Plasma Cell Diseases MGUS, Smoldering Myeloma, Multiple Myeloma

Plasma Cell DiseasesPlasma Cell Diseases

MGUS, Smoldering Myeloma, Multiple Myeloma

MGUS, Smoldering Myeloma, Multiple Myeloma

he heritage and the dynamics of plasma-cell life in humoral immune responses are shown. B cells that are generated in the bone marrow exit as

precursor B cells (pre-B cells), which are immature and express IgM. These cells further mature into naive B cells and then into either marginal-zone B

cells or follicular B cells. When activated, these marginal-zone and follicular B cells can differentiate into plasmablasts (not shown) and short-lived

plasma cells, both of which can secrete antibody. Alternatively, with the help of T helper cells, follicular B cells can also differentiate into memory B cells,

which are long-lived, and express antibodies of switched class and high affinity for antigen. When reactivated by antigen, memory B cells can

differentiate into plasmablasts, which are competent to become long-lived plasma cells. A small proportion of these plasmablasts stay in the secondary

lymphoid organ (the spleen or the lymph node) where they were generated. Most of the plasmablasts migrate either to inflamed tissue, under the

control of interferon--induced expression of CXC-chemokine receptor 3 (CXCR3; which binds CXC-chemokine ligand 9 (CXCL9), CXCL10 and CXCL11), or

to the bone marrow, under the control of chemotaxis towards CXCL12 (which binds CXCR4). All three tissues have finite numbers of plasma-cell survival

niches. Plasmablasts that succeed in the acquisition of such a niche differentiate into plasma cells and become immobile. Resolution of inflamed tissue

after a successful immune response terminates the survival niches in the tissue and therefore eliminates the resident plasma cells, and this is the peak

of the immune response. In the bone marrow, and to a lesser degree in secondary lymphoid organs, long-lived plasma cells survive and provide humoral

memory.

he heritage and the dynamics of plasma-cell life in humoral immune responses are shown. B cells that are generated in the bone marrow exit as

precursor B cells (pre-B cells), which are immature and express IgM. These cells further mature into naive B cells and then into either marginal-zone B

cells or follicular B cells. When activated, these marginal-zone and follicular B cells can differentiate into plasmablasts (not shown) and short-lived

plasma cells, both of which can secrete antibody. Alternatively, with the help of T helper cells, follicular B cells can also differentiate into memory B cells,

which are long-lived, and express antibodies of switched class and high affinity for antigen. When reactivated by antigen, memory B cells can

differentiate into plasmablasts, which are competent to become long-lived plasma cells. A small proportion of these plasmablasts stay in the secondary

lymphoid organ (the spleen or the lymph node) where they were generated. Most of the plasmablasts migrate either to inflamed tissue, under the

control of interferon--induced expression of CXC-chemokine receptor 3 (CXCR3; which binds CXC-chemokine ligand 9 (CXCL9), CXCL10 and CXCL11), or

to the bone marrow, under the control of chemotaxis towards CXCL12 (which binds CXCR4). All three tissues have finite numbers of plasma-cell survival

niches. Plasmablasts that succeed in the acquisition of such a niche differentiate into plasma cells and become immobile. Resolution of inflamed tissue

after a successful immune response terminates the survival niches in the tissue and therefore eliminates the resident plasma cells, and this is the peak

of the immune response. In the bone marrow, and to a lesser degree in secondary lymphoid organs, long-lived plasma cells survive and provide humoral

memory.

Plasma CellsPlasma Cells

Once in the Bone MarrowOnce in the Bone Marrow

•The abnormal precursor B-cells originate in the lymph nodes and migrate to the bone marrow, which provides a microenvironment conducive to terminal plasma cell differentiation

•the malignant plasma cells is “nourished” by the microenvironment of the bone marrow, becomes widely disseminated throughout the axial skeleton

•The abnormal precursor B-cells originate in the lymph nodes and migrate to the bone marrow, which provides a microenvironment conducive to terminal plasma cell differentiation

•the malignant plasma cells is “nourished” by the microenvironment of the bone marrow, becomes widely disseminated throughout the axial skeleton

