1. MGUS, Smoldering Myeloma, Multiple Myeloma
Plasma Cell Diseases
MGUS, Smoldering Myeloma, Multiple Myeloma

2. 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.

3. Plasma Cells

4. 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
Once in the Bone Marrow

5. Bone Marrow Specimen from a Patient with MGUS
Figure 1. Bone Marrow Specimen from a Patient with MGUS (May-Grunwald-Giemsa Staining). The arrows indicate plasma cells.
Blade J. N Engl J Med 2006;355:

6. abnormal SPEP
Consequently, clonal plasma cells expand, accompanied by secretion of a monoclonal immunoglobulin

7. Characteristics of Active MM and Its Precursors
Figure 4. Characteristics of Active Multiple Myeloma and Its Precursors. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma are asymptomatic precursors of active multiple myeloma. Serum protein electrophoresis in each of these disorders shows a prominent monoclonal protein in the {gamma} region that can be easily identified as a dense band or spike. Other clinical features that can be used to distinguish these disorders are also shown. End-organ damage is defined as hypercalcemia, anemia, renal failure, or lytic bone lesions attributable to a plasma-cell disorder. Alb denotes albumin.
Kyle R et al. N Engl J Med 2007;356:

8. 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.

9. Disease Progression, clonal evolution

10. MGUS
(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)

11. Recommended Testing in Patients with Suspected MGUS
Table 2. Recommended Testing in Patients with Suspected MGUS.
Blade J. N Engl J Med 2006;355:

12. IgG
IgA
IgM
Free Light Chains
24 hr Urine Collection for UPEP

13. Characteristics of Active MM and Its Precursors
Figure 4. Characteristics of Active Multiple Myeloma and Its Precursors. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma are asymptomatic precursors of active multiple myeloma. Serum protein electrophoresis in each of these disorders shows a prominent monoclonal protein in the {gamma} region that can be easily identified as a dense band or spike. Other clinical features that can be used to distinguish these disorders are also shown. End-organ damage is defined as hypercalcemia, anemia, renal failure, or lytic bone lesions attributable to a plasma-cell disorder. Alb denotes albumin.
Kyle R et al. N Engl J Med 2007;356:

14. 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

15. 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

16. Prognosis 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

17. Characteristics of Active MM and Its Precursors
Figure 4. Characteristics of Active Multiple Myeloma and Its Precursors. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma are asymptomatic precursors of active multiple myeloma. Serum protein electrophoresis in each of these disorders shows a prominent monoclonal protein in the {gamma} region that can be easily identified as a dense band or spike. Other clinical features that can be used to distinguish these disorders are also shown. End-organ damage is defined as hypercalcemia, anemia, renal failure, or lytic bone lesions attributable to a plasma-cell disorder. Alb denotes albumin.
Kyle R et al. N Engl J Med 2007;356:

18. Kyle R et al. N Engl J Med 2007;356:2582-2590
Probability of Progression to Active MM or Primary Amyloidosis in Patients with Smoldering MM or MGUS
Figure 2. Probability of Progression to Active Multiple Myeloma or Primary Amyloidosis in Patients with Smoldering Multiple Myeloma or Monoclonal Gammopathy of Undetermined Significance (MGUS). I bars denote 95% confidence intervals.
Kyle R et al. N Engl J Med 2007;356:

19. Disorders 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

20. Non-Hodgkin's lymphoma CLL
B-cell lymphoproliferative disorders
Non-Hodgkin's lymphoma
CLL
Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia) IgM
Post-transplant monoclonal gammopathies
Heavy chain diseases
Connective tissue disorders SLE, RA
Associated with infections: HIV Hep C
Dermatologic Disorders

