Hallym University Medical Center

Hyo Jung Kim

CASE 1

• 71세 남자로 내원 3개월 전부터 움직이면 더 심해지는

허리의 통증으로 정형외과 및 한방병원에서 척추압박골

절로 치료받던 환자로, 내원 1주전부터 두통과 양안의 시

력저하로 안과 방문하여 망막출혈을 진단받고 혈액종양

내과로 의뢰됨.

Present Illness

• 과거력: 15년 전 appendectomy

• 가족력: 아들이 위암으로 사망

• 음주력: 소주 반병/1개월

• 흡연력: 40PY

• 약물복용력: 없음

Medical History

Physical examination

• 환자는 창백하며 오래 아팠던 것처럼 보이고 허리가 약간 굽은

상태로 의식은 명확함.

• 혈압은 120/70 mmHg, 맥박은 96/분, 호흡수 18/분, 체온 36.8

도, 전신 림프절 종대 없음.

• 흉부 청진에서 호흡음 정상 및 심잡음도 들리지 않았음.

• 복부 진찰에서 촉진되는 장기비대는 없음.

• 흉추하부 및 요추 상부에 압통 있음.

• 양측하지에 1도의 부종이 있음.

Fundoscopic finding

Lab Data

PBS

환자의 증상과 검사소견을 종합하였을

때, 현재 환자에게 가장 응급으로

처치하여야 하는 상황과 그 치료는?

Hyperviscosity syndrome

Plasmapheresis

환자에게 추가적으로 시행하여 진단

및 병기, 예후를 알기 위하여 도움이

되는 검사들은?

PEP IFE

Serum

Urine

M-peak 3.8 g/dL

BM aspiration

Plasma cell 31%

Chromosome study: 46, XY

환자는 MPT 치료를 3주기 시행하고

빈혈이 호전되며 허리의 통증이 많이

호전되었다.

환자의 치료 반응에 대해서 어떻게

평가하겠는가?

환자는 MPT를 7회까지 시행하고 말초신경병 Gr III로

치료를 중단하였다.

이후 8개월간 손발의 통증은 점차 호전되고 있었다.

그러나 1주일전부터 심해지는 등의 통증과 더불어 보행의

장애, 내원 3일전부터 배변장애로 외래를 내원하였다.

신체검진에서 하지근력이 감소하였고, 감각장애가 있었다.

이 환자에서 바로 시행하여야 하는 검사 및 처치는?

Sarah Newbury, the first reported

patient with multiple myeloma.

Blood2008

CLASSIFICATION OF PLASMA CELL

PROLIFERATIVE DISORDERS

I. Monoclonal gammopathies of undetermined significance (MGUS)

A. Benign (IgG, IgA, IgD, IgM, and rarely, free light chains)

B. Associated neoplasms or other diseases not known to produce monoclonal proteins

C. Biclonal gammopathies

D. Idiopathic Bence Jones proteinuria

II. Malignant monoclonal gammopathies

A. Multiple myeloma (IgG, IgA, IgD, IgE, and free light chains)

1. Overt multiple myeloma

2. Smoldering multiple myeloma

3. Plasma cell leukemia

4. Nonsecretory myeloma

5. IgD myeloma

6. Osteosclerotic myeloma (POEMS syndrome)

7. Solitary plasmacytoma of bone

8. Extramedullary plasmacytoma

B. Waldenström's macroglobulinemia

1. Other lymphoproliferative diseases

III. Heavy chain diseases (HCDs)

A. γ-HCD

B. α-HCD

C.μ -HCD

IV. Cryoglobulinemia

V. Primary amyloidosis (AL)

Multiple Myeloma

Clonal proliferation of malignant

plasma cells

Overall incidence 5/100,000 but

much higher in the elderly

Median age ~ 65years

Genetic component recently

recognized

Blood 2011;635-637

Multiple myeloma key features of biology-1

All patients progress through an MGUS phase

Myeloma is not one disease2

At least 7 subtypes based on cytogenetic and molecular features

Highest risk cytogenetic subtypes by FISH

▪ t(4;14), - del 17p

▪ t(14;16), - abnormalities of chromosome 1

End stage disease may be characterized by Extramedullary disease

Loss of monoclonal protein Int J cancer 2009;125;2417-2150, Int J Hematol 2013;97;313-323

Multiple myeloma key features of biology-2

Pathophysiology depends on interaction with marrow microenvironment

Progression is not linear process - concept of “Darwinian evolution and tiding clones”