Blade J. N Engl J Med 2006;355:2765-2770

Bone Marrow Specimen from a Patient with MGUS

abnormal SPEPabnormal SPEP

• Consequently, clonal plasma cells expand, accompanied by secretion of a monoclonal immunoglobulin

• Consequently, clonal plasma cells expand, accompanied by secretion of a monoclonal immunoglobulin

Kyle R et al. N Engl J Med 2007;356:2582-2590Kyle R et al. N Engl J Med 2007;356:2582-2590

Characteristics of Active MM and Its PrecursorsCharacteristics of Active MM and Its Precursors

•During the evolution of MM and progression to advanced stages, additional genetic events (eg, loss of chromosome 13, secondary MYC translocation, activation of other oncogenes such as Ras, p53, and Rb) and dysregulation of the cell cycle may take place.

•The result is loss of apoptosis and immortalization of plasma cells.

•During the evolution of MM and progression to advanced stages, additional genetic events (eg, loss of chromosome 13, secondary MYC translocation, activation of other oncogenes such as Ras, p53, and Rb) and dysregulation of the cell cycle may take place.

•The result is loss of apoptosis and immortalization of plasma cells.

Disease Progression, clonal evolution

Disease Progression, clonal evolution

MGUSMGUS

• (MGUS) is an asymptomatic genetically malignant but clinically premalignant clonal plasma cell proliferative disorder.

• It occurs in over 3 percent of the general population over the age of 50.

• It is typically an incidental finding as part of a w/u for a wide variety of clinical syndromes (eg, peripheral neuropathy, vasculitis, hemolytic anemia, skin rashes, hypercalcemia, elevated sedimentation rate)

• (MGUS) is an asymptomatic genetically malignant but clinically premalignant clonal plasma cell proliferative disorder.

• It occurs in over 3 percent of the general population over the age of 50.

• It is typically an incidental finding as part of a w/u for a wide variety of clinical syndromes (eg, peripheral neuropathy, vasculitis, hemolytic anemia, skin rashes, hypercalcemia, elevated sedimentation rate)


Recommended Testing in Patients with Suspected MGUS

•IgG

•IgA

•IgM

•Free Light Chains

•24 hr Urine Collection for UPEP

•IgG

•IgA

•IgM

•Free Light Chains

•24 hr Urine Collection for UPEP



MGUS Treatment: No Treatment

Periodic follow-up is recommended, as MGUS can transform to a more serious disorder at a rate of approximately 1 percent/year

MGUS Treatment: No Treatment

Periodic follow-up is recommended, as MGUS can transform to a more serious disorder at a rate of approximately 1 percent/year

Current model to stratify MGUS Current model to stratify MGUS

uses three adverse risk factors: 1. a serum M protein level ≥1.5 gm/dL, 2. non-IgG MGUS, and 3. an abnormal serum FLC ratio

the risk of disease progression over 20 years is as follows :

•3 risk factors (high-risk MGUS) — 58 percent•2 risk factors (high-intermediate risk MGUS) — 37 percent•1 risk factor (low-intermediate risk MGUS) — 21 percent•no risk factors (low-risk MGUS) — 5 percent

PrognosisPrognosis

Patients with low-risk MGUS:

1. serum M protein ≤1.5 gm/dL,

2. IgG subtype, and

3. normal serum free light chain (FLC) ratio

have a risk of progression of only 5 % over 20 years, and may be followed less frequently

Patients with low-risk MGUS:

1. serum M protein ≤1.5 gm/dL,

2. IgG subtype, and

3. normal serum free light chain (FLC) ratio

have a risk of progression of only 5 % over 20 years, and may be followed less frequently




Probability of Progression to Active MM or Primary Amyloidosis in Probability of Progression to Active MM or Primary Amyloidosis in Patients with Smoldering MM or MGUSPatients with Smoldering MM or MGUS

Disorders associated with a MGUSDisorders associated with a MGUS

Plasma cell disorders

Monoclonal gammopathy of undetermined significance (MGUS)