21. Miscellaneous 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

22. A 76-year-old woman was admitted with an exacerbation of chronic obstructive pulmonary disease
A 76-year-old woman was admitted with an exacerbation of chronic obstructive pulmonary disease. Her condition improved with bronchodilators, prednisolone, an antibiotic, oxygen, and supportive measures. Two years previously, she had presented with vertebral compression fractures, Bence Jones proteinuria, and IgG paraproteinemia. The diagnosis of multiple myeloma had been confirmed by examination of the bone marrow, which showed 36 percent atypical plasma cells. The patient had tolerated chemotherapy poorly and was treated only with opiates and sodium clodronate. Three days after the present admission, pain and swelling developed in her right arm without previous trauma. Radiographs of the arm showed a displaced fracture of the right humerus and multiple lytic lesions (Panels A and B), which are typical of myeloma. The serum calcium level was normal, but the alkaline phosphatase level was raised, at 390 U per liter (normal range, ). The patient underwent intramedullary pinning of the fracture. She died on the fifth postoperative day after cardiac arrest.
Nair S and Pearson S. N Engl J Med 2004;351:1874

23. Multiple myeloma (MM)
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

24. 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

25. Diagnostic Criteria for MGUS, Multiple Myeloma, and Other Conditions
Table 1. Diagnostic Criteria for MGUS, Multiple Myeloma, and Other Conditions.
Blade J. N Engl J Med 2006;355:

26. 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.

27. Bone Marrow Specimen from a Patient with MGUS (May-Grunwald-Giemsa Staining)
Figure 1. Bone Marrow Specimen from a Patient with MGUS (May-Grunwald-Giemsa Staining). The arrows indicate plasma cells.
Blade J. N Engl J Med 2006;355:

28. Multiple Myeloma Marrow

31. 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       
Adapted from Br J Haematol 2003;121:749 and Rajkumar, SV et al. Leukemia 2001;15:1274.

32. Durie-Salmon staging system
Stage I (Low cell mass - <0.6 x 10(12) cells/m2)
All of the following present:
Hgb >10 g/dL
Serum IgG <5 g/dL
Serum IgA <3 g/dL
Normal serum calcium
Urine monoclonal protein excretion <4 g/day
No generalized lytic bone lesions
Stage II
Intermediate 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/dL
Serum IgG >7 g/dL
Serum IgA > 5 g/dL
Serum calcium >12 mg/dL (3 mmol/L)
Urine monoclonal protein excretion >12 g/day
Advanced lytic bone lesions
A: Serum creatinine <2 mg/dL
B: Serum creatinine >2 mg/dL

33. 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

34. Prognosis by ISS Median Overall Survival Median Overall Survival
Stage Criteria          Median Overall Survival
I Serum Beta 2-microglobulin < 3.5 mg/L months
AND Serum albumin > 3.5 g/dL
II Neither stage I or stage III         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                               months
II  50 months                               months
III 33 months                                       months
Median Overall Survival     Median Overall Survival
High-Dose Chemotherapy            Conventional-Dose
Stage                        Chemotherapy
I   111 months                                      55 months
II   66 months                             months
III 45 months                            months

35. Risk Group Cytogenetics
Prognosis by
Poor                                                 Median Overall Survival
t(4;14)                                      24.7 months
t(14;16)
–17p13
Intermediate
–13q14                                 42.3 months
Good
All others and                     months
Hyperodiploidy
t(11;14), t(6;14)

36. Treatment Plan Induction of Remission Maintenance Therapy
Infectious Disease Prophylaxis
Bone Disease: Fractures and Osteoporosis

37. Changing Treatment Paradigm
OLD DRUGS
Melphalan Prednisone
Vincristine Doxoribicine Dexamethasone (VAD)
Dexamethasone
NEW DRUGS
Thalidomide
Bortezomib
Lenalidomide
iv Melphalan

38. An Approach to the Treatment of Newly Diagnosed Multiple Myeloma
Figure 2. An Approach to the Treatment of Newly Diagnosed Multiple Myeloma. Induction therapy for patients eligible for transplantation is administered in four cycles before stem cells are harvested. The term "plateau" indicates a minimum of 12 months of therapy and the achievement of stable disease for at least 2 months. Asterisks denote investigational therapies.