Blood. 2012;120;1067-76 Harrison’s Principles of Internal Medicine, 17th Ed,

Multiple myeloma

Diagnosis based on finding over 10% plasma cells in bone marrow

In most cased, plasma cells make a monoclonal immunoglobulin protein

“CRAB”= symptomatic myeloma requiring treatment

Anemia-Hb <10g/dL (or 2 g/dL below normal)

Bone lesions

Creatinine > 176 umol/L (2mg/dL)

Hypercalcemia > 2.8 mmol/L (11.5mg/dL)

Diagnostic criteria for MGUS, asymptomatic myeloma and symptomatic myeloma (adapted from IMWG 2003).

MGUS Asymptomatic myeloma Symptomatic myeloma

M-protein in serum <30 g/l

Bone marrow clonal plasma

cells <10% and low level of

plasma cell infiltration in a

trephine biopsy (if done)

No related organ or tissue

impairment (no end organ

damage including bone

lesions)

M-protein in serum ‡30 g/l

and/or Bone marrow clonal

plasma cells ‡10%

No related organ or tissue

impairment (no end organ

damage including bone

lesions) or symptoms

M-protein in serum and/or

urine* Bone marrow (clonal)

plasma cells&#2; or biopsy

proven plasmacytoma

Myeloma-related organ or

tissue impairment (including

bone lesions)

*No specific concentration required for diagnosis. A small percentage of patients have no detectable M-protein in serum or urine but do have myeloma-related organ impairment (ROTI) and increased bone marrow plasma cells (non-secretory myeloma). &#2;If flow cytometry is performed, most plasma cells (‡90%) will show a ‘neoplastic’ phenotype. Some patients may have no symptoms but have related organ or tissue impairment.

Myeloma-related organ or tissue impairment (ROTI)

Clinical effects due to

myeloma Definition

*Increased calcium levels

*Renal insufficiency

*Anaemia

*Bone lesions

Other

• Corrected serum calcium >0.25 mmol/l above the upper limit of

normal or >2.75 mmol/l

• Creatinine >173 lmol/l

• Haemoglobin 2 g/dl below the lower limit of normal or haemoglobin

<10 g/dl

• Lytic lesions or osteoporosis with compression fractures (MRI or CT

may clarify)

• Symptomatic hyperviscosity, amyloidosis, recurrent bacterial

infections (>2 episodes in 12 months)

MRI, Magnetic resonance imaging; CT, Computerized tomography.

*CRAB (calcium, renal insufficiency, anaemia or bone lesions).

IMWG 2003

Guidelines for standard investigative workup: diagnosis Dimopoulos MA, et al for the international myeloma workshop

History and physical examination :

Pain, comorbidities, amyloid symptoms

Blood counts & chemistry :

Hb, cytopenia, calcium and creatinine, B2MG, LDH

Protein : Serum & 24h Urine :

electrophoresis, immunofixation + lgs quantitation, Measurement of

serum free light chains*

Radiological skeletal bone survey

Bone Marrow aspirate and/or biopsy: Morphology, Cytogenetics (FISH)

FLC : mandatory in non-secretory, oligosecretory: BJ escape & Risk of progression in MGUS and SMM not replace 24h urine, Measurement of urine-free light chain levels or urine total , and total levels is not recommended

M/75 with chest wall pain CASE2

When to repeat special tests: follow-up or at relapse

Do not repeat skeletal survey unless bone symptoms

BM aspirate & / or biopsy if:

Suspicion of oligosecretory myeloma progression

When myelodysplastic syndrome is considered (presence of cytopenias)

New clinical trial

FISH analyses only if :

Standard-risk FISH at diagnosis

Equivocal tests

Anemia in a “low tumor MM”

Exclude other causes of anemia

Mild hypercalcemia without bone lesions

Exclude primary hyperparathyroidism

Lytic lesions with <10% PC and small MC

Exclude metastatic carcinoma with MGUS

ADVANCES !! : sensitive tests for diagnosis, prognosis and to monitor treatment efficacy

Outside BM Heavy-light chain

CT & PET

At BM level Molecular cytogenetics

Flow cytometry

Molecular biology ▪ ASO-PCR

▪ Next generation sequencing

Can we improve the measurement of involved an uninvolved immunoglobulins?

