma.


Myeloma Can Result in a Broad Spectrum of Clinical Manifestations

Hoffman R. Hematology: basic principles and practice, 5th edition; 2008. Ropper AH, et al. N Engl J Med. 1998;338:1601-1607.

M-protein

Bone pain

Neuropathy (33%)Hyperviscosity

Amyloidosis

Hypercalcemia (15% to 20%)

Immunedeficiency

Anemia (10% to 35%)

Lytic lesions (70%)

Infection (15%)

Marrow infiltration

Multiple myeloma

cells Destruction of bone

Renal compromise (30%)


Kumar SK, et al. Mayo Clinic Proc. 2009;84:1095-1110. Schmidt-Hieber M, et al. Haematologica. 2013;98:279-287.

Classification of Myeloma

Heavy chain: IgG, IgA, IgD, IgM, IgE 77% of myeloma cases IgG and IgA most common

Nonsecretory: No detectable

immunoglobulin 1% to 2% of myeloma cases

Light chain (Bence-Jones protein):Kappa (κ) or lambda (λ)

20% of myeloma cases

Serum free light chain

Heavy chain

Light chain

Variable region

Consta

nt region


Disease Trajectory

< 3 g M-protein

< 10% clonal BMPC

No MM-related end-organ damage

1%/yr risk of progression to MM

Multiple Myeloma

Plasma cell

leukemia

MGUS Smoldering Myeloma

≥ 30 g/L M-protein

≥ 10% clonal BMPC

No MM-related end-organ damage

10%/yr risk of progression to MM in the first 5 yrs

Nonmalignant Accumulation Malignant Transformation Aggressive and

Stromal Independent

Stromaangiogenesis

and IL-6dependent

≥ 10% clonal BMPC

M-protein in serum and/or urine

≥ 1 CRAB features of disease related to organ damage

C: Calcium elevation > 11.5 mg/L or ULN

R: Renal dysfunction (serum creatinine > 2 mg/dL)

A: Anemia (Hb < 10 g/dL or 2 g < normal)

B: Bone disease (lytic lesions or osteoporosis)

Kuehl WM, et al. Nat Rev Cancer. 2002;2:175-187. Vacca A, et al. Leukemia. 2006;20:193-199. Agarwal A, et al. Clin Cancer Res. 2013;19:985-994. Durie BG, et al. Hematol J. 2003;4:379-398. Kurtin SE. JAdPrO, 2010;1:19-29.


Myeloma cells

Bone marrow stromal cells

PBMC

IL-6TNFIL-1

IL-2IFN

CD8+ T cellsNK cells

Bone marrow vessels

ICAM-1

VEGF

bFGF

Hideshima T, et al. Blood. 2000;96:2943-2950.Davies FE, et al. Blood. 2001;98:210-216.Gupta D, et al. Leukemia. 2001;15:1950-1961.

Mitsiades N, et al. Blood. 2002;99:4525-4530.Lentzsch S, et al. Cancer Res. 2002;62:2300-2305.

Role of Bone Marrow Microenvironment in Myeloma


Diagnostic Evaluation

NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014. Kurtin S. JAdPrO. 2010;1:19-29.

History and physical

CBC, differential and platelet count

Additional laboratory tests

Serum immunoglobulins

− Quantitative (IgG, IgM, IgA, IgD)

− SPEP

− Serum free light chain assay (kappa, lambda)

− BUN, creatinine, electrolytes

− Serum calcium (corrected)

− Serum albumin

− β2-microglobulin

− LDH

− Additional testing based on preliminary analysis

24-hr urine

Bone marrow biopsy and aspiration

Hematopathology

− Presence of plasma cells, %

− Cellularity

− Ploidy

Cytogenetics

FISH

Gene expression profiling

Radiology

Skeletal survey

MRI if vertebral compression fractures suspected

PET/CT

Establish diagnosis of MMMGUSSmolderingActive

Determine subtypeHeavy chain/light chainNonsecretorySolitary plasmacytoma

Determine stage International Staging SystemDurie-Salmon staging system

Estimate prognosisCytogeneticsAlbumin

β2-microglobulinPloidy

Identify need for immediate intervention

Severe hypercalcemiaAcute renal failureCord compressionSevere pain or impending fracture


Monoclonal 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

Barlogie B, et al. In: Williams Hematology; 2006. p. 1501. Durie. IMF 2007. MMRF. Intro to Myeloma. 2005.

Normal SPEP Abnormal SPEP


International Staging System

Serum β2m reflects tumor load and is elevated in renal failure

Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.Dimopoulos M, et al. Leukemia. 2009;23:1545-1556.

Stage Criteria Median OS, Mos

ISerum β2m < 3.5 mg/L

Serum albumin ≥ 3.5 g/dL62

II Serum β2m < 3.5 mg/LSerum albumin < 3.5 g/dL

OR

Serum β2m 3.5 through < 5.5 mg/L

44

III Serum β2m ≥ 5.5 mg/L 29


Cytogenetic Testing Methodologies

Methodology Advantages Disadvantages

Karyotype analysis

Highly sensitive for the detection of chromosomal abnormalities in dividing cells

Low yield of karyotype abnormalities from MM bone marrow samplesDoes not detect some aberrationsCannot describe possible heterogeneity within a population of clonal cells

FISH Can be performed in non dividing cellsCan detect translocationsValidation with positive and negative controls is standard

Variable scoring criteriaSome aberrations technically difficult to detect

GEP May be helpful with prognosisMay lead to development of more targeted therapies

Not performed locallyExpensiveUnclear what should be done with the information


Cytogenetic Classification

mSMART 2.0: classification of active myeloma

High Risk 20% Intermediate Risk 20% Standard Risk 60%

FISH− Del(17p)− t(14;16)− t(14;20)

GEP− High-risk signature

FISH− t(4;14)− 1q gain

Complex karyotype Metaphase deletion

13 or hypodiploidy High PCLI

All others including: Trisomies t(11;14) t(6;14)

OS 3 Yrs OS 4-5 Yrs OS 8-10 Yrs

Dispenzieri A, et al. Mayo Clin Proc. 2007;82:323-341. Kumar SK, et al. Mayo Clin Proc. 2009;84:1095-1110. Mikhael JR, et al. Mayo Clin Proc. 2013;88:360-376.


Normal Karyotypes

Female Male

Strupp C, et al. Leukemia. 2003;17:1200-1202.


Hyperdiploidy

Belurkar S, et al. Ind J Med Sci. 2013;67:188-192.


Fluorescence in Situ Hybridization Analysis t(14;20)

Chromosome 14 stained green

Chromosome 20 stained red

Stralen E, et al. Leukemia. 2009;23:801-803.


Gene Expression Profiling in Myeloma

Decaux O, et al. J Clin Oncol. 2008;26:4798-4805.


Natural History of Myeloma

MGUS or smoldering myeloma

Asymptomatic Symptomatic

ACTIVE MYELOMA

M-P

rote

in (

g/L

)

20

50

100

1. RELAPSE

2. RELAPSE

REFRACTORY RELAPSE

First-line therapy

Plateau remission

Second-line therapy

Third-line therapy

Kuehl WM, et al. Nat Rev Cancer. 2002;2:175-187. Vacca A, et al. Leukemia. 2006;20:193-199. Siegel DS, et al. Community Oncol. 2009;6:12:22-29. Durie BG, et al. Hematol J. 2003;4:379-398; adapted with permission from Durie B.


Survival in Myeloma Is Improving With Novel Agents

5-Yr Survival by Age

≤ 65 Yrs > 65 Yrs

2006-2010 73% 56%

2001-2005 63% 31%

Kumar SK, et al. ASH 2012. Abstract 3972.