39. 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.

40. Mechanism of Action of Bortezomib
Proteins 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
Mechanism of Action of Bortezomib
Mechanism of Action of Bortezomib. Proteins 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.
Mitchell B. N Engl J Med 2003;348:

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

42. 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

43. 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

44. Lenalidomide
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

45. 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.
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 {alpha} (TNF-{alpha}) 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-{gamma} (INF-{gamma}), 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.
List A. N Engl J Med 2007;357:

46. Myeloma cells and the Microenviroment

47. Summary of Novel Agent Induction Trials (Randomized Studies)
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Summary of Novel Agent Induction Trials (Randomized Studies)
≥ VGPR Rates Postinduction and Posttransplantation
76%
Postinduction
Posttransplantation
57%
59%
PAD, bortezomib/doxorubicin/dexamethasone; RD, lenalidomide plus high-dose dexamethasone; Rd, lenalidomide plus low-dose dexamethasone; TAD, thalidomide/doxorubicin/dexamethasone; VAD, vincristine/doxorubicin/dexamethasone; VD, bortezomib/dexamethasone; VGPR, very good partial response; VTD, bortezomib/thalidomide/dexamethasone.
Results with new induction therapies, including 1 or 2 novel agents, are shown on this slide. As discussed, bortezomib/dexamethasone is significantly superior to vincristine/doxorubicin/dexamethasone. Results are not available yet for lenalidomide/dexamethasone after ASCT, but the 3-drug combinations, especially bortezomib/thalidomide and dexamethasone, yield impressive VGPR rates.
49%
44% to 50% * *
15% to 16%
39%
42%
24%
33%
42%
62%
VincAD[1]
BortD[1]
RD[2,3]
Rd[2,3]
TAD[4]
PAD[5,6]
BortThalD[7,8]
*Posttransplantation data not available.
1. Harousseau et al. ASH/ASCO symposium during ASH Rajkumar SV, et al. ASCO Abstract Rajkumar SV. ASH/ASCO symposium during ASH Lokhorst HM, et al. Haematologica. 2008;93: Sonneveld P, et al. ASH Abstract Sonneveld P, et al. IMW Abstract Cavo M, et al. ASH Abstract Cavo M, et al. IMW Abstract 451.

48. Effect of Novel Agents on Outcome in Newly Diagnosed Myeloma
Practical Applications and Clinical Advances in Multiple Myeloma
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Effect of Novel Agents on Outcome in Newly Diagnosed Myeloma
100
OS From Diagnosis 80
OS, overall survival.
The data displayed on this slide correspond to outcomes among myeloma patients from a study conducted by Kumar and colleagues at the Mayo Clinic. As shown in the slide, survival remained stable for more than 30 years, but by the end of the 1990s, a clear improvement in overall survival was observed that was mainly attributed to the efficacy of autologous stem cell transplantation. The major improvement in outcomes has occurred since 2000 and is clearly attributed to the availability of novel agents at the time of relapse. 60
Alive (%) 40 20 20 40 60 80
100
120
140
Mos
Kumar SK, et al. Blood. 2008;111: This research was originally published in Blood. © American Society of Hematology.

49. Improvements in Survival by Age
Practical Applications and Clinical Advances in Multiple Myeloma
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Improvements in Survival by Age
Period Estimates of 10-Yr Survival by Major Age Groups in Defined Calendar Periods 50
Age, yrs 45
< 50 40
However, if when analyzing the survival improvement by age, we observe that the major benefit occurred in young patients, whereas only a marginal change occurred in patients older than 60 years, and almost no improvement in those older than 70 years. Therefore, the use of novel agents has resulted in little benefit among the elderly population; therefore, further effort from the myeloma community is needed to improve outcomes among these patients. 35 30
50-59
10-Yr Relative Survival (%) 25 20
60-69 15 10
70-79
80+ 5
Calendar Period
Improvements in survival for elderly patients expected with longer follow-up of ongoing trials
Brenner H, et al. Blood. 2008;111:
This research was originally published in Blood. © American Society of Hematology.