The novel HevyliteTM assay enables to accurately measure each isotype-specific heavy and light chain (HLC) (i.e., lgGκ, lgGλ, IgAκ, lgAλ, lgMk, and lgMλ)

Specific measurement of the monoclonal (intact) lg

Measures isotype-specific suppression of the uninvolved HLC-pair to test the impact of immune paresis

HLC-pair suppression is a risk factor for progression of MGUS HLC rations after treatment correlate with survival in symptomatic multiple

myeloma

Innovations to evaluate the disease outside the BM: Bone Disease

imaging techniques : skeletal survey

80% of patients with MM will have radiological evidence of skeletal lesion (can’t be substituted by MRI or CT)

Disadvantages: Low sensitivity, low specify Only demonstrate lyric disease when at least 30% of bone substance

has been lost Blood 2011;635-637

Rx (AP & L) Skull (AP & L) Cervical spine (AP & L) Thoracic spine (AP & L) Lumbar spine

(AP & L) Femurs (AP & L) Humerus (PA) Chest (ribs and scapula) (PA) Pelvis

Magnetic resonance imaging (MRI)

Mandatory Presumed diagnosis of solitary plasmacytoma Detailed evaluation of a painful skeletal area Suspicion of cord compression Pre-kyphoplasty

Recommended Smoldering (asymptomatic) myeloma Vertebral collapse in the contract of osteoporosis Non secretory myeloma

Consider Screening of spine or pelvic plasmacytomas in symptomatic MM

Identification of diffuse pattern (prognosis)

Other imaging techniques

CT scan When MRI unavailable or contraindicated (metal devices)

Bone pain without lytic lesions To clarify lytic lesions ribs, sternum & scapulae To clarify the extent of soft tissues & risk of

fracture To plan radiotherapy or surgery

PET-scan Not recommended for routine use Selected cases:

• Suspected extramedullary disease • Evaluations of rib bone lesions • High LDH • Bence Jones scape • Rapidly recurrent disease

Staging systems for Multiple Myeloma

Combinations for Induction in Myeloma

IMWG uniform Response criteria (I)

Response

sub-category Response criteria

Stringent complete

response (sCR)

Complete

response (CR)*

Very good partial

response (VGPR)*

Partial response (PR)*

Stable disease (SD)

CR as defined below plus

• Normal SFLC ratio

• Absence of phenotypically aberrant plasma cells by multiparameter flow cytometry

• Negative immunofixation on the serum and urine and

• Disappearance of any soft tissue plasmacytomas and

• <5% bone marrow plasma cells

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

or

• 90% reduction in serum M-protein plus reduction in 24-h urinary M-protein by 90% or

to <100 mg/24 h

• 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by 90% or

to <200 mg/24 h

• Not meeting criteria for CR, VGPR, PR or progressive disease

* In patients with light-chain only and non-secretory myeloma, it is recommended that the SFLC assay is used to assess response. It is recognised that a proportion of patients have a low level M-protein in the serum and/or urine and in these patients the SFLC assay should be considered for the assessment of response and subsequent progression. It should be noted that monitoring of response to therapy should be carried out by the same test, using the same test platform and laboratory to optimise monitoring. When SFLC assay is used to monitor disease response, the response criteria are as follows: CR is defined by negative immunofixation and a normal SFLC ratio, VGPR is defined by 90% decrease in the difference between the involved and uninvolved free light chain concentrations and PR by a 50% decrease in the difference between involved and uninvolved SFLC levels. If SFLC assay is also uninformative, PR is defined by >50% reduction in BM plasma cells provided baseline BM plasma cell percentage was 30%, and if present at baseline, a 50% reduction in the size of soft tissue plasmacytomas.

Durie et al 2006, Rajkumar et al, 2011

Relapse subcategory Relapse criteria

Progressive

disease (PD)

Requires at least one of the following:

• 25% increase in serum M-protein (absolute increase must be ‡5 g/l)

• 25% increase in urine M-protein (absolute increase must be ‡200 mg/24 h)

• 25% increase in the difference between involved and uninvolved SFLC levels (used in patient

s with light-chain, non-secretory and oligo-secretory disease) (absolute increase must be >10

0 mg/l)

• 25% increase in bone marrow plasma cell percentage (absolute percentage must be ‡10%)

• Development of new bone lesions or soft tissue plasmacytoma

• Development of hypercalcaemia

Clinical relapse Requires at least one of the following:

• Development of new bone lesions or soft tissue plasmacytoma

• Increase in size of existing plasmacytomas or bone lesions

• Any of the following attributable to myeloma:

Development of hypercalcaemia

Development of anaemia (drop in Hb ‡2 g/dl)

Rise in serum creatinine

Relapse from CR Requires at least one of the following:

• Reappearance of serum or urine M-protein by immunofixation or electrophoresis

• Development of >5% plasma cells in the bone marrow

• Appearance of any other sign of progression (e.g. new plasmacytoma, new lytic bone lesion)

IMWG uniform Response criteria (II)

Voting (1)

Which of the following changes, detectable by FISH cytogenetics, is associated with a better outcome in multiple myeloma patients? 1. del 17p

2. t(14; 16)

3. t(4;14)

4. Hyperdiploidy with trisomies of odd numbered chromosomes

5. Abnormalities of chromosome 1, including amplification of 1q and/or deletion of 1p

Timeline depicting the history and treatment of multiple myeloma from 1844 to the present.

Blood 2008;111:2962-72

Overall survival from diagnosis of MM

Blood 2008;111:2516-20

1.0

0.8

0.6

0.4

0.2

0.0

Pro

port

ion s

urv

ivin

g

A 1.0

0.8

0.6

0.4

0.2

0.0

Surv

ival

B

P<0.001

Diagnosis after 1996 Diagnosis during before 1996

0 20 40 60 80 100 120 140

Time from diagnosis (months)

0 20 40 60 80 100 120 140

Time

1977-82

1983-88

1989-94

1994-00

2001-06

NEJM 2011;164: 1046-1060

Suggested Treatment for newly diagnosed MM

Transplantation-eligible patient Transplantation-ineligible patient

Three-drug induction Two-drug induction Three-drug induction Two-drug induction

Veldex +cyclophosphamide

or doxorubicin

or lenalidomide

or thalidomide for 3-6 cycle

Veldex for 3-6 cycels

or Rd for 4 cycles

MPT for 6-12 cycles

or MPB for 9 cycles

or MPR for 9 cycles

followed by maintenance

with R until progression

or intolerance

Veldex for 8 cycles

or Rd until progression

or intolerance

Maintenance with thalidomide or lenalidomide until progression or intolerance

Autologous stem-cell transplantation

Patient with newly diagnosed multiple myeloma

Induction Therapy for

Transplantation Candidate

• To induce high remission rates rapidly

• With minimal toxicity

• To preserve haemopoietic stem cell

function

ASCT in Myeloma - Where we were ……

Induction High-dose

melphalan + ASCT

Stem cell mobilization /collection

VAD Dexamethasone alone Dexamethasone + thalidomide

Outcomes Overall response rate CR/nCR rate

80% 20%

Median PFS 20-28mos

Median overall survival 48-68mos

Response Before ASCT Is An Important Predictor of Outcome in MM

• Retrospective analysis (n=1567)

→ Patient who achieved CR or VGPR before undergoing an auto-HCT had significantly

longer TTP, PFS and OS after the transplant.

(importance of effective anti-myeloma therapy to maximize the response before

proceeding to auto-HCT)

ASH 2011(Abstract 4119), poster presentation

PFS OS

Importance of achieving CR post-transplant

• Retrospective analysis (n=126)

→ Achievement of CR post-ASCT is the only important prognostic regardless of response following induction

ASH 2011(Abstract 2018), poster presentation

CR following HDM + ASCT

<CR following HDM + ASCT

p=0.002

Phase III trials of novel induction regimens before ASCT

Study /Author N Induction regimen #ASCT Consoli-dation

Maintenance

HOVON-50 Lokhost1 536

TAD VAD

1 - -

Thal INF-a

MRC IX Morgan2 1144

CTD CVAD

1 - -

Thal -

IFM2005-02 Harousseau3 482

BD VAD

1 or 2 +/- len +/- len in some

HOVON 65/GMMG-HD Sonneveld4 613

PAD VAD

1 or 2 - -

B 1.3mg/m2 Thal 50mg/d

GIMEMA MMY-3006 Cavo5 474

VTD Thal+dexa

2 VTD

Thal+dex Dex Dex

PETHEMA/GEM Rosinol6 306

Thal+dexa VTD

VBMCP/VBAD/Vel 1

- -

IFN-a2b Thal

Thal + B

IFM 2007-02 Moreau7 199

BD vTD

1 or 2 NA NA

1. Lohorst HM et al. Blood.2010;115:1113-20 2. Morgan GJ et al. Blood . 2012;119:7-15 3. Harousseau JL et al. J Clin Oncol. 2010;28:4621-9 4. Sonneveld P et al. Blood 2010;116;40[abstract] 5. Cavo M et al. Lancet 2010;376:2075-85 6. Rosinol L et al. Hematologica 2011;96:69[Abstract] 7. Moreau P et al. Blood 2011;118:5752-8