Median 7.3 yrs1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Pro

po

rtio

n S

urv

ivin

g

0 1 2 3 4 5 6 7 8 9 10Follow-up From Diagnosis (Yrs)

2006-2010

2001-2005

The use of novel agent inductions with melphalan and ASCT have doubled median survival for nearly all patients


Treatment of Multiple Myeloma

Continued TreatmentSalvage therapy Maintenance therapy

Confirmed Diagnosis of Multiple Myeloma: CRAB Criteria

Determination of transplant eligibility

Immediate interventions for serious adverse events

Individualized Treatment Selection for Induction Therapy

Transplant EligibleWorks rapidly (CR, nCR, VGPR)

Well toleratedSpares stem cells

Level of evidence: 1 or 2A

Transplant IneligibleAchieving a CR or nCR

Level of evidence: 1 or 2ATolerability and QoLPS and comorbidities

NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014.


Clinical Considerations in Deciding Induction Therapy High tumor burden

– Pulse dexamethasone– Combination therapies with

alkylators and IMiDS and bortezomib

Renal failure– Pulse dexamethasone– Combination therapies with

alkylators and thalidomide and bortezomib (role of lenalidomide uncertain)

Hypercalcemia– Pulse dexamethasone– Bisphosphonates

Frail– Avoid high-dose

dexamethasone Clotting or bleeding history

– Assess risk of use of lenalidomide/ thalidomide and anticoagulation

Preexisting neuropathy– Assess use of bortezomib/

thalidomide Cytogenetic abnormalities

– Indication for bortezomib/ lenalidomide

Niesvizky R, et al. Oncology (Williston Park). 2010;24:14-21. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014. Stadtmauer EA. Oncology (Williston Park). 2010;24:7-13.


NCCN Recommendations for Adjunctive Treatment Bone disease

– Bisphosphonates (category 1)

– Radiation therapy

– Orthopedic consultation

– Vertebroplasty or kyphoplasty

Hypercalcemia– Hydration, steroids, furosemide

– Zoledronic acid preferred

Hyperviscosity– Plasmapheresis

Anemia– Consider erythropoietin

Infection– IVIG for recurrent infections

– Pneumovax and influenza vaccine

– PCP, herpes and antifungal prophylaxis for high-dose orlong-term steroids

– Herpes zoster prophylaxis with bortezomib

Renal dysfunction– Avoid aggravating factors: contrast,

NSAIDs, dehydration

– Not a contraindication to HCT

– Monitor bisphosphonates closely

Coagulation/thrombosis– Prophylactic anticoagulation with

IMiDsNCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014. Miceli T, et al. Clin J Oncol Nurs. 2011;15(suppl):9-23. Faiman B, et al. Clin J Oncol Nurs. 2011;15(suppl):66-76.

clinicaloptions.com/oncologyMultiple Myeloma: Case-Based Workshops With the Experts

Epidemiology of Multiple Myeloma

23,500 new cases and 10,710 deaths from myeloma were expected in the United States in 2012

More common in men than in women

Higher incidence in blacks vs whites (2:1)

Median age at diagnosis: 70 yrs

Cancer facts and figures 2012. American Cancer Society; 2012. Altekruse SF, et al, eds. SEER cancer statistics review, 1975-2007. National Cancer Institute. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2013.


Multistep Pathogenesis of Multiple Myeloma


Natural History of Noncurable Malignancies

MGUS or smoldering myeloma

Asymptomatic Symptomatic

ACTIVE MYELOMA

M-P

rote

in (

g/L

)

20

50

100

1. RELAPSE

2. RELAPSE

REFRACTORY RELAPSE

First-line therapy

Plateau remission

Second-line therapy

Third-line therapy


Clinical Manifestations of Symptomatic Multiple Myeloma Renal

compromise (30%)M-protein

Bone pain (75% to 80%)

Neuropathy (33%)

Hypercalcemia (15% to 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;338:1601-1607. Rajkumar SV. Curr Probl Cancer. 2009;33:7-64. IMF update 2003 (http://myeloma.org/ArticlePage.action?articleId=1044).


Challenges in Treatment

“High-risk” disease, expected OS: 2-3 yrs

– t(4;14), t(14;16), del(17p), 1q21 amplification by FISH

– del(13q) by cytogenetics, hypodiploid cytogenetics

– High β2-M (≥ 5.5 mg/L)

– IgA, high plasma cell labeling index

Clinical treatment challenges

– Renal failure

– Older population, median age at diagnosis: 70 yrs

– Significant comorbidities: heart, lung disease

– Extramedullary disease

– Managing light-chain disease

Patient Assessment


Diagnostic Criteria for Myeloma

Patient Criteria MGUS[1,2] Smoldering Myeloma[1]

Symptomatic Myeloma[1]

M-protein < 3 g/dL spike ≥ 3 g/dL spike and/or

In serum and/or urine[2]

Monoclonal plasma cells in bone marrow, %

< 10 ≥ 10 ≥ 10[2]

End-organ damage

None None ≥ 1 CRAB* feature[3]

1. IMWG. Br J Haematol. 2003;121:749-757. 2. Kyle RA, et al. N Engl J Med. 2002;346:564-569.3. Durie BG, et al. Hematol J. 2003;4:379-398.

*C: Calcium elevation (> 10.5 mg/L or ULN)R: Renal dysfunction (serum creatinine > 2 mg/dL)A: Anemia (Hb < 10 g/dL or 2 g < normal)B: Bone disease (lytic lesions or osteoporosis)


Progression to Symptomatic Myeloma

MGUS: up to 3% of persons 50 yrs of age or older and ~ 6% of those older than 70 yrs

For asymptomatic myeloma, maximum risk in the first 5 yrs

Kyle RA, et al. N Engl J Med. 2007;356:2582-2590. Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.

100

80

60

40

20

00 5 10 15 20 25

Yrs Since Diagnosis

Pro

bab

ility

of

Pro

gre

ssio

n (

%)

51

6673 78

410

1621

MGUS

Smoldering Multiple Myeloma


Initial Diagnostic Evaluation


Evaluation

History and physical

Blood workup CBC with differential and platelet countsBUN, creatinineElectrolytes, calcium, albumin, LDHSerum quantitative immunoglobulinsSerum protein electrophoresis and immunofixationβ2-MSerum free light chain assay

Urine 24-hr protein Protein electrophoresis (quantitative Bence-Jones protein)Immunofixation electrophoresis

Other Skeletal surveyUnilateral bone marrow aspirate and biopsy evaluation with immunohistochemistry or flow cytometry, cytogenetics, and FISHMRI and PET/CT as clinically indicated


Symptomatic Myeloma Staging

Risk factors: higher M spike, higher plasma cell burden, type of M-protein, abnormal free light-chain ratio, circulating plasma cells

Stage ISS Criteria for

Symptomatic Myeloma

Stage I ß2-M < 3.5 mg/L and serum albumin ≥ 3.5 g/dL

Stage II Not stage I or III

Stage III ß2-M ≥ 5.5 mg/L

Kyle RA, et al. N Engl J Med. 2007;356:2582-2590. Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.


Multiple Myeloma: Risk Categories

Kumar SK, et al. Mayo Clin Proc. 2009;84:1095-1110. Fonseca R, et al. Leukemia. 2009;23:2210-21. Kyle RA, et al. Clin Lymphoma Myeloma. 2009;9:278-288. Munshi N, et al. Blood. 2011;117:4696-4700.

Risk Factors Standard Risk(Expected OS: 6-7 Yrs)

High Risk(Expected OS: 2-3 Yrs)

FISH t(11;14)t(6;14)

Del(17p)Del(1p)

Gain(1q)t(4;14)*t(14;16)

Cytogenetics Hyperdiploidy Hypodiploidy

β2-microglobulin* Low (< 3.5 mg/L) High (≥ 5.5 mg/L)

Isotype -- IgA

Gene expression profile Good risk High risk

*Patients with t(4;14), β2-microglobulin < 4 mg/L, and Hb ≥ 10 g/dL may have intermediate-risk disease.


Effect of t(4;14), FISH Status, ISS Staging and Age on OS in Multiple Myeloma

Avet-Loiseau H, et al. Leukemia. 2013;27:711-717.