Biclonal gammopathy of undetermined significance

Idiopathic Bence Jones proteinuria

POEMS syndrome, Osteosclerotic myeloma

Castleman's disease

AL (light chain) amyloidosis,

Solitary plasmacytoma

Multiple myeloma, Smoldering multiple myeloma

Plasma cell disorders

Monoclonal gammopathy of undetermined significance (MGUS)

Biclonal gammopathy of undetermined significance

Idiopathic Bence Jones proteinuria

POEMS syndrome, Osteosclerotic myeloma

Castleman's disease

AL (light chain) amyloidosis,

Solitary plasmacytoma

Multiple myeloma, Smoldering multiple myeloma

B-cell lymphoproliferative disorders

Non-Hodgkin's lymphomaCLLLymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia) IgMPost-transplant monoclonal gammopathiesHeavy chain diseases

Connective tissue disorders SLE, RA

Associated with infections: HIV Hep C

Dermatologic Disorders

B-cell lymphoproliferative disorders

Non-Hodgkin's lymphomaCLLLymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia) IgMPost-transplant monoclonal gammopathiesHeavy chain diseases

Connective tissue disorders SLE, RA

Associated with infections: HIV Hep C

Dermatologic Disorders

Miscellaneous disordersMiscellaneous disorders

Acquired von Willebrand disease

Acquired C1 esterase inhibitor deficiency (angioedema)

Eosinophilic fasciitis

Cryoglobulinemia, cryofibrinogenemia

Myelodysplastic syndrome

Chronic neutrophilic leukemia

Sensorimotor neuropathy with MGUS

Capillary leak syndrome

T-cell large granular lymphocyte leukemia

Cold agglutinin disease

Acquired von Willebrand disease

Acquired C1 esterase inhibitor deficiency (angioedema)

Eosinophilic fasciitis

Cryoglobulinemia, cryofibrinogenemia

Myelodysplastic syndrome

Chronic neutrophilic leukemia

Sensorimotor neuropathy with MGUS

Capillary leak syndrome

T-cell large granular lymphocyte leukemia

Cold agglutinin disease

Nair S and Pearson S. N Engl J Med 2004;351:1874

A 76-year-old woman was admitted with an exacerbation of chronic obstructive pulmonary disease

accounts for approximately 1 percent of all cancers and slightly more than 10 percent of hematologic malignancies in the United States (US)

The annual incidence in the US is approximately 4 to 5 per 100,000. About 20,000 new cases a year.

MM is a disease of older adults. The median age at diagnosis is 66 years

accounts for approximately 1 percent of all cancers and slightly more than 10 percent of hematologic malignancies in the United States (US)

The annual incidence in the US is approximately 4 to 5 per 100,000. About 20,000 new cases a year.

MM is a disease of older adults. The median age at diagnosis is 66 years

Multiple myeloma (MM)

Most patients with MM present with signs or symptoms related to the infiltration of plasma cells into the bone or other organs (kidney)

Most patients with MM present with signs or symptoms related to the infiltration of plasma cells into the bone or other organs (kidney)

• Anemia - 73 percent

• Bone pain - 58 percent

• Elevated creatinine - 48 percent

• Fatigue/generalized weakness - 32 percent

• Hypercalcemia - 28 percent

• Weight loss - 24 percent

• Anemia - 73 percent

• Bone pain - 58 percent

• Elevated creatinine - 48 percent

• Fatigue/generalized weakness - 32 percent

• Hypercalcemia - 28 percent

• Weight loss - 24 percent


Diagnostic Criteria for MGUS, Multiple Myeloma, and Other Conditions

Panel B: A dense, localized band (red asterisk) representing a monoclonal protein of gamma mobility is seen on serum protein electrophoresis on agarose gel (anode on left).

Panel A: Densitometer tracing of these findings reveals a tall, narrow-based peak (red asterisk) of gamma mobility and a reduction in the normal polyclonal gamma band.


