1. tumore delle plasmacellule
MIELOMA MULTIPLO
tumore delle plasmacellule
producono immunoglobuline
vivono nelle ossa
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

2. Multiple myeloma
uncontrolled proliferation of Ig secreting plasma cells
most commonly IgG (57%), IgA (21%) or light chain only (18%)
twice as common in men as women
and in blacks as whites
1% of all cancers
2% in african americans
incurable
median survival 3 years
few therapeutic advances since the introduction of melphalan (Bergsagel, 1962)

3. Myeloma bone pathology

4. Multiple Myeloma (MM)
B-cell neoplasia, characterized by the expansion of plasma cells producing an abnormal monoclonal immunoglobulin
21,500 new cases yearly in Europe
Median age at diagnosis: 65 years
incurable disease

5. MM – Impact for Patients
Consequences of MM include:
Painful osteolytic bone lesions
Bone marrow infiltration, causing anemia, fatigue, and immunodeficiency, with an increased risk of serious infections
The abnormal proteins may cause renal dysfunction or kidney failure

6. Bruno B, Rotta M, and Boccadoro M, Lancet Oncology 2004

7. IL-6 CRP IL-1 MIELOMA MULTIPLO hepatocyte OAF OSTEOCLAST
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA S. GIOVANNI BATTISTA TORINO, ITALY

8. 350 pazienti/anno in Piemonte
MIELOMA MULTIPLO
malattia dell'anziano
5/ /pazienti/anno
350 pazienti/anno in Piemonte
età media alla diagnosi 70 anni
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

9. Serum protein electrophoresis (SPEP)
Elevated total protein suggests hypergammaglobulinemia
Total protein= Albumin + Globulins
albumin    

10. Serum protein electrophoresis (SPEP)
Elevated total protein suggests hypergammaglobulinemia
Total protein= Albumin + Globulins
Quantitative immunoglobulins
measures amount of IgM, IgG and IgA
in myeloma, typically see “reciprocal depression” of uninvolved Igs
albumin    

11. Serum protein electrophoresis (SPEP)
Immunoeletrophoresis  
albumin     

12. Serum protein electrophoresis (SPEP)
Immunoeletrophoresis
Immunofixation SP    
albumin        

13. Serum protein electrophoresis (SPEP)
IgG 57%
IgA 21%
IgD 1%
IgM or IgE almost never
Light chain only 18%
Immunofixation SP     

14. Serum protein electrophoresis (SPEP)
IgG 57%
IgA 21%
IgD 1%
IgM or IgE almost never
Light chain only 18%
Immunofixation SP 
M-spike stands for Monoclonal, not IgM    

15. Serum protein electrophoresis (SPEP)
IgG 57%
IgA 21%
IgD 1%
IgM or IgE almost never
Light chain only 18%
Immunofixation SP 
M-spike stands for Monoclonal, not IgM  
IgM, IgG and IgA are all gamma-globulins  

16. Serum protein electrophoresis (SPEP)
IgG 57%
IgA 21%
IgD 1%
IgM or IgE almost never
Light chain only 18%
Immunofixation SP 
M-spike stands for Monoclonal, not IgM  
IgM, IgG and IgA are all gamma-globulins  
Light chains (Bence-Jones proteins) are not detected in the serum, because of their low molecular weight, they are secreted in the urine

17. Table 1 Multiple myeloma* Diagnostic criteria
1 Monoclonal plasma cells in the bone marrow 10% and/or
presence of a biopsy-proven plasmacytoma
2 Monoclonal protein present in the serum and/or urinea
3 Myeloma-related organ dysfunction (1 or more)
[C] Calcium elevation in the blood (serum calcium >10.5 mg/l or
upper limit of normal)
[R] Renal insufficiency (serum creatinine >2mg/dl)
[A] Anemia (hemoglobin o10 g/dl or 2 gonormal)
[B] Lytic bone lesions or osteoporosisc

18. Myeloma - clinical features
bone pain - often with loss of height
constitutional - weakness, fatigue and weight loss
anemia - responds to erythropoeitin
renal disease -renal tubular dysfunction
susceptibility to infections - neutropenia, hypogammaglobulinemia)
hypercalcemia - myeloma cells secrete osteoclast activating factors
hyperviscosity - 2 % with myeloma, 50 % with macroglobulinemia
neurologic dysfunction - spinal cord or nerve root compression