Pat

ient

s re

mai

ning

aliv

e, %

A vs B: P < .0001C vs D: P < .03E vs F: P < .05

Pat

ien

ts R

em

ain

ing

Ali

ve

(%)

A vs B: P < .0001C vs D: P < .03E vs F: P < .05

Yrs From Start of Treatment

100

80

60

40

20

05 10 150

Events, n/N Estimated 4-Yr OS, % (Range)

a. ISS I/II & -FISH & aged < 65 yrs 270/935 75 (72-78)

b. ISS I/II & -FISH & aged ≥ 65 yrs 159/409 62 (56-67)

c. ISS/II/III & -FISH or ISS I & + FISH & aged < 65 yrs 278/526 48 (44-53)

d. ISS II/III & -FISH or ISS I +FISH & aged ≥ 65 yrs 136/230 38 (31-45)

e. ISS II/III & +FISH & aged < 65 yrs 241/378 37 (32-43)

f. ISS II/III & +FISH & aged ≥ 65 yrs 113/160 24 (16-32)


Initial Approach to Treatment of Myeloma

Nontransplantation candidate (based on age, performance score,

and comorbidities)

Induction treatment

Transplantationcandidate

Induction treatment (nonalkylator-based

induction x 4-6 cycles)

Stem cell harvest

Stem cell transplantation

Maintenance

Maintenance

Consolidation therapy ?


Case: 43-Yr-Old Male Presents With Acute Severe Lower Back Pain From Lifting Groceries

Patient assessment:

X-ray of lumbar spine: L4 compression fracture, lytic disease in L2 and L5

Blood work: Hb 9.5 mg/L, plt 178/mm3, creatinine 1.5 mg/dL, albumin 3.5 mg/dL, β2-M 3.1 mg/L, Ca 9.8 mg/dL, LDH 190 U/L

SPEP M-protein 4.5 g/dL, IgG lambda, IgG 5200 mg/dL, IgA 35 g/L, IgM 25 g/L, UPEP + lambda light chains

Bone marrow: 40% plasma cells, cytogenetics normal; FISH: no t(4;14), t(14;16), or del(17p)

Skeletal survey: multiple lytic lesions

Overview of Induction Regimens


Induction Therapies: Transplantation Eligible NCCN Category 1

– Bortezomib/dexamethasone (VD)

– Bortezomib/thalidomide/dexamethasone (VTD)

– Bortezomib/doxorubicin/dexamethasone (PAD)

– Lenalidomide/dexamethasone (RD)

NCCN Category 2A

– Bortezomib/cyclophosphamide/dex (CyBorD)

– Bortezomib/lenalidomide/dexamethasone (VRD)

NCCN Category 2B

– Thalidomide/dexamethasone (TD)

– Dexamethasone

– Liposomal doxorubicin/vincristine/dexamethasone (DVD)


New (3/8/2013): Carfilzomib in combination with lenalidomide and dexamethasone


Trial Regimens n ≥ VGPR, %

After Induction

After First ASCT

After Maintenance

Cavo[1] VTD x 3TD

241239

6228

7958

IFM 2005-01[2] VD x 4VAD

223218

37.715.1

54.337.2

HOVON-65/GMMG-HD4[3]

PAD x 3VAD

371373

4214

6236

PETHEMA/GEM[4]

TVT

a2-IFN

74

CR rate improved by 23% (TV), 11% (T), 19%

(a2-IFN)

PETHEMA/GEM[5] VTDTD

VMBCP/VBAD/B

130127129

602936

E4A03[6] RDRd

445422

5040

1. Cavo M, et al. Lancet. 2011;376:2075-2085. 2. Harousseau JL, et al. J Clin Oncol. 2010;28:4621-4629. 3. Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955. 4. Rosiñol L, et al. ASH 2011. Abstract 3962. 5. Rosiñol L, et al. Blood. 2012;120:1589-1596. 6. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

Phase III Trials: Novel Agent Induction for Transplantation-Eligible Patients


Lenalidomide/Dexamethasone Induction Followed by SCT: OS

Siegel D, et al. ASH 2010. Abstract 38. Reprinted with permission.

94%

78%

E4A03 trial RD vs Rd

Landmark analysis: 4 mos

Early SCT after 4 cycles vs continued therapy with lenalidomide

94% OS at 3 yrs for those undergoing SCT vs 78% for those continuing protocol therapy

Pro

bab

ilit

y

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 4812 24 36

Mo

Early SCT: no 141Early SCT: yes 68

13268

12264

5334

00

Log-rank test: Chi sq = 6.971 (P = .008)

Early SCT: no (n = 141)Early SCT: yes (n = 68)


1. Cavo M, et al. Blood. 2012;120:9-19. 2. Cavo M, et al. Lancet. 2010;376:2075-2085.

VTD vs TD for SCT Induction in Newly Diagnosed Myeloma

Median follow-up: 36 mos

Estimated 3-yr OS: 86% for VTD vs 84% for TD (P = .30)[2]

Progression-free survival[1]

PFS[1]

100

75

50

25

00

PF

S (

%)

6 12 18 24 30 35

Mos From Start of Consolidation Therapy

VTDTD 60%

48%

P = .042

HR: 0.69 (95% CI: 0.48-0.99; P = .043)

EventsTDVTD

N7151

%4432

Patients at Risk, nTDVTD

161160

153154

136142

114125

8486

4353

2126


Case

Your 43-yr-old patient receives bortezomib/lenalidomide/ dexamethasone (VRD) for 3 cycles

Re-evaluation

– M-protein not detectable in blood or urine, IFE positive

– Serum free light chain: kappa 0.8 mg/dL, lambda 4.3 mg/dL

– Bone marrow: 2% PC, 0.8% clonal PC by flow cytometry

– Skeletal survey unchanged

– CBC, creatinine, calcium within normal limits

How would you treat this patient now?


CR to Novel Agents Correlates With Long-term PFS and OS in Elderly Patients Retrospective analysis of frontline treatment in 3 randomized European trials

(GISMM-2001, GIMEMA MM0305, and HOVON groups; N = 1175)

Regimens: MP (n = 332), MPT (n = 332), VMP (n = 257), VMPT-VT (n = 254)

Gay F, et al. Blood. 2011;117:3025-3031.

PFS OS

P < .001 P < .001Pro

bab

ility

of

PF

S

1.0

0.8

0.6

0.4

0.2

00 24 48 72

Mos

Pro

bab

ility

of

OS

1.0

0.8

0.6

0.4

0.2

00 24 48 72

MosCR VGPR PR


Trial Regimens n Median Follow-up,Mos

Median OS Median PFS, Mos

IFM 99-06[1]

MPMPT

MEL100

196125126

51.533.2 mos51.6 mos 38.3 mos

17.827.519.4

IFM 01/01[2] MPTMP

223218

47.544.0 mos29.1 mos

24.118.5

Rajkumar SV et al[3] RDRd

371373

1-yr interim96%*87%*

19.125.3

MM-015[4]

MPR-RMPRMP

152153154

3045.2 mos

NRNR

311413

VISTA[5] VMPMP

344338

6056.4 mos43.1 mos

NANA

1. Facon T, et al. Lancet. 2007;370:1209-1218. 2. Hulin C, et al. J Clin Oncol. 2009;27:3664-3670. 3. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. 4. Palumbo A, et al. N Engl J Med. 2012;366:1759-1769. 5. San Miguel JF, et al. J Clin Oncol. 2013;31:448-455.

*Median OS not yet reached; % alive at time of follow-up is reported.

Phase III Trials: Novel Agent Induction for Transplantation-Ineligible Patients


MM-015: MPR Induction Plus Lenalidomide in Newly Diagnosed Elderly MM Patients Updated analysis of randomized, multicenter, placebo-controlled phase III trial

Palumbo A, et al. N Engl J Med. 2012;366:1759-1769.