Bone Marrow Specimen from a Patient with MGUS (May-Grunwald-Giemsa Staining)

Multiple Myeloma Marrow

Diagnostic criteria Diagnostic criteria Multiple Myeloma (all 3 criteria must be met)

1.Presence of a serum or urinary monoclonal protein 2.Presence of clonal plasma cells in the bone marrow or a plasmacytoma 3.Presence of end organ damage felt related to the plasma cell dyscrasia, such as:

•Increased calcium concentration•Lytic bone lesions•Anemia, or•Renal failure

Asymptomatic (smoldering) multiple myeloma (SMM, both criteria must be met)

1. Serum monoclonal protein >3 g/dL and/or bone marrow plasma cells >10 percent 2. No end organ damage related to plasma cell dyscrasia (see list above)

MGUS

1. Serum monoclonal protein <3 g/dL

2. Bone marrow plasma cells <10 percent

3. No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disease

Multiple Myeloma (all 3 criteria must be met)

1.Presence of a serum or urinary monoclonal protein 2.Presence of clonal plasma cells in the bone marrow or a plasmacytoma 3.Presence of end organ damage felt related to the plasma cell dyscrasia, such as:

•Increased calcium concentration•Lytic bone lesions•Anemia, or•Renal failure

Asymptomatic (smoldering) multiple myeloma (SMM, both criteria must be met)

1. Serum monoclonal protein >3 g/dL and/or bone marrow plasma cells >10 percent 2. No end organ damage related to plasma cell dyscrasia (see list above)

MGUS

1. Serum monoclonal protein <3 g/dL

2. Bone marrow plasma cells <10 percent

3. No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disease

Adapted from Br J Haematol 2003;121:749 and Rajkumar, SV et al. Leukemia 2001;15:1274.

Stage I (Low cell mass - <0.6 x 10(12) cells/m2)

All of the following present:Hgb >10 g/dLSerum IgG <5 g/dLSerum IgA <3 g/dLNormal serum calciumUrine monoclonal protein excretion <4 g/dayNo generalized lytic bone lesions

Stage IIIntermediate cell mass - neither stage I nor stage III

Stage III (High cell mass - >1.2 x 10(12) cells/m2)

One or more of the following:Hgb < 8.5 g/dLSerum IgG >7 g/dLSerum IgA > 5 g/dLSerum calcium >12 mg/dL (3 mmol/L)Urine monoclonal protein excretion >12 g/dayAdvanced lytic bone lesions

Stage I (Low cell mass - <0.6 x 10(12) cells/m2)

All of the following present:Hgb >10 g/dLSerum IgG <5 g/dLSerum IgA <3 g/dLNormal serum calciumUrine monoclonal protein excretion <4 g/dayNo generalized lytic bone lesions

Stage IIIntermediate cell mass - neither stage I nor stage III

Stage III (High cell mass - >1.2 x 10(12) cells/m2)

One or more of the following:Hgb < 8.5 g/dLSerum IgG >7 g/dLSerum IgA > 5 g/dLSerum calcium >12 mg/dL (3 mmol/L)Urine monoclonal protein excretion >12 g/dayAdvanced lytic bone lesions

Durie-Salmon staging Durie-Salmon staging system system

A: Serum creatinine <2 mg/dLB: Serum creatinine >2 mg/dL

The International staging system (ISS)

The International staging system (ISS)

An International Staging System (ISS), based on 10,750 previously untreated patients with myeloma from over 17 institutions worldwide has been developed. It is based on the levels of serum beta-2 microglobulin (B2M) and serum albumin alone

Stage I — B2M <3.5 mg/L and serum albumin less 3.5 g/dL

Stage II — neither stage I nor stage III

Stage III — B2M 5.5 mg/L

An International Staging System (ISS), based on 10,750 previously untreated patients with myeloma from over 17 institutions worldwide has been developed. It is based on the levels of serum beta-2 microglobulin (B2M) and serum albumin alone