Post-induction Results in Phase III trials

Study Induction regimen

Post-Induction Post-ASCT Median

PFS (mos)

Median OS

(mos)

3 yr OS (%)

ORR (%)

≥VGPR (%)

CR/ nCR(%)

ORR (%)

≥VGPR (%)

CR/ nCR(%)

HOVON-50 TAD VAD

71 57

37 18

3 2

84 76

54 44

14 12

34 25

73 60

- -

MRC IX CTD CVAD

82 71

33 27

13 8

91 90

84 62

50 37

27 25

NYR 63

- -

IFM2005-02 BD VAD

78 63

38 15

15 6

80 77

54 37

35 18

36 30

- -

81% 77%

HOVON 65/GMMG-HD

PAD VAD

83 59

42 11

15 5

- -

61 36

30 15

34 24

- -

78% 71%

GIMEMA MMY-3006

VTD Thal+dexa

93 79

62 28

31 11

93 84

62 58

31 11

3yr:68% 3yr:56%

- -

86% 84%

PETHEMA/GEM

VTD Thal+dexa

VBMCP/VBAD/Vel

82 64 75

60 29 38

35 14 22

77 58 73

60 29 36

46 24 38

NYR 27 38

- - -

80% 80% 80%

IFM 2007-02 vTD BD

88 81

49 36

31 22

89 86

58 74

61 52

26 30

- -

- -

Comparison of side effects related to myeloma treatment with novel agents.

Thalidomide Bortezomib Lenalidomide

Neutropenia No No Yes

Thrombocytopenia No Yes Yes

Neuropathy Yes Yes No

Constipation Yes Low risk Low risk

Diarrhoea No Yes No

Somnolence Yes No No

Fatigue Yes Yes Yes

Thrombotic risk Yes No Yes

Route of administration Oral Intravenous Oral

Modern components of ASCT

Considerations in interpreting phase III studies

Timing of randomization may affect result

most include novel agents before and after ASCT

Induction High-dose

therapy + ASCT CONSOLIDATION

MAINTENANCE THERAPY

Potential integrations of novel agents

Stem cell mobilization /collection

Jan Waldenström

(courtesy of Giampaolo

Merlini, Pavia, Italy)

Induction Therapy for

Transplantation Non-candidate

• To achieve the maximum durable

response

• With minimal treatment related

toxicity

Important aim of treatment:

Achievement of high-quality, sustained

CR balanced with acceptable toxicity

• Retrospective analysis: 3 randomized European trials of GIMEMA and HOVON groups (N=1175)

• First-line treatment

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

•Significant benefit also seen when analysis is restricted to patients >75 years old

Hematologic CR correlates with long-term PFS and

OS in elderly patients treated with novel agents

Gay et al. Blood 2011; 117(11):3025-31

PFS OS

P<0.001 P<0.001

CR

VGPR

PR

CR

VGPR

PR

Pro

babili

ty

Pro

babili

ty

60 50 40 30 20 10 0

100

80

60

40

20

0

Months

P =0.001

PFS

Immunophenotypic CR 90% at 3y

“Stringent CR” 38% at 3y

Conventional CR 57% at 3y

PR (≥70% reduction) 28% at 3y

Paiva et al; J Clin Oncol. 2011;29(12):1627-33.

The better the quality of the response the longer the survival (Immunophenotypic CR): GEM2005>65y

Comorbidity Is a Key Factor in Survival

Charlson et al. J Chronic Dis. 1987;40:373.

Age-Comorbidity Score

N Actual 10-Year Survival (%)

0-1 369 97-99

2 136 87

3 109 79

4 42 47

5 29 34

Summary of randomized trials

MPT vs MP as induction in elderly patients.