Newlydiagnosed

transplantation-ineligible

MM patients65 yrs

of age or older(N = 459)

MPR-RMelphalan 0.18 mg/kg on Days 1-4 +Prednisone 2 mg/kg on Days 1-4 +

Lenalidomide 10 mg/day on Days 1-21

MPMelphalan 0.18 mg/kg on Days 1-4 +Prednisone 2 mg/kg on Days 1-4 +

Placebo on Days 1-21

MPRMelphalan 0.18 mg/kg on Days 1-4 +Prednisone 2 mg/kg on Days 1-4 +

Lenalidomide 10 mg/day on Days 1-21

Continued lenalidomide

Discontinued lenalidomide,

placebo added

Continued placebo

Dis

eas

e p

rog

ress

ion

Len

alid

om

ide

25 m

g/d

ay

± D

exam

eth

aso

ne

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

Double-blind treatment phase Open-label extension/ follow-up phase

Stratified by age and disease stage

Primary endpoint: PFS


Mos

MPR-R vs MPR: HR: 0.49 (P < .001)

Median PFS, Mos

MPR-R 31

MPR 14

MP 13

Data cutoff : May 11, 2010

All Patients66% Reduced Risk of Progression

Palumbo A, et al. N Engl J Med. 2012;366:1759-1769.Palumbo A, et al. ASH 2011. Abstract 475. Reprinted with permission.

MM-015: Progression-Free Survival

0 5 10 15 20 25 30 35 40

Pat

ien

ts (

%)

0

25

50

75

100

MPR-R vs MP: HR: 0.40 (P < .001)

Mos

HR: 0.301(P < .001)

Median PFS, Mos

MPR-R 31

MPR 15

MP 12

65-75 Yrs of Age70% Reduced Risk of Progression

0 10 20 30 40

Pat

ien

ts (

%)

0

25

50

75

100

HR: 0.618(P = .006)


Data cutoff : February 28, 2011

0

All Patients 65-75 Yrs of AgeMPR-R MPR MP

MM-015: Overall Survival

Mos0 10 20 30 40 50

0

25

50

75

100

Mos

Pat

ien

ts (

%)

0 10 20 30 40 500

25

50

75

100

Pat

ien

ts (

%)

MPR-R MPR MP

Palumbo A, et al. N Engl J Med. 2012;366:1759-1769.Palumbo A, et al. ASH 2011. Abstract 475. Reprinted with permission.


Delforge M, et al. Eur J Haematol. 2012;89:16-27.

Median OS benefit: 13.3 mos5-yr OS rates: 46.0% vs 34.4%

100

90

80

70

60

50

40

30

20

10

0

Pat

ien

ts A

live

(%

)

0 6 12 18 24 30 36 42 48 54 60 66 72 78Mos

Pts at Risk, n338 301 262 240 216 196 168 153 133 112 61 24 3344 300 288 270 246 232 216 199 176 158 78 34 1

Group n Events Median HR (95% CI) P Value

MP 338 211 43.1

VMP 344 176 56.4 0.695 (0.567-0.852) .0004

VISTA: VMP vs MP in Patients With Multiple Myeloma > 65 Yrs of Age


PFS

VMPT + VT Maintenance vs VMP as Frontline Therapy

VMPT VMP P

5 yr PFS 29% 13% <.00015 yr TTNT 41% 19% <.00015 yr OS 61% 51% .01

Palumbo A, et al. ASH 2012. Abstract 200. Reprinted with permission.

1.00

0.75

0.50

0.25

0.00

Pat

ien

ts (

%)

700 10 30 40 50 6020

Median 35.3 months

Median 24.8 months

HR 0.58 (95% CI, 0.47-0.71, P < 0.0001)


Novel Agents for Frontline Treatment of MyelomaStudy Treatment n Outcomes Safety

Richardson et al[1] RVD 66 ≥ VGPR: 67%; 18-mo PFS: 75%; 24-mo OS: 97%

Sensory neuropathy: 80% (mostly grade 1);

fatigue: 64% (mostly grade 1)

Jakubowiak et al[2] Carfilzomib/Rd

53 ≥ nCR: 62%ORR: 98%

Only grade 1/2 PN

Berdeja et al[3] Ixazomib/Rd

15 No DLT up to 2.23 mg/m2 ixazomib;

MTD: 2.97 mg/m2/wk

Only grade 1 PN in 3 pts;6 pts required dose reductions

due to AEs

Lonial et al[4] Elotuzumab/Rd

73 ORR: 82%≥ VGPR: 48%

Grade 3/4 cytopenias: 16%, grade 1/2 diarrhea: 56%

Kaufman et al[5] Vorinostat/RVD

11 1 pt completed 8 cycles, 1 completed 4 cycles and

transplantation

DLTs (1 each): syncope, grade 3 ALT elevation; PN: 6 pts

1. Richardson PG, et al. Blood. 2010;116:679-686. 2. Jakubowiak, et al. Blood. 2012;120:1801-1809. 3. Berdeja JG, et al. ASH 2011. Abstract 479. 4. Lonial S, et al. ASH 2011. Abstract 303. 5. Kaufman JL, et al. ASH 2010. Abstract 3034.

Maintenance Therapy


Case: 43-Yr-Old Male With Stage I Myeloma He received VRD induction x 3 cycles and achieved CR.

He then received melphalan 200 mg/m2 and ASCT, and by Day 60, he was fully recovered

Patient assessment

– SPEP, UPEP no monoclonal protein

– IFE negative, normal serum free light chains ratio

– Bone marrow normal, no clonal plasma cells by flow cytometry

– Findings consistent with stringent CR



Phase III Maintenance Studies

1. Mellqvist UH, et al. ASH 2009. Abstract 530. 2. Attal M, et al. N Engl J Med. 2012;366:1782-1791. 3. McCarthy PL, et al. N Engl J Med. 2012;366:1770-1781. 4. Niesvizky R, et al. ASH 2011. Abstract 478.


IFM 2005-02: Lenalidomide vs Placebo Maintenance After ASCT for Myeloma

Stratified based on diagnostic β2-M, del(13q), VGPR after ASCT


Secondary endpoints: CR, TTP, OS, feasibility of long-term lenalidomide

Attal M, et al. N Engl J Med. 2012;366:1782-1791.

Placebo(n = 307)

Patients younger than 65 yrs of age with

nonprogressive disease, ≤ 6 mos

after first-line ASCT

(N = 614)

Lenalidomide 10-15 mg/day

(n = 307)

Consolidation: Lenalidomide 25 mg/day on Days 1-21 of

every 28 days for 2 mos



IFM 2005-02: PFS and OS

PFS OS

HR: 0.50; P < .001

100

75

50

25

0

PF

S (

%)

0 6 12 18 24 30 36 42 48

Mos of Follow-up

23% 41%

Lenalidomide

Placebo

Pts at Risk, nLenalidomidePlacebo

307307

267255

236211

216169

172102

10357

4922

106

11

P = .29

100

75

50

25

0

OS

(%

)

0 6 12 18 24 30 36 42 48

Mos of Follow-up

Lenalidomide

Placebo

Pts at Risk, n LenalidomidePlacebo

307307

298297

292282

282279

240247

162167

9287

3831

56


Type of Lesion, n Placebo (n = 302)

Lenalidomide (n = 306)

Total(N = 608)

Hematologic 5 13 18

AML/MDS 4 5 9

ALL 0 3 3

Hodgkin’s lymphoma 0 4 4

Non-Hodgkin’s lymphoma 1 1 2

Nonhematologic 4 10 14

Esophageal/hypopharynx 0 1 2

Colon 0 3 3

Prostate 1 2 3

Breast 0 2 2

Renal 1 1 2

Melanoma 1 0 1

Basal cell carcinoma 3 5 8

Total 6 25 31


IFM 2005-02: Second Malignancies at 3 Yrs

Risk factors for second malignancies (P = .01): treatment (placebo vs lenalidomide), age (≤ 55 vs > 55 yrs), sex (male vs female), ISS stage (I + II vs III), induction with DCEP (yes vs no; P = .02)


CALGB 100104: Lenalidomide vs Placebo as Maintenance Therapy After ASCT

Outcome Lenalidomide(n = 231)

Placebo(n = 229)

P Value HR(95% CI)

Median PFS, mos 46 27 .001 NR

3 yr OS, % 88 80 NR 0.62(0.40-0.95)

McCarthy PL, et al. N Engl J Med. 2012;366:1770-1781.