Stage I — B2M <3.5 mg/L and serum albumin less 3.5 g/dL

Stage II — neither stage I nor stage III

Stage III — B2M 5.5 mg/L

Stage Criteria Median Overall Survival

I Serum Beta 2-microglobulin < 3.5 mg/L 62 months

AND Serum albumin > 3.5 g/dL

II Neither stage I or stage III 44 months

III Serum Beta2-microglobulin > 5.5 mg/L 29 months

Median Overall Survival Median Overall Survival

Stage Age < 65 years Age > 65 years

I 69 months 47 months

II 50 months 37 months

III 33 months 24 months


High-Dose Chemotherapy Conventional-Dose

Stage Chemotherapy




Stage Criteria Median Overall Survival

I Serum Beta 2-microglobulin < 3.5 mg/L 62 months

AND Serum albumin > 3.5 g/dL

II Neither stage I or stage III 44 months

III Serum Beta2-microglobulin > 5.5 mg/L 29 months


Stage Age < 65 years Age > 65 years





High-Dose Chemotherapy Conventional-Dose

Stage Chemotherapy




Prognosis by ISS Prognosis by ISS

Risk Group Cytogenetics Risk Group Cytogenetics

Poor Median Overall Survival

t(4;14) 24.7 months

t(14;16)

–17p13

Intermediate

–13q14 42.3 months

Good

All others and 50.5 months

Hyperodiploidy

t(11;14), t(6;14)

Poor Median Overall Survival

t(4;14) 24.7 months

t(14;16)

–17p13

Intermediate

–13q14 42.3 months

Good

All others and 50.5 months

Hyperodiploidy

t(11;14), t(6;14)

Prognosis by Prognosis by

Treatment PlanTreatment Plan

•Induction of Remission

•Maintenance Therapy

•Infectious Disease Prophylaxis

•Bone Disease: Fractures and Osteoporosis

•Induction of Remission

•Maintenance Therapy

•Infectious Disease Prophylaxis

•Bone Disease: Fractures and Osteoporosis

Changing Treatment ParadigmChanging Treatment Paradigm

OLD DRUGS

Melphalan Prednisone

Vincristine Doxoribicine Dexamethasone (VAD)

Dexamethasone

OLD DRUGS

Melphalan Prednisone

Vincristine Doxoribicine Dexamethasone (VAD)

Dexamethasone

NEW DRUGS

Thalidomide

Bortezomib

Lenalidomide

iv Melphalan

NEW DRUGS

Thalidomide

Bortezomib

Lenalidomide

iv Melphalan

An Approach to the Treatment of Newly Diagnosed Multiple Myeloma

Bortezomib or Velcade™Bortezomib or Velcade™Proteasome inhibitors target the ubiquitin-proteasome system, which is the primary intracellular degradation pathway for protein.

Within cells, this system plays a key role in regulating the transcriptional activity of nuclear factor-kappa B (NF-kB). Bortezomib, a boronic acid dipeptide, is a reversible inhibitor of the 26S proteasome complex.

Through proteasome inhibition, bortezomib causes the downregulation of NF-kB activity, thereby reducing NF-kB–mediated tumor growth, angiogenesis, and cell survival.

Proteasome inhibitors target the ubiquitin-proteasome system, which is the primary intracellular degradation pathway for protein.

Within cells, this system plays a key role in regulating the transcriptional activity of nuclear factor-kappa B (NF-kB). Bortezomib, a boronic acid dipeptide, is a reversible inhibitor of the 26S proteasome complex.

Through proteasome inhibition, bortezomib causes the downregulation of NF-kB activity, thereby reducing NF-kB–mediated tumor growth, angiogenesis, and cell survival.

Mitchell B. N Engl J Med 2003;348:2597-2598

Mechanism of Action of BortezomibProteins are targeted to the 26S proteasome for degradation by a process of polyubiquitination. Bortezomib inhibits the catalytic activity of the proteasome, thus preventing proteolysis. Ub denotes ubiquitin.

26S Proteosome is a garbage disposal of proteins

This inhibition disrupts signaling within cancer cells, fostering antiproliferative, proapoptotic, antiangiogenic, and antitumor activity.

This inhibition disrupts signaling within cancer cells, fostering antiproliferative, proapoptotic, antiangiogenic, and antitumor activity.

Thalidomide and Lenalidomide (Revlimid™) Thalidomide and Lenalidomide (Revlimid™)

•immunomodulary agents with antiangiogenic properties.

•Thalidomide is approved for first-line treatment of multiple myeloma in combination with dexamethasone.

•Lenalidomide is an analogue of thalidomide

•immunomodulary agents with antiangiogenic properties.