Study Regimen n CR (%) >PR (%) Median PFS Median OS

(months) (months)

IFM 99-06 (Facon et al, 2007)

MPT vs. MP vs. MEL100*

125 13 76 27.5 51.6

196 2 35 17.8 33.2

126 18 65 19.4 38.3

IFM 01-01 (Hulin et al, 2009)

MPT vs. MP 113 7 61 24.1 45.3

116 1 31 19 27.7

(Gulbrandsen et al, 2008) MPT vs. MP 357 6 42 16 29

evaluable 3** 28 14 33

HOVON 49 study (Wijermans et al, 2008)

MPT vs. MP 165 2 66 13 37

168 2 47 9 30

GIMEMA (Palumbo et al, 2006),

MPT vs. MP 129 15.5 76 21.8 45.0

updated in (Palumbo et al, 2008a)

126 2 48 14.5 47.6

(n)CR, (near) complete response; PR, partial response; MPT, melphalan, prednisolone, thalidomide; MP, melphalan, prednisolone; MEL100, melphalan 100 mg/m2. *This study involved a 3-way randomization, including an arm consisting of standard induction followed by intermediate dose melphalan and stem cell rescue. **CR/nCR only reported.

VISTA Study: VMP vs MP

Overall survival Time to next therapy

JCO 2010;28:2259-66

Best Overall Response Overall Survival

Lenalidomide + high dose vs low dose Dexa

Lancet Oncol 2010;11:29-37

High dose (n=214)

Low dose (n=208)

Total (n=422)

P value

Overall response rate 81 70 76 0.009

CR + VGPR 50 40 45 0.040

CR 5 4 50 -

Immunofixation(-) CR 13 10 11 -

VGPR 33 26 30 -

PR 31 30 30 -

MR 5 13 9 -

No response/SD 4 8 6 -

PD 4 2 3 -

unevaluable 6 7 6 -

Data are number(%), *Odds ration for differnce in response 1-85(80% CI 1.37-2.49)

Once-weekly administration of bortezomib as a

strategy to improve tolerability

Study details

Grade ¾ GI toxicity

Grade 3/4 peripheral neuropathy

Discontinuation due to AE

VISTA: VMP1-3

Bortezomib twice-weekly

20% 14% 34%

(GIMEMA)4 Bortezomib once-weekly

- 5% 17%

(PETHEMA/GEM)5 Bortezomib once-weekly

7% 7% 12%†

†Discontinuations due to SAEs

1. San Miguel et al. NEJM 2008;359:906 2. San Miguel et al. NEJM 2008;359:906; Supplementary Appendix 3. Mateos et al. J Clin Oncol 2010;28:2259-66

4. Palumbo et al. JCO 2010; 28:5101-09 5. Mateos et al. Lancet Oncol 2010;11:934-41

Study details CR+PR CR PFS 3 yrs-OS

VISTA: VMP1-3

Bortezomib twice-weekly 71% 30% TTP:24 m 68%

Modified VISTA4 (GIMEMA) Bortezomib once-weekly VMPTVT VMP

90% 81%

42% 24%

37 m 27 m

85% 80%

Modified VISTA5 (PETHEMA) Bortezomib once-weekly VMP vs VTPVT vs VP

80%

23%42%

31 m

70%

Once-weekly administration of bortezomib as a

strategy to maintain/improve the efficacy

1. San Miguel et al. NEJM 2008;359:906 2. San Miguel et al. NEJM 2008;359:906; Supplementary Appendix 3. Mateos et al. J Clin Oncol 2010;28:2259-66

4. Palumbo et al. J Clin Oncol 2010;28:5101-9 5. Mateos et al. Lancet Oncol 2010;11:934-41

Once-weekly administration of bortezomib as a

strategy to improve tolerability

Study details Planned

bortezomib dose

Delivered bortezomib dose

VISTA: VMP1

Bortezomib twice-weekly 67.6 mg/m2 38.5 mg/m2

Modified VISTA2 Bortezomib once-weekly (GIMEMA)

46.8 mg/m2 39.4 mg/m2

Modified VISTA3 Bortezomib once-weekly (PETHEMA/GEM)

36.4 mg/m2 32.9 mg/m2

Mateos et al. IMW 2011: abstract 175

Bortezomib IV versus SC 222 relapsed and/or refractory MM patients. Bz is given at conventional dose and scheme

Moreau et al. Lancet Oncology 2011; 12(5): 431-40 Arnulf B et al. Haematologica 2012: Epub ahead of print

Bortezomib IV (n=73) Bortezomib SC (n=145)

Primary endpoint: response after 4/8cycles (single agent bortezomib or +/-dex))

ORR 42%/52% 42%/52%

CR 8%/12% 6%/10%

TTP 9·4 m 10·4 m

Bortezomib IV Bortezomib SC

All grades Grade ≥3 All grades Grade ≥3

Periph Neurop 53% 16% 38% 6% P=0·04 and 0·03

No diferences in pharmakokinetics studies

Voting (2)

Which of the following regimens, which include an

immunomodulatory derivative, has been shown to produce better

progression-free and/or overall survival in phase III trials when

compared to melphalan and prednisone alone (MP) in elderly

myeloma patients not eligible of autologous stem cell transplantation?