19. Myeloma staging system
Median
Survival
(months) 12 2
cells x 10 /m
Stage I No anemia >60 <0.6
No hypercalcemia
no more than one bony lesion
low M protein
Stage II in between I and III
Stage III Anemia >1.2
hypercalcemia
advanced lytic bone disease
high M protein

20. Principles of treatment
no evidence that early treatment prolongs survival
wait for symptoms, or evidence of disease progression to start treatment
supportive measures are critically important
drink 3l of fluids daily
treat infections promptly
prophylactic bisphosphonates reduce skeletal cmplications
anemia responds to erythropoeitin

21. Causes of death in multiple myeloma
Progressive myeloma 45%
Sepsis 25%
Renal failure 10%
Other (old age) 20%

22. Treatment course
Asymptomatic
MGUS
Stable MM
Years
Months
Days

23. Treatment course Asymptomatic Symptomatic MGUS Stable MM M protein
Treatments
Years
Months
Days

24. Treatment course Asymptomatic Symptomatic Acute MGUS Stable MM
Pancytopenia
Plasma cell leukemia
M protein
Treatments
Years
Months
Days

25. trattato con blande chemioterapie
MIELOMA MULTIPLO
trattato con blande chemioterapie
parzialmente chemiosensibile
il tumore si riduce ma dopo breve intervallo riprende a crescere
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

26. Melphalan e Prednisone (MP)
MIELOMA MULTIPLO
chemioterapia
Melphalan e Prednisone (MP)
(Alexanian, 1969)
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27. MIELOMA MULTIPLO sopravvivenza 100 50 36 mesi
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

28. Melphalan dose-response curve
MULTIPLE MYELOMA
Melphalan dose-response curve
RESPONSE
DOSE
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

29. relazione dose-risposta
MIELOMA MULTIPLO
relazione dose-risposta
ALTA-DOSE =
+ risposte complete
+ lunga sopravvivenza
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

30. CELLULE STAMINALI PERIFERICHE
FATTORI DI CRESCITA
CELLULE STAMINALI PERIFERICHE
RIDUZIONE DELLA TOSSICITA' DELLE TERAPIE AD ALTE DOSI
tossicità comparabile alla terapia convenzionale
possibilità di trattare pazienti anziani
alte percentuali di risposte complete

31. A PROSPECTIVE, RANDOMIZED TRIAL OF AUTOLOGOUS BONE MARROW TRANSPLANTATION AND CHEMOTHERAPY IN MULTIPLE MYELOMA
Sopravvivenza a 5 anni
52% trapianto
12% convenzionale
Attal, et al., NEJM, 1996

32. EFS TOT % of patients MEL100 p<0.001 MP Months
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33. OS TOT MEL100 % of patients MP p<0.005 Months
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

34. MULTIPLE MYELOMA AGE AT DIAGNOSIS 55 60 65 70 AGE
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

35. MULTIPLE MYELOMA AGE AT DIAGNOSIS HIGH-DOSE CONVENTIONAL 55 60 65 70
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

36. MALATTIA INCURABILE survival % years 100
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37. Multiple myeloma Unmet Medical Need Relapsed Disease
Diagnosis
Survival 3-5 yrs
Relapsed Disease
Transient Response to Therapy
Survival 1-3 years
Relapsed and Refractory
Resistant to all therapy
Universally fatal
Survival 6-9 months
Unmet
Medical Need
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

38. Bruno B, Rotta M, and Boccadoro M, Lancet Oncology 2004
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

39. Advancing Treatment Options in MM
1962 Prednisone + melphalan
1999 First report thalidomide
Thalidomide Pharmion licence Aus/NZ 2003
Melphalan
From 1990s
Myeloablation + ASCT
VELCADE® US licence 2003
VELCADE® EU positive opinion 2004
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

40. MULTIPLE MYELOMA scenario NEW DRUGS +
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

41. Thalidomide
Originally developed in 1950s as a treatment for insomnia and morning sickness in pregnancy
Thalidomide is an immunomodulatory agent
Precise mechanism of action not yet understood
Multiple actions, including anti-angiogenic effects
Anti-angiogenic effects of thalidomide provide the rationale for its use in MM
Angiogenesis in bone marrow supports growth and development of MM cells
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