•Thalidomide is approved for first-line treatment of multiple myeloma in combination with dexamethasone.

•Lenalidomide is an analogue of thalidomide

The mechanisms of action The mechanisms of action

both lenalidomide and thalidomide are similar and incompletely characterized

inhibiting the actions of TNF-α and IL-6

both agents may exhibit antiangiogenic

Both are oral agents

both lenalidomide and thalidomide are similar and incompletely characterized

inhibiting the actions of TNF-α and IL-6

both agents may exhibit antiangiogenic

Both are oral agents

LenalidomideLenalidomide

Lenalidomide is a thalidomide derivative that down-regulates IL-6 and NF -B and activates caspase 8 in vitro.

The drug is up to 50,000 times as potent as its parent molecule in inhibiting TNF

Lenalidomide is a thalidomide derivative that down-regulates IL-6 and NF -B and activates caspase 8 in vitro.

The drug is up to 50,000 times as potent as its parent molecule in inhibiting TNF

List A. N Engl J Med 2007;357:2183-2186

Actions of Immunomodulatory Drugs in Multiple Myeloma

Figure 1. Actions of Immunomodulatory Drugs in Multiple Myeloma.Immunomodulatory drugs arrest growth and induce apoptosis in myeloma cells and inhibit adhesion to bone marrow stroma. Stromal elaboration of and cellular response to vascular endothelial growth factor (VEGF) and basic fibroblast growth factor are reduced by immunomodulatory drugs, a process that results in decreased angiogenesis. Generation of the paracrine myeloma growth factor, interleukin-6, and tumor necrosis factor (TNF-) by stromal cells is reduced, which, in turn, inhibits myeloma-cell growth. The immunomodulatory drugs costimulate T lymphocytes to promote secretion of interleukin-2 and interferon- (INF-), which cooperate to activate natural killer cells and myeloma-specific immune response. Data are adapted from Teo.6 VCAM denotes vascular-cell adhesion molecule, and Th1 type 1 helper T.

Myeloma cells and the MicroenviromentMyeloma cells and the Microenviroment

clinicaloptions.com/oncology

Practical Applications and Clinical Advances in Multiple Myeloma

Summary of Novel Agent Induction Trials (Randomized Studies)

≥ VGPR Rates Postinduction and Posttransplantation

*Posttransplantation data not available.

1. Harousseau et al. ASH/ASCO symposium during ASH 2008. 2. Rajkumar SV, et al. ASCO 2008. Abstract 8504. 3. Rajkumar SV. ASH/ASCO symposium during ASH 2008. 4. Lokhorst HM, et al. Haematologica. 2008;93:124-127. 5. Sonneveld P, et al. ASH 2008. Abstract 653. 6. Sonneveld P, et al. IMW 2009. Abstract 152. 7. Cavo M, et al. ASH 2008. Abstract 158. 8. Cavo M, et al. IMW 2009. Abstract 451.

Postinduction Posttransplantation

44% to 50%

VincAD[1]

15% to

16%

57%

BortD[1]

39%

*

RD[2,3]

42%

*

Rd[2,3]

24%

49%

TAD[4]

33%

59%

PAD[5,6]

42%

76%

BortThalD[7,8]

62%



Ali

ve (

%)

20 40 60 80 100 120 1400Mos

1971-1976

1977-1982

1983-1988

1989-1994

1994-2000

2001-2006

OS From Diagnosis

Kumar SK, et al. Blood. 2008;111:2516-2520. This research was originally published in Blood. © American Society of Hematology.

Effect of Novel Agents on Outcome in Newly Diagnosed Myeloma

0

20

40

60

80

100



Improvements in survival for elderly patients expected with longer follow-up of ongoing trials

Period Estimates of 10-Yr Survival by Major Age Groups in Defined Calendar Periods

10-Y

r R

elat

ive

Su

rviv

al (

%)

1984-19861987-1989

1990-1992

1993-1995

1996-1998

1999-2001 2002-2004

0

5

10

15

20

25

3035

4045

50

Calendar Period

< 50

50-59

60-69

70-7980+

Age, yrs

Brenner H, et al. Blood. 2008;111:2521-2526. This research was originally published in Blood. © American Society of Hematology.