1. Thalidomide + dexamethasone

2. Melphalan + prednisone + pomalidomide

3. Lenalidomide + dexamethasone

4. Melphalan + prednisone + thalidomide

5. Carfilzomib+ dexamethasone

Henry Bence Jones.

Blood2008

High Dose Therapy

ASCT vs AlloSCT

Summary of randomized controlled trials

Conventional chemotherapy vs HDT & ASCT.

Trial n EFS

(median, months) OS

(median, months) References

IFM90

Conventional 100 8% at 7 years 25% at 7 years Attal et al (1996)

SCT 100 16% at 7 years 43% at 7 years Harousseau et al (2005)

MRC Myeloma VII

Conventional 200 32 20 Child et al (2003)

SCT 201 54 months 42

MAG91

Conventional 91 13 64 Fermand et al (1998)

SCT 94 39 65

PETHEMA

Conventional 83 34 67 Blade et al (2001)

SCT 81 43 67

EFS, event-free survival; OS, overall survival; SCT stem cell transplantation.

ASCT for ≥ 70 years

Age

Am J hematol 2008;83:614-7

Time to progression Overall Survival

No Maintenance 28-day courses until relapse

Lenalidomide: 10 mg/day, D1-21

Secondary Randomization

Two courses Melphalan: 200 mg/m2, D-2

Stem cell support: D0

• Primary endpoints: PFS, RR, DoR

• Secondary endpoint: OS

Six 28-day courses Melphalan: 0.18 mg/kg/day, D1-4 Prednisone: 2 mg/kg/day, D1-4 Lenalidomide: 10 mg/day, D1-21

Primary Randomization

Four 28-day courses

Lenalidomide: 25 mg/day, D1-21 (low dose) Dexamethasone: 40 mg/day, D1, 8, 15, 22

Stratified by ISS & age

Phase III: MPR versus tandem ASCT

ASH 2011 (Abstract 3069), poster presentation

Timing of ASCT

• Median follow up 26 months

MPR (n=202) MEL 200 (n=200) p

CR 20% 25% 0.49

≥VGPR 60% 58% 0.24

2-year PFS 54% 73% <0.001

2-year OS 87% 90% 0.19

Standard-risk patients 2-year PFS

46% 78% 0.007

High-risk patients 2-year PFS

27% 71% 0.004

Patients who achieved CR 2-year PFS

66% 87% <0.001

Patients who achieved PR 2-year PFS

56% 77% <0.001

Gr 3/4 neutropenia 55% 89% <0.001

Gr 3/4 infections 0% 17% <0.001

Gr 3/4 gastrointestinal toxicity 0% 21% <0.001

DVT 2.44% 1.13% 0.43

Second tumors 0.5% 1.5% 0.12

•High risk : t(4;14), t(14;16), del17p ASH 2011 (Abstract 3069), poster presentation

Phase III: MPR versus tandem ASCT

Timing of ASCT

Summary of selected reported series of

Allo-SCT in myeloma.

Conditioning regimen n CR % TRM % EFS (%) OS (%) References

FI AlloSCT

Cyclophosphamide/TBI 39 47.2 31.5 13.3 (5 years) 28.1 (5 years) Hunter et al (2005)

Melphalan/TBI 78 54.7 35.3 36.2 (5 years) 44.1 (5 years) Hunter et al (2005)

Bu/Cyclo/TBI 15 53.3 17 31 (6 years) 77 (6 years) Kro¨ger et al (2003)

Cyclo/TBI (+/) Idarubicin) 53 19 34 Median 18 months Median 25 months Lokhorst et al (2003)

Cyclo/TBI 53 22 (7 years) 39 (7 years) Barlogie et al (2006a)

Mel/TBI 72 38 22 31.4 (10 years) 39.9 (10 years) Kuruvilla et al (2007)

RIC AlloSCT

Flu/Bu/ATG 41 24 17 41 (2 years) 62 (2 years) Mohty et al (2004)

Flu/TBI200Gy 52 27 17 29.4(1.5 years) 41 (1.5 years) Gerull et al (2005)