50. Practical Applications and Clinical Advances in Multiple Myeloma
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Influence of Response After Induction: Superior Outcome When CR Is Achieved Before ASCT
CR vs nCR: P = .1
CR vs PR: P = .05
nCR vs PR: P = .9
CR vs nCR: P = .1
CR vs PR: P = .07
CR vs SD: P = .02
nCR vs PR vs SD: P = .9
1.0
1.0
0.9
0.9
0.8
0.8
ASCT, autologous stem cell transplantation; CR, complete remission; EFS, event-free survival; nCR, near complete remission; OS, overall survival; PD, progressive disease; PR, partial response; SD, stable disease.
It may be possible to further increase the level of CR by continuing treatment after CR is achieved. This study showed that it is important to achieve a CR at different stages of the treatment. The left graph shows that patients achieving a CR before ASCT in this study had a better outcome than patients achieving CR only after ASCT.
0.7
0.7
0.6
0.6
EFS (Probability)
0.5
OS (Probability)
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1 12 24 36 48 60 72 84 96 12 24 36 48 60 72 84 96
Mos
Mos
CR (n = 101)
nCR (n = 96)
PR (n = 346)
SD (n = 63)
PD (n = 26)
Lahuerta JJ, et al. J Clin Oncol. 2008;26: Reprinted with permission. © American Society of Clinical Oncology. All rights reserved.

51. Impact of Result of 1st ASCT on the 2nd ASCT
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Impact of Result of 1st ASCT on the 2nd ASCT
VGPR or CR After First ASCT (P = .70)
< VGPR After First ASCT (P < .001)
100
100
Double transplantation
(n = 46)
ASCT, autologous stem cell transplantation; CR, complete remission; VGPR, very good partial response. 
Another possibility is to offer a second course of intensive treatment followed by ASCT. This is the current strategy in the Arkansas group, which offers a second transplantation regardless of the results of the first transplantation. However, in Europe and especially after the results of the French IFM 94 trial and a similar study by Cavo and colleagues from Italy, we currently do not offer a second transplantation to patients who achieve a CR or VGPR after the first transplantation. Our choice is based on the results shown on this slide.
In this study, no significant benefit was seen in favor of a second transplantation in patients who achieved CR or VGPR after the first transplantation (left graph); however, in patients achieving less than a VGPR, the second transplantation did improve outcomes compared with single transplantation.
Double transplantation
(n = 128) 75 75 OS 50 OS 50
Single transplantation
(n = 81)
Single transplantation
(n = 84) 25 25 23 46 69 92 24 48 72 96
Mos After First Transplantation
Mos After First Transplantation
Attal M, et al. N Engl J Med. 2003;349:
Copyright © 2003 Massachusetts Medical Society. All rights reserved.

52. Summary
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
ASCT, autologous stem cell transplantation; PAD, bortezomib/doxorubicin/dexamethasone; PFS, progression-free survival; TAD, thalidomide/doxorubicin/dexamethasone; TD, thalidomide/dexamethasone; VD, bortezomib/dexamethasone; VGPR, very good partial response.
In summary, bortezomib-based combinations appeared to be superior to thalidomide-based combinations; bortezomib/dexamethasone is superior to thalidomide/dexamethasone; and bortezomib/doxorubicin/dexamethasone appeared to be slightly superior to thalidomide/doxorubicin/dexamethasone, although no randomized trial has compared these different induction treatments.
The addition of a third agent to either thalidomide/dexamethasone or bortezomib/dexamethasone appears to improve the pre- ASCT and post-ASCT CR plus VGPR rate. Preliminary results with bortezomib/dexamethasone induction show that a higher initial tumor burden reduction may translate into a longer progression-free survival, and there is a preliminary indication that bortezomib might overcome poor prognosis related to poor-risk cytogenetic abnormalities.