Improvements in Survival by Age



Influence of Response After Induction: Superior Outcome When CR Is Achieved Before ASCT

0

0.2

0.4

0.6

0.8

1.0

0Mos

EF

S (

Pro

bab

ility

)

12 24 36 48 84 96

0.1

0.3

0.5

0.7

0.9

60 72

CR (n = 101) nCR (n = 96) PR (n = 346) SD (n = 63) PD (n = 26)

CR vs nCR: P = .1CR vs PR: P = .05nCR vs PR: P = .9

0

0.2

0.4

0.6

0.8

1.0

0Mos

OS

(P

rob

abili

ty)

12 24 36 48 84 96

0.1

0.3

0.5

0.7

0.9

60 72

CR vs nCR: P = .1CR vs PR: P = .07CR vs SD: P = .02nCR vs PR vs SD: P = .9

Lahuerta JJ, et al. J Clin Oncol. 2008;26:5775-5782. Reprinted with permission. © 2008American Society of Clinical Oncology. All rights reserved.



VGPR or CR After First ASCT (P = .70)

Double transplantation (n = 46)

Single transplantation (n = 81)

Attal M, et al. N Engl J Med. 2003;349:2495-2502. Copyright © 2003 Massachusetts Medical Society. All rights reserved.

OS

Mos After First Transplantation

0

25

50

75

100

0 23 46 69 92

< VGPR After First ASCT (P < .001)

Double transplantation (n = 128)

Single transplantation (n = 84)

OS

Mos After First Transplantation

0

25

50

75

100

0 24 48 72 96

Impact of Result of 1st ASCT on the 2nd ASCT

SummarySummary

Bortezomib-based combinations appear to be superior to thalidomide-based combinations

The addition of a third agent to TD or VD appears to improve the pre- and post-ASCT VGPR rate and may translate into a longer PFS

Bortezomib-based combinations appear to be superior to thalidomide-based combinations

The addition of a third agent to TD or VD appears to improve the pre- and post-ASCT VGPR rate and may translate into a longer PFS

ConclusionConclusion

The use of novel agents has changed the treatment paradigm for younger patients without severe comorbidities

The use of novel agents has changed the treatment paradigm for younger patients without severe comorbidities



Need for New First-line Regimens for Patients Ineligible for Transplantation MP combination has been considered standard treatment; however,

results are disappointing

– Response rate: 40% to 60%

– CRs rare

Age a significant risk factor with conventional chemotherapy

Other complications may contribute to poor outcomes

– Eg, renal impairment

Urgent need for more active therapies for elderly patients and patients not eligible for transplantation

– Median RFS: 18 mos

– Median OS: 3 yrs

Brenner H, et al. Blood. 2008;111:2521-2626.Ludwig H, et al. Blood. 2008;111:4039-4047.

Reece DE. Hematology Am Soc Hematol Educ Program. 2005:353-359. National Comprehensive Cancer Network. http://www.nccn.org.


Practical Applications and Clinical Advances in Multiple MyelomaExploring Alternatives to Melphalan/Prednisone in Elderly Myeloma Patients

Novel Combinations as Induction Therapy for Patients Who Are Not Eligible for Transplantation:– Thalidomide-Based

– Lenalidomide-Based

– Bortezomib-Based

Special Considerations: Treatment Choices in Patients With Comorbidities, the Role of Cytogenetic Abnormalities, and Considerations in Very Elderly Patients



MP vs MPTThal/Dex

CTD

MP vs VMPVMP vs VTP

VMP vs VMPTMPR

RD vs Rd

Thalidomide Bortezomib Lenalidomide

MP

Novel Agents as Induction Therapy for Patients NOT Eligible for Transplantation



Thalidomide + Dexamethasone for 4 cycles

< PR

CR/PR/SD

CR/PR

Proceed to SCT, or continue RD/Rd, or no further treatment

RD (n = 223)

Lenalidomide25 mg/day, Days 1-21

Dexamethasone (high dose) 40 mg/day, Days 1-4, 9-12, 17-20

Four 28-day cycles

Rd (n = 222)

Lenalidomide25 mg/day, Days 1-21

Dexamethasone (low dose)40 mg/day, Days 1,8,15, 22 Four 28-day cycles

Newly diagnosed MM

patients(transplant

eligible)

(N = 445)

Phase III ECOG E4A03 Trial: Lenalidomide + High-Dose Dex (RD) vs Low-Dose Dex (Rd)

Rajkumar SV, et al. ASCO 2008. Abstract 8504.