42. Antitumor activity of thalidomide
in refractory multiple myeloma Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P,
Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B. N Engl J Med 1999 Nov 18;341(21):
Myeloma and Lymphoma Program, South Carolina Cancer Center, University of South Carolina, Columbia, USA BACKGROUND: Patients with myeloma who relapse after high-dose chemotherapy have few therapeutic options. Since increased bone marrow vascularity imparts a poor prognosis in myeloma, we evaluated the efficacy of thalidomide, which has antiangiogenic properties, in patients with refractory disease. METHODS: Eighty-four previously treated patients with refractory myeloma (76 with a relapse after high-dose chemotherapy) received oral thalidomide as a single agent for a median of 80 days (range, 2 to 465). The starting dose was 200 mg daily, and the dose was increased by mg every two weeks until it reached 800 mg per day. Response was assessed on the basis of a reduction of the myeloma protein in serum or Bence Jones protein in urine that lasted for at least six weeks. RESULTS: The serum or urine levels of paraprotein were reduced by at least 90 percent in eight patients (two had a complete remission), at least 75 percent in six patients, at least 50 percent in seven patients, and at least 25 percent in six patients, for a total rate of response of 32 percent. Reductions in the paraprotein levels were apparent within two months in 78 percent of the patients with a response and were associated with decreased numbers of plasma cells in bone marrow and increased hemoglobin levels. The microvascular density of bone marrow did not change significantly in patients with a response. At least one third of the patients had mild or moderate constipation, weakness or fatigue, or somnolence. More severe adverse effects were infrequent (occurring in less than 10 percent of patients), and hematologic effects were rare. As of the most recent follow-up, 36 patients had died (30 with no response and 6 with a response). After 12 months of follow-up, Kaplan-Meier estimates of the mean (+/-SE) rates of event-free survival and overall survival for all patients were 22+/-5 percent and 58+/-5 percent, respectively. CONCLUSIONS: Thalidomide is active against advanced myeloma. It can induce marked and durable responses in some patients with multiple myeloma, including those who relapse after high-dose chemotherapy

44. Bruno B, Rotta M, and Boccadoro M, Lancet Oncology 2004, in Press
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

45. ~ Thalidomide: mechanism of action ??
“Thal metabolism required for its anti-myeloma efficacy”
Human
myeloma
Human
myeloma
Human
liver
Thal
reduced
Thal ~
unchanged
Yaccoby et Al, Blood, 2002
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46. INTERIM ANALYSIS PROSPECTIVE RANDOMIZED TRIAL
GRUPPO ITALIANO PER LO STUDIO DEL MIELOMA MULTIPLO
INTERIM ANALYSIS
PROSPECTIVE RANDOMIZED TRIAL
NEWLY DIAGNOSED PATIENTS, AGE > 65 YEARS
MELPHALAN, PREDNISONE + THALIDOMIDE (MPT)
versus
MELPHALAN PREDNISONE (MP)
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

47. ADVERSE EVENTS WHO (grade) 1-2 3-4 1-2 3-4 Hematologic (%)
MPT MP
WHO (grade)
1-2
3-4
1-2
3-4
Hematologic (%)
Constipation (%)
Neurologic (%)
Cardiac (%)
Cutaneous (%)
Infection (%)
Thromboemb.(%)
Early death (%) 29 28 32 17 15 14 18 7 9 3 2 10 35 - 11 3 12 25 - 4 1 19 5 4 5
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

48. Dept. Hematology, University of Torino
RESPONSE TO THERAPY
77.1%
15.6%
46.7%
% of Response
33.8%
28%
27.7%
13.3%
5.4%
Dept. Hematology, University of Torino

49. (median follow up 13.6 months)
EVENT-FREE SURVIVAL
(median follow up 13.6 months)
Proportion
MPT
p<0.001 MP
Months
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

50. RESPONSE TO THERAPY 27.7% % CR 5% 3-5% MP Thal MP + Thal 30 20 10
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

51. Revlimid ™ (lenalidomide)
Thalomid®
(thalidomide)
Actimid™ (CC-4047)
Revlimid ™ (lenalidomide)
(CC-5013)

52. The Proteasome: A Target for Novel Therapies
Bruno B, Rotta M, and Boccadoro M, Lancet Oncology 2004, in Press
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

53. IkB IkB IkB IkB IkB TNFa TNFaR p65 p50 p65 p65 p50 p50
Protein kinases
IkB
p65
p50 P Ub
IkB
p65
p50
TNFaR
Degradation of IkB by 26S proteasome
p50
p65
IkB P Ub
NFkB-IkB complex
IkB P Ub