53. Conclusion
The use of novel agents has changed the treatment paradigm for younger patients without severe comorbidities
ASCT, autologous stem cell transplantation; CR, complete remission; VGPR, very good partial response.
In conclusion, the treatment paradigm for multiple myeloma is evolving. Until now, ASCT has been considered the standard of care for frontline therapy in younger patients without severe comorbidities. However, we now know that it is possible to achieve high response rates, including CR or CR plus VGPR, with nonintensive treatment using novel agents in combination with chemotherapy or dexamethasone. Clearly, a randomized comparison of the intensive approach plus novel agents vs the nonintensive approach with novel agents is needed.
In addition, the results of ASCT that were achieved in the 1990s have been improved and it is now possible to increase the number of patients with CR or with CR plus VGPR. This might translate into a longer progression-free survival. It is even possible to improve the level of CR and to achieve at least immunophenotypic or even molecular remission by adding novel agents to ASCT.
Many questions remain regarding the optimal regimen of intensive treatment. We need more follow-up to determine the best induction treatment and more studies to determine the best consolidation or maintenance post- ASCT.

54. Practical Applications and Clinical Advances in Multiple Myeloma
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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
Median RFS: 18 mos
Median OS: 3 yrs
CRs, complete responses; OS, overall survival; RFS, relapse- free survival.
MP has been considered the standard of care for transplantation-ineligible patients, but the response rate is low, with complete responses only at a maximum of 5%. Relapse‑free survival ranges from months, and overall survival ranges from 2-4 years. These poor results indicate an urgent need for more active therapies for the elderly population and for younger patients who are not eligible for transplantation.
Urgent need for more active therapies for elderly patients and
patients not eligible for transplantation
Brenner H, et al. Blood. 2008;111:
Ludwig H, et al. Blood. 2008;111:
Reece DE. Hematology Am Soc Hematol Educ Program. 2005:
National Comprehensive Cancer Network.

55. Practical Applications and Clinical Advances in Multiple Myeloma
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Exploring 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
MM, multiple myeloma; MP, melphalan/prednisone.
This presentation focuses on the treatment of newly diagnosed myeloma patients who are not candidates for autologous transplantation. We first address the question of whether a better treatment approach than conventional melphalan/prednisone (MP) is available for elderly myeloma patients. We analyze novel combinations as induction therapy for this cohort of patients, specifically regimens that contain thalidomide, lenalidomide, or bortezomib, with a focus on the efficacy and toxicity of these novel approaches. The talk concludes with a discussion on special considerations, including treatment preferences according to comorbidities, the role of cytogenetics, and treatment approaches for the very old population (older than 75-80  years).

56. Practical Applications and Clinical Advances in Multiple Myeloma
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Novel Agents as Induction Therapy for Patients NOT Eligible for Transplantation MP
CTD, cyclophosphamide/ thalidomide/dexamethasone; MP, melphalan/prednisone; MPT, melphalan/prednisone/thalidomide; MPR, melphalan/prednisone/lenalidomide; RD, lenalidomide/high- dose dexamethasone; Rd, lenalidomide/low-dose dexamethasone; VMP, bortezomib/melphalan/prednisone; VMPT, bortezomib/melphalan/prednisone/thalidomide; VTP, bortezomib/thalidomide/prednisone.
Novel therapies used as induction treatment can be based on thalidomide, bortezomib, or lenalidomide. We first discuss a thalidomide combination—more specifically, the MP plus thalidomide, or MPT, regimen.
Thalidomide
Bortezomib
Lenalidomide
MP vs MPT
Thal/Dex
CTD
MP vs VMP
VMP vs VTP
VMP vs VMPT
MPR
RD vs Rd