Phase III ECOG Trial: RD vs Rd

After 4 induction cycles:– ≥ VGPR 51% with RD vs 40% with Rd

– ≥ PR 81% with RD vs 70% with Rd

OS: 75% at 3 years – Although initial findings suggested better OS with Rd; – OS at 3 years identical for both treatment arms– (P = .46 log-rank; P = .01 Pepe-Fleming)

Rajkumar SV, et al. 2008 ASH/ASCO. Abstract.



Phase III VISTA Study: VMP vs MP in Untreated MM Pts Ineligible for HDT-ASCT Pts (N = 682): symptomatic MM/end organ damage with measurable disease

– ≥ 65 yrs or < 65 yrs

– Not transplantation eligible

– KPS ≥ 60%

Stratification: β2-microglobulin, albumin, region

VMPCycles 1-4Bortezomib 1.3 mg/m2 IV, Days 1,4,8,11,22,25,29,32Melphalan 9 mg/m2 IV, and prednisone 60 mg/m2 IV, Days 1-4

Cycles 5-9Bortezomib 1.3 mg/m2 IV, Days 1,8,22,29Melphalan 9 mg/m2 IV and prednisone 60 mg/m2 IV, Days 1-4

MPCycles 1-9 Melphalan 9 mg/m2 IV and prednisone 60 mg/m2 IV, Days 1-4

9 x 6-week cycles (54 weeks) in both arms

Primary endpoint: TTP

Secondary endpoints: CR rate, ORR, time to response, DOR, time to next therapy, OS, PFS, QoL (PRO)

San Miguel JF, et al. N Engl J Med. 2008;359:906-917.

RANDOMIZE



San Miguel JF, et al. ASH 2008. Abstract 650.

ORR: VMP 71%, MP 35% CR: VMP 30%, MP 4%

0 3 6 9 12

Mos

15 18 21 24 270

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100 VMPMP

Pat

ien

ts W

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t (%

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Mos

0 4 8 12 16 20 24 28 32 36 40

VMPMP

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)

TTP OS~ 52% reduced risk of progression on VMP ~ 36% reduced risk of death on VMP

Median follow-up: 25.9 mos3-year OS:VMP: 72%MP: 59%P = .0032

VMP: 24.0 mosMP: 16.6 mosP < .000001

San Miguel JF, et al. ASH 2008. Abstract 650.San Miguel JF, et al. N Engl J Med. 2008;359:906-917. Copyright © 2008

Massachusetts Medical Society. All rights reserved.

VMP vs MP in Untreated Myeloma: Efficacy Data

43% of MP patients received bortezomib upon progression OS with > 4 cycles bortezomib: 98.5% at 1 yr, 89% at 2 yrs Treatment-related death: 2% in both arms

0

20

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100



1.Consolidate data............................. TMP, VMP

2.Antecedent or risk of DVT............... VMP

3.Antecedent of PN............................ LMP/Rd

4.Renal insufficiency.......................... Bort-based combination

5.Distance from hospital.................... LMP or MPT

6.Poor patient accomplishment......... VMP

7.Costs............................................... MPT

Preferences for 1 MP Combination?

ConclusionsConclusions

•New Agents are transforming the life expectancy in the young with MM but also in the elderly.

•Better and more effective pain control, better and longer quality of life

•New drugs and combination may bring “cure” to MM in my life time.

•New Agents are transforming the life expectancy in the young with MM but also in the elderly.

•Better and more effective pain control, better and longer quality of life

•New drugs and combination may bring “cure” to MM in my life time.

Documents

Plasma Cell Diseases MGUS, Smoldering Myeloma, Multiple Myeloma