ASCT fi Flu/TBI200Gy 16 62 16 36 (3 years) 62 (3 years) Bruno et al (2007)

ASCT fi Flu/Bu 46 33 11 . 57 (2 years) Gahrton et al (2001)

ASCT fi Flu/Mel/ATG 17 73 18 56 (2 years) 74 (2 years) Kro¨ger et al (2002)

ASCT fi TBI200Gy 54 57 7 45 (4 years) 69 (4 years) Maloney et al (2003)

ASCT fi Flu/Bu/ATG 65 62.2 10.9 Median 32 months Median 35 months Garban et al (2006)

ASCT fi Flu/Mel/TBI200Gy 45 64 36 13 (3 years) 36 (3 years) Lee et al (2003b)

[Non-relapse/Ref] 12 . . 80 (3 years) 80 (3 years)

FI, full intensity/myeloablative conditioning; RIC, reduced intensity conditioning; TRM, treatment-related mortality; ASCT fi , Planned tandem autologous stem cell transplantation followed by an allogeneic stem cell transplantation; Flu, Fludarabine; TBI200Gy, single fraction total body irradiation; Bu, intravenous busulphan; Cyclo, cyclophosphamide; ATG, anti-thymocyte globulin; Mel, high dose Melphalan

Maintenance Therapy

Thalidomide Maintenance after ASCT

Study /Author N Thalidomide dose Duration PFS/ EFS

OS

IFM99-02 Attal/20061 597

Thal 200mg (median) vs Observation

Until prog + +

(Australia) Spencer/20062 243

Thal 200mg + PRD vs PRD

12mos + +

(Brazil) Maiolino/20083 212

Thal 200mg +Dex vs Dex

12mos + NS

Total therapy 2 Barlogie/20064 668

Thalidomide -

Until prog + NS

(+ in high-risk)

Hovon-505 Lokhorst/2010 556

Thal 50mg -

Until prog + NS

NCIC MY. 10 Stewart/20106 325

Thal 200mg + PRD vs Observation

48mos + NS

MRC IX5 Morgan/2012 492 Thal 100mg vs Observation Until prog +

NS (- in high-risk)

1. Attalet al. Blood.2006;108:3289-94 2. Spencer A et al. JCO . 2009;27:1788-93 3. Maiolino et al. Blood. 2008;112:3703 4. Barlogie B et al. NEJM 2006;354;1021-1030 5. Lokhost HMet al. Blood 2010;115:1113-1120 6. Stewart AK et al. 2010;116:39[Abstract] 7. Morgan GJ et al. Blood 2012;119:7-15

2011 ASH education program Book 197-204

Lenalidomide and Bortezomib Maintenance after ASCT

Study /Author N maintenance dose Duration PFS/E

FS OS

IFM2005-02 Attal/20101 614

Lenali 10-15mg vs Placebo

Until prog + -

CALGB100104 McCarthy/20102 568 Lenali 10mg vs Placebo Until prog + +

Hovon-65/GMMG-HD4 Sonneveld /2010

613 B 1.3mg/m2 every 2 wks

Thal 50mg/d

24mos +(?) +(?)

1. Attal et al. Blood.2010;116:310[Abstract] 2. McCarthy PL et al. Blood. 2010;116:37 [Abstract] 3. Sonneveld P et al. Blood. 2010;116:23

2011 ASH education program Book 197-204

MP vs MPR vs MPR-R (65-75 Yrs)

Palumbo A et al NEJM2012; 366:1759-69

Progression free survival (months) Overall Survival (months)

NEJM 2011;164: 1046-1060

Suggested Treatment for newly diagnosed MM

Transplantation-eligible patient Transplantation-ineligible patient

Three-drug induction Two-drug induction Three-drug induction Two-drug induction

Veldex +cyclophosphamide

or doxorubicin

or lenalidomide

or thalidomide for 3-6 cycle

Veldex for 3-6 cycels

or Rd for 4 cycles

MPT for 6-12 cycles

or MPB for 9 cycles

or MPR for 9 cycles

followed by maintenance

with R until progression

or intolerance

Veldex for 8 cycles

or Rd until progression

or intolerance

Maintenance with thalidomide or lenalidomide until progression or intolerance

Autologous stem-cell transplantation

Patient with newly diagnosed multiple myeloma

Timeline depicting the history and treatment of multiple myeloma from 1844 to the present.

Blood 2008;111:2962-72