1.0

0.8

0.6

0.4

0.2

0

Pro

bab

ilit

y o

f P

FS

Mos Since Autologous HSCT

700 10 20 30 40 50 60

2-sided P < .001

Lenalidomide

Placebo

1.0

0.8

0.6

0.4

0.2

0

Pro

bab

ilit

y o

f O

SMos Since Autologous HSCT

700 10 20 30 40 50 60

2-sided P = .03

Lenalidomide

Placebo


CALGB 100104: Subgroup Analysis

Placebo Better Lenalidomide Better

-2 -1 0 1 2

OS Subgroup HR (95% CI) P Value for InteractionLenalidomide induction

YesNo

Thalidomide inductionYesNo

Elevated β2-M levelYesNo

CR at randomizationYesNo

.031.40 (0.43-2.4) 0.18 (-0.32 to 0.67)

.050.01 (-0.62 to 0.64)0.89 (0.29-1.5)

.560.37 (-0.39 to 1.1)0.58 (0.06-1.1)

.640.25 (-0.67 to 1.2)0.53 (0.05-1.0)

-2 -1 0 1 2

TTP Subgroup HR (95% CI) P Value for InteractionLenalidomide induction

YesNo

Thalidomide inductionYesNo

Elevated β2-M levelYesNo

CR at randomizationYesNo

.061.10 (0.58-1.7)0.57 (0.25-0.89)

.360.57 (0.17-0.98)0.86 (0.49-1.2)

.760.67 (0.17-1.2)0.77 (0.44-1.1)

.380.53 (-0.001 to 1.1)0.86 (0.53-1.2)

McCarthy PL, et al. N Engl J Med. 2012;366:1770-1781.


Newly diagnosed MM patients with

stage II/III disease aged

18-65 yrs (N = 744)

Stem cell collection: cyclophosphamide/doxorubicin/dexamethasone + granulocyte colony-stimulating factor

Transplantation: ASCT + melphalan 200 mg/m2. Allogeneic stem cell transplantation with no maintenance offered when possible. German patients enrolled through GMMG underwent 2 ASCTs.

PAD x 3 cyclesBortezomib 1.3 mg/m2 on

Days 1, 4, 8, 11 +Doxorubicin 9 mg/m2 on

Days 1-4 + Dexamethasone 40 mg on

Days 1-4, 9-12, 17-20 (n = 371)

2 yrsVAD x 3 cycles

Vincristine 0.4 mg on Days 1-4 + Doxorubicin 9 mg/m2

on Days 1-4 + Dexamethasone 40 mg on Days 1-4, 9-12, 17-20

(n = 373)

Bortezomib 1.3 mg/m2

every 2 wks

Thalidomide 50 mg/day

Stem cell collection and transplantation

Stem cell collection and transplantation

Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955.

HOVON-65 Phase III Trial: Bortezomib in Induction and Maintenance


Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955.

HOVON-65 Phase III Trial of Bortezomib in Induction and Maintenance: PFS and OS

PFS OS

100

75

50

25

0

PF

S (

%)

0 12 24 36 48 60

Mos

VADPAD

Pts at Risk, nArm A:VADArm B: PAD

414413

325356

227261

120140

4451

89

VADPADP = .008

n

414413

F

273242

100

80

60

20

0

OS

(%

)0 12 24 36 48 60

Mos

VADPAD

Pts at Risk, nArm A:VADArm B: PAD

414413

361374

327338

200224

86104

1618

VADPADP = .07

n

414413

D

130109

40


Maintenance: Why Not?

No survival advantage in IFM or MM-015 trials

– Longer follow-up needed in all trials

Cost ~ $8000/mo

Toxicities

– Myelosuppression

– Second primary malignancies

– Quality of life

Unknown response to higher doses of lenalidomide at relapse

– Potential development of resistant clones


Case: What Would You Do if the Initial Patient Were 78 Yrs of Age Instead of 43?Patient assessment: X-ray of lumbar spine: L4 compression fracture, lytic disease in

L2,5

Blood work: Hb 9.5 mg/L, plt 178k/mm3, creatinine 1.5 mg/dL, albumin 3.5 mg/dL, β2-M 3.1 mg/L, Ca 9.8 mg/dL, LDH 190 U/L

SPEP M-protein 4.5 g/dL, IgG lambda, IgG 5200 mg/dL, IgA 35 g/L, IgM 25 g/L, UPEP + lambda light chains

Bone marrow: 40% plasma cells, cytogenetics normal; FISH: no t(4;14), t(14;16) or del(17p)

Skeletal survey: multiple lytic lesions

In addition to zoledronic acid, what would you choose for induction therapy?


Case: 78-Yr-Old Male With Stage I Myeloma He received VD induction x 8 cycles and achieved very

good PR


Management of Adverse Events


Risk Assessment for VTEs in Patients Receiving Thalidomide or Lenalidomide VTE prophylaxis for individual risk factors or myeloma-

related risk factors (eg, hyperviscosity)

– If ≤ 1 risk factor present, aspirin 81-325 mg/day

– If ≥ 2 risk factors present, LMWH (equivalent to enoxaparin 40 mg/day) or full-dose warfarin (target INR: 2-3)

VTE prophylaxis for myeloma therapy–related risk factors (eg, high-dose dexamethasone, doxorubicin, multiagent chemotherapy)

– LMWH (equivalent to enoxaparin 40 mg/day) or full-dose warfarin (target INR: 2-3)

Palumbo A, et al. Leukemia. 2008;22:414-423.


Current Treatment of MM Bone Disease

Bisphosphonates

– Pamidronate

– Zoledronic acid

Denosumab (investigational)

Surgical procedures

– Vertebroplasty

– Balloon kyphoplasty

Radiotherapy

Treatment of myelomaRoodman GD. Hematology Am Soc Hematol Educ Program. 2008:313-319.


Bisphosphonates 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 revealed

– 5% incidence with zoledronic acid

– 4% incidence with pamidronateDurie BG, et al. N Engl J Med. 2005;353:99-102.

Peripheral Neuropathy


Thalidomide- and Bortezomib-Emergent Peripheral Neuropathy: SymptomsPeripheral Neural Tract Symptom(s) Thalidomide Bortezomib

Sensory Hypo-esthesiaparesthesia: numbness,

tingling, pin-prick sensationhyperesthesia

Common Common

Ataxia, gait disturbance Rare Rare

Neuropathic pain Rare Common

Motor Weakness Rare Rare

Tremor Common Rare

Autonomic Gastrointestinal Constipation Constipation

Others Impotence Bradycardia

OrthostaticHypotension

1. Chaudhry V, et al. Neurology 2002;59:1872-1875. 2. Mileshkin L, et al. Leuk Lymphoma. 2006;47:2276-2279. 3. Argyriou AA, et al. Blood 2008;112:1593-1599. 4. Cata JP, et al. J Pain 2007;8:296-306.


Proposed Guidelines for Bortezomib Dose Modification for Management of PN

Subcutaneous bortezomib substantially decreases PN

Severity of PN Signs/Symptoms Modification of Dose and Regimen

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

Reduce current bortezomib dose by 1 level (1.3 to 1.0 to 0.7 mg/m2). For patients receiving a twice-weekly schedule, change to a once-per-wk schedule using the same dose. For patients with previous PN, consider starting with 1.3 mg/m2 once per wk

Grade 1 with pain or grade 2 (no pain but interfering with basic activities of daily living)

For patients receiving twice per wk bortezomib, reduce current dose by 1 level or change to a once-per-wk schedule using the same doseFor patients receiving bortezomib on a once-per-wk schedule:reduce current dose by 1 level or consider temporary discontinuation; upon resolution (grade ≤ 1), restart once-per-wk dosing at lower dose level in cases of favorable benefit-to-risk ratio

Grade 2 with pain, grade 3(limiting self-care and activitiesof daily living), or grade 4

Discontinue bortezomib

Richardson PG, et al. Leukemia. 2012;26:595-608.