57. Practical Applications and Clinical Advances in Multiple Myeloma
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Phase III ECOG E4A03 Trial: Lenalidomide + High-Dose Dex (RD) vs Low-Dose Dex (Rd)
RD (n = 223)
Lenalidomide 25 mg/day, Days 1-21
Dexamethasone (high dose) 40 mg/day, Days 1-4, 9-12, 17-20
Four 28-day cycles
Proceed to SCT, or continue RD/Rd, or no further treatment
CR, complete response; Dex, dexamethasone; MM, multiple myeloma; PR, partial response; SCT, stem cell transplantation; SD, stable disease.
The ECOG E4A03 trial compared lenalidomide plus high‑dose dexamethasone, or RD, vs lenalidomide plus low‑dose dexamethasone, or Rd. Lenalidomide was given at a dose of 25 mg/day on Days 1-21 in both treatment arms. High-dose dexamethasone was given at the conventional dose of 40 mg/day on Days 1-4, 9-12, 17-20; whereas low-dose dexamethasone was given as 40 mg/day on Days 1, 8, 15, and 22. In other words, patients in the low-dose dexamethasone arm received 3 times less dexamethasone. After 4 cycles, patients were allowed to proceed to autologous stem cell transplantation, to continue treatment with lenalidomide/dexamethasone, or to stop treatment. Patients with less than partial response could switch to thalidomide/dexamethasone.
CR/PR
Newly diagnosed MM patients
(transplant eligible)
(N = 445)
CR/PR/SD
Rd (n = 222)
Lenalidomide 25 mg/day, Days 1-21
Dexamethasone (low dose) 40 mg/day, Days 1,8,15, 22
Four 28-day cycles
Thalidomide + Dexamethasone for 4 cycles
< PR
Rajkumar SV, et al. ASCO Abstract 8504.

58. Phase III ECOG Trial: RD vs Rd
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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)
OS, overall survival; PFS, progression-free survival; PR, partial response; RD, lenalidomide/high-dose dexamethasone; Rd, lenalidomide/low-dose dexamethasone; VGPR, very good partial response.
In the correct answer, the response rate after 4 induction cycles shows that most patients responded. A partial response or higher was reported in 81% and 70% of patients in the high- dose and low-dose arms, respectively. Half of the patients in the high-dose arm achieved a very good partial response or better, although the complete response rate after 4 cycles was relatively low. The progression-free survival rate in this trial was 24-26 months, and data updated at the 2008 American Society of Hematology meeting indicated that 3‑year overall survival is identical, 75% at 3 years, in the low- and high‑dose dexamethasone treatment groups. Although initial findings showed that survival was better for patients treated with low‑dose dexamethasone, the curves appear to merge after 3 years.
Rajkumar SV, et al ASH/ASCO. Abstract.

59. 9 x 6-week cycles (54 weeks) in both arms
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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
ASCT, autologous stem cell transplantation; DOR, duration of response; HDT, high-dose therapy; KPS, Karnofsky performance score; MP, melphalan/prednisone; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PRO, patient-reported outcome; QoL, quality of life; VMP, bortezomib/melphalan/prednisone.
Bortezomib is the third novel agent for use in newly diagnosed myeloma patients who are ineligible for transplantation. The VISTA trial was a large, randomized trial that included 682 symptomatic myeloma patients and compared bortezomib in combination with MP (VMP) vs MP. The control arm consisted of 9 cycles of the standard MP, whereas the experimental arm consisted of the same MP scheme plus the conventional dose of bortezomib 1.3 mg twice weekly for the first 4 cycles. However, the patients subsequently moved to the weekly dose of bortezomib. In cycles 5-9, patients received weekly bortezomib, 2 weeks on and 2 weeks off. R A N D O M I Z E
VMP
Cycles 1-4
Bortezomib 1.3 mg/m2 IV, Days 1,4,8,11,22,25,29,32
Melphalan 9 mg/m2 IV, and prednisone 60 mg/m2 IV, Days 1-4
Cycles 5-9
Bortezomib 1.3 mg/m2 IV, Days 1,8,22,29
Melphalan 9 mg/m2 IV and prednisone 60 mg/m2 IV, Days 1-4
Primary endpoint: TTP
Secondary endpoints: CR rate, ORR, time to response, DOR, time to next therapy, OS, PFS, QoL (PRO)
9 x 6-week cycles (54 weeks) in both arms MP
Cycles 1-9
Melphalan 9 mg/m2 IV and prednisone 60 mg/m2 IV, Days 1-4
San Miguel JF, et al. N Engl J Med. 2008;359:

60. VMP vs MP in Untreated Myeloma: Efficacy Data
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ORR: VMP 71%, MP 35% CR: VMP 30%, MP 4%
TTP OS
~ 52% reduced risk of progression on VMP
~ 36% reduced risk of death on VMP
100
100
VMP MP
VMP MP
CR, complete response; MP, melphalan/prednisone; ORR; overall response rate; OS, overall survival; VMP, bortezomib/melphalan/prednisone.
The trial was stopped in September 2007, based on the recommendation of an independent data-monitoring committee, because of the superiority of VMP in all endpoints. The overall response rate was double for VMP compared with MP, including 30% complete responses by EBMT  criteria. On the primary endpoint, a 52% reduction in time to progression was observed in patients treated with VMP, with a median of 24. vs 16 months with MP. Updated data with a longer follow‑up of 26 months show that the benefit in terms of overall survival continued to be statistically significantly in favor of the VMP arm, with a 36% reduction in risk of death and a 3‑year overall survival of 72%, vs 59% for the MP arm. This benefit was observed despite the fact that 43% of MP patients received bortezomib on progression. Moreover, for patients who received more than 4 cycles of bortezomib, the 2-year overall survival was 89%, and the rate of treatment‑related deaths was only 2%. 80 80 60 60
Patients Without Event (%)
Patients Without Event (%)
Median follow-up: 25.9 mos
3-year OS:
VMP: 72%
MP: 59%
P = .0032 40 40
VMP: 24.0 mos
MP: 16.6 mos P < 20 20 3 6 9 12 15 18 21 24 27 4 8 12 16 20 24 28 32 36 40
Mos
Mos
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
San Miguel JF, et al. ASH Abstract 650.
San Miguel JF, et al. N Engl J Med. 2008;359: Copyright © 2008 Massachusetts Medical Society. All rights reserved.
San Miguel JF, et al. ASH Abstract 650.

61. Preferences for 1 MP Combination?
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Preferences for 1 MP Combination?
Consolidate data TMP, VMP
Antecedent or risk of DVT VMP
Antecedent of PN LMP/Rd
Renal insufficiency Bort-based combination
Distance from hospital LMP or MPT
Poor patient accomplishment VMP
Costs MPT
LMP, lenalidomide/melphalan/prednisone; MP, melphalan/prednisone; Rd, lenalidomide/low-dose dexamethasone; MPT, melphalan/prednisone/thalidomide; MP, bortezomib/melphalan/prednisone
Dr. San Miguel’s preferences for MP combinations are summarized on the slide. The most consolidated data correspond to MPT and MPV combinations. Lenalidomide/dexamethasone and MPR may also soon show consolidated data regarding the efficacy and superiority of these regimens over the conventional MP schemes. With an antecedent or risk of deep-vein thrombosis, it is safe to use VMP. By contrast, with an antecedent of peripheral neuropathy, the best choice would be lenalidomide with either dexamethasone or MP. With renal insufficiency, we have already seen that bortezomib‑based regimens can overcome the impaired renal function, so this could be the first choice. If the patient lives far from the hospital, oral regimens are preferable, but if the patient will be unable to adhere to the treatment schedule, intravenous therapy is preferred. Finally, if cost is an issue, at least in European countries, the MPT regimen tends to cost less.

62. Conclusions
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.