Drugs, Dietary Modifications, and Supplements Used for Neuropathy Vitamins/supplements

– Multi-B complex vitamins with B1, B6, B12

– Folic acid

– Vitamin E

– Magnesium for muscle cramps

– Potassium (ie, apple cider vinegar, bananas, oranges) for muscle cramps

FDA-approved drugs for diabetic neuropathy

– Duloxetine

– Pregabalin

Amino acid supplements

– Acetyl-carnitine

– α-lipoic acid

Miscellaneous

– Topical creams, eg, cocoa butter (rich in vitamin E)

– Tonic water (quinine) for leg cramps

Colson K, et al. Clin J Oncol Nurs. 2004;8:473-480. Maestri A, et al. Tumori. 2005;91:135-138. Pisano C, et al. Clin Cancer Res. 2003;9:5756-5767.


Conclusions

All combination therapies provide high response rates during induction: the optimal choice depends on patient characteristics, patient and physician preference and toxicity profiles

Doublets or triplets are appropriate induction for transplant ineligible patients

Cytogenetics have the strongest prognostic significance

Maintenance therapy is now an accepted standard for most myeloma patients, although gains need to balanced with cost and QOL

Best treatment of neuropathy is prevention

Optimal Treatment of Relapsed/Refractory Multiple Myeloma

This program is supported by educational grants from

clinicaloptions.com/oncology

Multiple Myeloma: Case-Based Workshops With the Experts

Symptoms and End-Organ Damage

Bones– Pain– Lytic lesions, fractures – High calcium

Kidneys– Elevated creatinine– Reversible renal failure

Hematopoietic organ– Anemia– Reversible cytopenias

Peripheral nerves

Humoral immune system– Low Ig levels – Hyperviscosity



Multiple Myeloma: Risk Categories

Risk Factors Standard Risk(Expected OS: 6-7 Yrs)

High Risk(Expected OS: 2-3 Yrs)

FISH t(11;14)t(6;14)

del(17p)t(4;14)*t(14;16)

Cytogenetics Hyperdiploidy Hypodiploidydel(13q)

β2-M* Low (< 3.5 mg/L) High (≥ 5.5 mg/L)

PCLI < 3% High (≥ 3%)

Isotype -- IgA

Gene expression profile Good risk High risk

*Patients with t(4;14), β2-M < 4 mg/L, and Hb ≥ 10 g/dL may have intermediate-risk disease.Kumar SK, et al. Mayo Clin Proc. 2009 Dec;84(12):1095-1110. Fonseca R, et al. Leukemia. 2009;23:2210-21. Kyle RA, et al. Clin Lymphoma Myeloma. 2009;9:278-88. Munshi N, et al. Blood. 2011;117:4696-4700.



Considerations in Patients With Relapsed/Refractory Myeloma Types of previous therapy

Response to previous therapy

Patient characteristics and other prognostic factors

– Older than 65 yrs

– Increased β2-M, decreased serum albumin, low platelet count

– Cytogenetic abnormalities: t(4;14)

– Renal dysfunction

– Up to 50% of patients with MM have renal dysfunction

– Between 20% and 30% of patients have concomitant renal failure

– Extensive bone disease; extramedullary MM

Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33. Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874. Facon T, et al. Blood. 2001;97:1566-1571. Barlogie B, et al. Blood. 2004;103:20-32. Fonseca R, et al. Cancer Res. 2004;64:1546-1558. Kyle RA. Stem Cells. 1995;13(suppl 2):56-63. Bladé J, et al. Arch Intern Med. 1998;158:1889-1893.



Case 1

A 65-yr-old male with ISS stage 1 MM received lenalidomide plus low-dose dexamethasone induction therapy for 4 cycles followed by HDT consolidation treatment. He declined lenalidomide maintenance treatment and was in CR for 2 yrs

He now presents with M protein of 0.6 g/dL and no anemia or other abnormalities on skeletal survey

Hb is 14 g/dL, UPEP is negative, serum free light chain ratio is 2:1, and creatinine and calcium levels are normal

3 mos later, repeat testing shows M protein of 0.8 g/dL

6 mos later, M protein is 0.9 g/dL with no changes in the other laboratory values

What would you do now?



When to Consider Retreatment

Differences between biochemical relapse and symptomatic relapse need to be considered

Patients with asymptomatic rise in M protein can be observed to determine the rate of rise and nature of the relapse

Caveat: patients with known aggressive or high-risk disease should be considered for salvage even in the setting of biochemical relapse

CRAB criteria are still listed as the indication to treat in the relapse setting

C: Calcium elevation (> 11.5 mg/L or ULN)R: Renal dysfunction (serum creatinine > 2 mg/dL)A: Anemia (Hb < 10 g/dL or 2 g < normal)B: Bone disease (lytic lesions or osteoporosis)

Optimal Salvage Treatment



Case 2

A 65-yr-old female presents with ISS stage 2 MM. She is treated with RVD followed by ASCT. Posttransplantation, she achieves a VGPR and is started on lenalidomide maintenance therapy

After 2 yrs, she progresses on lenalidomide maintenance therapy. She has no neuropathy

M protein is 1.2 g/dL, Hb is 9.3 g/dL, calcium is normal, serum free light chain ratio is 6:1, and IgG is 2900 mg/dL

Skeletal survey shows new lytic disease. UPEP is negative, bone marrow shows 10% to 20% plasma cells with normal cytogenetics

What would you do now?



Overview of Phase III Trials With Len and Bortezomib in Relapsed/Refractory MM

1. Weber DM, et al. N Engl J Med. 2007;357:2133-2142. 2. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132. 3. Richardson PG, et al. Blood. 2007;110:3557-3560. 4. Orlowski RZ, et al. J Clin Oncol. 2007;25:3892-3901. 5. Weber D, et al. Blood. 2007;110:Abstract 412.

Regimen Trial ORR, %

CR or nCR, %

≥ VGPR, %

DOR, Mos

TTP or PFS, Mos

Median OS, Mos

Len + dex MM-009[1] 61 24 NE16

1135[5]

Len + dex MM-010[2] 60 25 NE 17 11

Bortezomib APEX[3] 43 16 NE 86

30

VdoxMMY-3001[4] 44 13 27

109 NE



Case 3

A 63-yr-old male with a history of relapsed MM after induction with RVD and transplantation presents now with relapse on maintenance therapy with lenalidomide. He is started on salvage therapy with RVD

After 2 cycles, he has rapid and significant progression with progressive anemia and creatinine increasing to 1.5 mg/dL

M protein increases to 2.5 g/dL, Hb is 9 g/dL, creatinine is 1.5 mg/dL, LDH is 250 mg/dL, marrow is packed, genetics shows del(17p)

What would you recommend now?



Carfilzomib

Trial N* Population Previous Lines, n

ORR, %

MR/SD, %

Median TTP, Mos

003-A0[1] 39 Relapsed/ refractory

> 2 18 8/41 6.2

003-A1[2] 257 Relapsed/ refractory

≥ 2 24 12/-- --

004 (Bz exposed)[3] 35 Relapsed/refractory

1-3 17 12/35 4.6

004 (Bz naive)[4] 20 mg/m2

20/27 mg/m2

5967

Relapsed/ refractory

1-3 42 52

17/2212/15

8.3NR

006 (combo with len/dex)[5] 50 Relapsed/refractory

1-3 78 2/8 --

Neuropathy from phase II experience: 9.6% grades 1/2 and 1.4% grade 31. Jagannath S, et al. ASCO 2009. Abstract 8504. 2. Siegel DSD, et al. ASCO 2011. Abstract 8027. 3. Vij R, et al. Br J Haematol. 2012;158:739-748. 4. Vij R, et al. Blood. 2012;119:5661-570. 5. Wang M, et al. ASCO 2011. Abstract 8025.

*Evaluable for response.

Approved for patients who progress within 60 days of last therapy and have received ≥ 2 therapies including bortezomib and an IMiD.



PX-171-003A1: Phase II Trial of Carfilzomib in Relapsed/Refractory MM

Primary endpoint: ORR (CR + VGPR + PR [IMWG criteria])

Secondary endpoints: CBR (ORR + MR [EBMT criteria]), DOR, PFS, TTP, OS, safety

Siegel DS, et al. Blood. 2012;120:2817-2825.

Study population (N = 266)

Progression during treatment or within 60 days of completion of the treatment, or stable disease (SD) as a best response = refractory to last regimen

Neuropathy: Grade 1 or 2 without pain

Cycle 1: 20 mg/m2 IV

Cycles 2-12: 27 mg/m2 IV



003A1: Overall Response Rate


Median DOR: 7.8 months (95% CI: 5.6-9.2)

Response Category, n (%)All Patients

(n = 257)

Patients With Unfavorable Cytogenetics/FISH Markers

(n = 71)

ORR 61 (23.0) 21 (3.0)

CR 1 (0.4) 0 (0)

VGPR 13 (5.1) 3 (4.2)

PR 47 (18.3) 18 (25.4)

MR 34 (13.2) 3 (4.2)

SD 81 (31.5) 28 (39.4)

PD 69 (26.8) 15 (21.1)

Not evaluable 12 (4.7) 4 (5.6)



003A1: Progression-Free Survival


100

75

50

25

0

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5Mos From Start of Treatment

Pro

po

rtio

n o

f P

atie

nts

Aliv

ean

d W

ith

ou

t P

rog

ress

ion

(%

)

Median PFS: 3.7 mos (95% CI: 2.8-4.6)

Censored observationsConfidence band



003A1: Overall Survival (N = 266)


100

75

50

25

0

0 3 6 9 12 15 18 21 24 27Mos From Start of Treatment

Pro

po

rtio

n o

f P

atie

nts

Aliv

e (%

)

Median OS: 15.6 mos (95% CI: 13.0-19.2)

Censored observationsConfidence band



003A1: Common Hematologic AEs


AEs Regardless of Relationship, % All Grades Grade 3 Grade 4

Anemia 46 22 2

Thrombocytopenia 39 17 12

Lymphopenia 23 18 2



003A1: Common Nonhematologic AEs


Nonhematologic AE, n (%) All Grades Grade 3/4Fatigue 130 (49.0) 20 (7.5)Nausea 119 (45.0) 5 (1.9)Dyspnea 90 (34.0) 9 (3.4)Diarrhea 86 (32.0) 2 (0.8)Pyrexia 83 (31.0) 4 (1.5)Headache 74 (28.0) 5 (1.9)Upper respiratory tract infection 71 (27.0) 12 (4.5)Increased serum creatinine 67 (25.0) 7 (2.6)Vomiting 59 (22.2) 2 (0.8)Peripheral neuropathy 33 (12.4) 3 (1.1)Hypophosphatemia 32 (12.0) 16 (6.0)Pneumonia 32 (12.0) 25 (9.4)Hyponatremia 31 (11.7) 22 (8.3)Renal failure (acute) 13 (4.9) 9 (3.4)Febrile neutropenia 2 (0.8) 2 (0.8)Tumor lysis syndrome 1 (0.4) 0 (0)



Results: Cardiac Analysis003-A0 (n = 46)

003-A1 (n = 266)

004 (n = 164)

005 (n = 50)

All Patients(N = 526)

SMQ grouping, n (%)

Cardiac arrhythmia 5 (10.9) 38 (14.3) 20 (12.2) 7 (14.0) 70 (13.3)

Grade 3/4/5 0 8 (3.0) 3 (1.8) 1 (2.0) 12 (2.3)

Cardiac failure 6 (13.0) 16 (6.0) 9 (5.5) 7 (14.0) 38 (7.2)

Grade 3/4/5 4 (8.8) 13 (4.9) 9 (5.5) 4 (8.0) 30 (5.7)

Cardiomyopathy 2 (4.3) 4 (1.5) 2 (1.2) 1 (2.0) 9 (1.7)

Grade 3/4 1 (2.2) 2 (0.8) 0 0 3 (0.6)

Ischemic heart disease 3 (6.5) 11 (4.1) 4 (2.4) 0 18 (3.4)

Grade 3 1 (2.2) 6 (2.3) 0 0 7 (1.4)

Patient disposition in response to cardiac AEs

Dose reduction 0 5 (1.9) 1 (0.6) 0 6 (1.1)

Discontinuation 6 (13.0) 16 (6.0) 8 (4.9) 2 (4.0) 28 (5.3)

Cardiac deaths* 0 4 (1.5) 1 (0.6) 0 5 (1.0)

Cardiac component to other deaths† 0 3 (1.1) 0 0 3 (1.1)

*003-A1, 3 cardiac arrest, 1 dyspnea; 004, 1 cardiac disorder. †Three deaths reported as disease progression by the investigator.

Lonial S, et al. ASH 2012. Abstract 4037. Reprinted with permission.



PX-171-004: PFS With Carfilzomib in Bortezomib-Naive Patients

1.00

0.75

0.50

0.25

00 5 10 15 20 25 30

Mos From the Start of Treatment

Pts at Risk 59 33 19 7 4

(n) 67 38 33 1 0

Cohort 1: 20 mg/m2

Cohort 2: 20/27 mg/m2

59

67

8.2

NR

6.0-12.3

11.3-NE

n Median 95% CI

Su

rviv

al D

istr

ibu

tio

n F

un

ctio

n

Vij R, et al. Blood. 2012;119:5661-570.



Palumbo A, et al. Blood 2012;120:730

CCd: Time to Onset for Best Response in Newly Diagnosed MM Patients

Median treatment duration, cycles (range): 5 (1-9)

% o

f P

atie

nts

Months

PR

sCR/CR/nCR

VGPR

1.00

0.75

0.50

0.25

0.02.5 5.0 7.5 10.0 12.50.0

• CCd: Carfilzomib (20/36 mg/m2), cyclophosphamide, dexamethasone

• AEs: Grade 4: neutropenia (5%); Grade 3/4: infection (10%), cardiac (5%), renal failure (5%); discontinued due to AEs: 0%

Management of Adverse Events



Case 4

A 63-yr-old male with a history of relapsed MM after induction with RVD and transplantation now presents with relapse on maintenance therapy with lenalidomide. He is started on salvage therapy with VCD

After 2 cycles of VCD, he develops PN with pain in the lower extremities. He is currently on twice-weekly dosing of IV bortezomib

Laboratory tests show a PR and normal renal function, and Hb is 10.5 g/dL (improved). Examination shows painful grade 2 PN in the lower extremities




Proposed Guidelines for Bortezomib Dose Modification for Management of PN

Subcutaneous bortezomib causes less peripheral neuropathy

Richardson PG, et al. Leukemia. 2011;26:595-608.

Severity of PN Signs/Symptoms Modification of Dose and Regimen

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

Reduce current bortezomib dose by 1 level (1.3 - 1.0 - 0.7 mg/m2). For patients receiving a twice-weekly schedule, change to a once-per-wk schedule using the same dose. For patients with prior PN, consider starting with 1.3 mg/m2 once per wk

Grade 1 with pain or grade 2 (no pain but interfering with basic activities of daily living)

For patients receiving twice-weekly bortezomib, reduce current dose by 1 level or change to a once-per-wk schedule using the same doseFor patients receiving bortezomib on a once-per-wk schedule,reduce current dose by 1 level, OR consider temporary discontinuation; upon resolution (grade ≤ 1), restart once-per-wk dosing at lower dose level in cases of favorable benefit-to-risk ratio

Grade 2 with pain, grade 3(limiting self-care and activitiesof daily living), or grade 4

Discontinue bortezomib



Risk Assessment for VTEs in Patients With MM Receiving Thal or Len VTE prophylaxis for individual risk factors or myeloma-

related risk factors (eg, hyperviscosity)

– If ≤ 1 risk factor present, aspirin 81-325 mg/day

– If ≥ 2 risk factors present, LMWH (equivalent to enoxaparin 40 mg/day) or full-dose warfarin (target INR: 2-3)

VTE prophylaxis for myeloma therapy–related risk factors (eg, high-dose dexamethasone, doxorubicin, multiagent chemotherapy)

– LMWH (equivalent to enoxaparin 40 mg/day) or full-dose warfarin (target INR: 2-3)

Palumbo A, et al. Leukemia. 2008;22:414-423.



Len/Dex: Cytopenia Management

Monitoring CBCs

– At least biweekly monitoring

– Standard dose reductions

Neutropenia

– For grade ≥ 3, monitor WBCs and consider G-CSF prophylaxis or lenalidomide dose reduction

Thrombocytopenia

– For grade ≥ 3, monitor platelet count and consider interrupting treatment or dose reductions

Anemia

– Consider ESAs for Hb < 10 g/dL

Palumbo A, et al. N Engl J Med. 2011;364:1046-1060.



Herpes Zoster Prophylaxis With Bortezomib Treatment Immunocompromised patients at risk of developing VZV

infection

Bortezomib is associated with increased risk of VZV infection[1]

Acyclovir and other antiviral prophylaxis appear effective at preventing VZV infection in patients treated with bortezomib for MM (with or without corticosteroids)[2]

Vaccine not recommended

1. Chanan-Khan AA, et al. J Clin Oncol. 2008;26:4784-4790. 2. Vickrey E, et al. Cancer. 2009;115:229-232.



Renal Dysfunction

To avoid renal failure

– Maintain hydration

– Avoid use of NSAIDs

– Avoid IV contrast

– Plasmapheresis (NCCN category 2B)

Renal dysfunction is not a contraindication to transplantation

With chronic use of bisphosphonates, it is crucial to monitor for renal dysfunction

NCCN Clinical Practice Guidelines: Multiple Myeloma (V.1.2013).



Lenalidomide [package insert].

Category Renal Function(Cockcroft-Gault)

CLcr, mL/min

Dose

Moderate renal impairment 30-6010 mg

Every 24 hr

Severe renal impairment< 30

(not requiring dialysis)15 mg

Every 48 hr

End-stage renal disease< 30

(requiring dialysis)

5 mg Once daily

(on dialysis days, administer following

dialysis)

Lenalidomide Starting Dose Adjustment for Renal Impairment



Current Treatment of MM Bone Disease

Bisphosphonates

– Pamidronate

– Zoledronic acid

Denosumab (investigational)

Surgical procedures

– Vertebroplasty

– Balloon kyphoplasty

Radiotherapy

Treatment of myeloma

Roodman GD. Hematology Am Soc Hematol Educ Program. 2008:313-319.



Bisphosphonates 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 revealed:

– 5% incidence with zoledronic acid

– 4% incidence with pamidronate

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

Novel Strategies



Case 5

A 63-yr-old man, with a history of relapsed MM after induction with RVD and transplantation, relapsed on maintenance therapy with lenalidomide and progressed after 2 cycles of RVD

M protein increased to 2.5 g/dL, Hb was 9 g/dL, creatinine 1.5 mg/dL, LDH 250 mg/dL, marrow was packed, and cytogenetics showed del(17p)

Carfilzomib was begun and the dose increased to 36 mg/m2 with stable disease

After 7 cycles of carfilzomib, he has progressive anemia and M-protein increase of 0.9 g/dL




PX-171-006: Phase II Trial of Carfilzomib Plus Len/Dex in Relapsed/Refractory MM

Response (N = 51) n (%)

CR/nCRVGPRPRMRSDORR

12 (24)9 (18)

19 (37)1 (2)3 (6)

40 (78)

Niezvizky R, et al. Clin Cancer Res. 2013;19:2248-2256.

Week 1 Week 2 Week 3 Week 4: rest

Carfilzomib20/27 mg/m2 IV

Dexamethasone40 mg/day PO

Lenalidomide D1-D2125 mg/day PO

D1/D2 D8/D9 D15/D16

D1 D8 D15 D22

20 mg/m2 cycle 1 Days 1 and 2 only,27 mg/m2 all days, all cycles thereafter



MM-002: Study Design

Open-label, randomized phase I/II trial[1]

– Phase I portion previously presented[2]

1. Richardson PG, et al. ASH 2011. Abstract 634. 2. Richardson PG, et al. ASH 2010. Abstract 864.

Patients with relapsed/

refractory MM

(N = 221)

PD

*Option to add low-dose dexamethasone40 mg/wk in cases of PD or no response after 4 treatment cycles (n = 61).

Pomalidomide 4 mg on Days 1-21 +Low-Dose Dexamethasone 40 mg/wk

28-day cycle(n = 113)

Pomalidomide* 4 mg on Days 1-2128-day cycle

(n = 108)Primary endpoint: PFS

Secondary endpoints: ORR, duration of response, OS, safety

Anticoagulants and granulocyte colony-stimulating factor added after cycle 1

Erythroid growth factors, bisphosphonates, platelet, and/or RBC transfusions added as clinically indicated



MM-002: Response and Survival Outcomes

Richardson PG, et al. ASH 2011. Abstract 634. Reprinted with permission.

Outcome Pomalidomide +Low-Dose Dexamethasone

Pomalidomide

Overall population (n = 113) (n = 108)

ORR, % 34 13

Median time to response, mos 1.9 2.9

Median duration of response, mos 7.9 8.5

Median PFS, mos 4.7 2.7

Median OS, mos 16.9 14

• For patients with PD as best response 5.4

Double-refractory population (n = 69) (n = 64)

ORR, % 30 16

Median time to response, mos 1.8 2.0

Median duration of response, mos 6.5 8.3

Median PFS, mos 3.9 2.0

Median OS, mos 13.7 12.7

• For patients with PD as best response 4.6



MM-002: Adverse Events

Richardson PG, et al. ASH 2011. Abstract 634. Reprinted with permission.

Grade 3/4 Adverse Event in ≥ 5% Patients, %

Pomalidomide +Low-Dose Dexamethasone

(n = 112)

Pomalidomide(n = 107)

Hematologic

Neutropenia 38 45

• Requiring dose reduction 4 7

Thrombocytopenia 19 21

• Requiring dose reduction 5 9

Anemia 21 17

Nonhematologic

Pneumonia 19 8

Fatigue 10 8



MM-003: Pomalidomide and Low-Dose Dex in Relapsed/Refractory Myeloma Randomized, phase III trial

Dimopoulos, et al. ASH 2012. Abstract LBA-6.

Patients with relapsed/refractory multiple

myeloma with ≥ 2 previous treatments, incl failure of

lenalidomide and bortezomib

(N = 455)

PD or unacceptable toxicity

Pomalidomide 4 mg on Days 1-21 +Low-Dose Dex (LoDex)40 mg/day

Days 1, 8, 15, 22; 28-day cycles(n = 302)

Dex (HiDex) 40 mg/dayDays 1-4, 9-12, 17-20; 28-day cycles

(n = 153)


Secondary endpoints: ORR (≥ PR), duration of response, OS, safety



MM-003: PFS (ITT Population)

Dimopoulos et al. ASH 2012, Abstract LBA-6. Reprinted with permission.

0 4 8 12 160.0

0.2

0.4

0.6

0.8

1.0

HR: 0.45; P < .001

Median PFS

POM + LoDEX: 3.6 mo

HiDEX: 1.8 mo

Months

Pro

po

rtio

n o

f P

atie

nts

W

ith

ou

t P

rog

ress

ion



MM-003: Other Findings

Median OS (95% CI)

– Pom + LoDex: Not reached (11.1 mos – NE)

– HiDex: 7.8 mos (5.4 – 9.2)

ORR significantly higher for Pom + LoDex

Response Pom + LoDex

HiDex P value

ORR (≥ PR), % 21 3 < .001

• VGPR 3 1 --

Median DOR (range)

10.1 mo(6.2 – 12.1)

NE --

Dimopoulos et al. ASH 2012. Abstract LBA-6. Reprinted with permission.

Documents

Overview of Multiple Myeloma. The Basics of Multiple Myeloma This program is supported by educational grants from Celgene Corporation, Millennium:, and