54. Increase in adhesion molecules
TNFa
IkB
p65
p50 P
Protein kinases
IkB
p65
p50 P Ub
IkB
p65
p50
TNFaR
Degradation of IkB by 26S proteasome
p50
p65
IkB P Ub
NFkB-IkB complex
IkB P Ub
NFkB Nuclear translocation
p65
p50
PS 341
NFkB binding site
NFkB Induced proteins
Block of programmed cell death
Increase in Cytokine production
Increase in adhesion molecules

55. Increase in adhesion molecules
TNFa
IkB
p65
p50 P
Protein kinases
IkB
p65
p50 P Ub
IkB
p65
p50
TNFaR
Degradation of IkB by 26S proteasome
p50
p65
IkB P Ub
NFkB-IkB complex
NFkB Nuclear translocation
p65
p50
PS 341
NFkB binding site
NFkB Induced proteins
Block of programmed cell death
Increase in Cytokine production
Increase in adhesion molecules

56. Increase in adhesion molecules
TNFa
IkB
p65
p50 P
Protein kinases
IkB
p65
p50 P Ub
IkB
p65
p50
TNFaR
Degradation of IkB by 26S proteasome
p50
p65
IkB P Ub
NFkB-IkB complex
p50
p65
IkB P Ub
p50
p65
IkB P Ub
NFkB Nuclear translocation
PS 341
NFkB binding site
NFkB Induced proteins
Block of programmed cell death
Increase in Cytokine production
Increase in adhesion molecules

57. Increase in adhesion molecules
TNFa
IkB
p65
p50 P
Protein kinases
IkB
p65
p50 P Ub
IkB
p65
p50
TNFaR
Degradation of IkB by 26S proteasome
p50
p65
IkB P Ub
NFkB-IkB complex
p50
p65
IkB P Ub
p50
p65
IkB P Ub
NFkB Nuclear translocation
PS 341
NFkB Induced proteins
Block of programmed cell death
Increase in Cytokine production
Increase in adhesion molecules

58. Increase in adhesion molecules
TNFa
IkB
p65
p50 P
Protein kinases
IkB
p65
p50 P Ub
IkB
p65
p50
TNFaR
Degradation of IkB by 26S proteasome
p50
p65
IkB P Ub
NFkB-IkB complex
p50
p65
IkB P Ub
p50
p65
IkB P Ub
NFkB Nuclear translocation
PS 341
NFkB Induced proteins
Block of programmed cell death
Increase in Cytokine production
Increase in adhesion molecules
Antimyeloma effect

59. SUMMIT (025): A Phase II Study of VELCADE™ (bortezomib) for Injection in Patients With Relapsed and Refractory Multiple Myeloma
Paul G. Richardson,1 Bart Barlogie,2 James Berenson,3 Seema Singhal,4 Ann Traynor,4 Sundar Jagannath,5 David Irwin,6 Vincent Rajkumar,7 Gordan Srkalovic,8 Melissa Alsina,9 Raymond Alexanian,10 David Siegel,11 Robert Orlowski,12 David Kuter,13 Steven Limentani,14 Dixie Esseltine,15 Gretchen Richards,15 Michael Kauffman,15 Julian Adams,15 David P. Schenkein,15 and Kenneth C. Anderson1
1Dana-Farber Cancer Institute, 2University of Arkansas, 3Cedars-Sinai Medical Center, 4Northwestern University Medical Center, 5St Vincent’s Comprehensive Cancer Center, 6Alta Bates Cancer Center, 7Mayo Clinic, 8Cleveland Clinic Foundation, 9H. Lee Moffitt Cancer Center, 10M.D. Anderson Cancer Center, 11Carol G. Simon Cancer Center, 12University of North Carolina at Chapel Hill, 3Massachusetts General Hospital, 14Charlotte Medical Clinic, 15Millennium Pharmaceuticals, Inc

60. SUMMIT – Prior Therapy
99.5%
92%
Median number of lines of prior therapy = 6 (range 2-15)
92% of patients received at least 3 of the drug therapies listed here (excluding stem cell transplant)
91% of patients were refractory to the last prior therapy
83%
81%
64%

61. SUMMIT – Response Rates with VELCADE® Alone
35%
35% response rate
10% CR (IF+ and IF-)
28% CR+PR
59% of patients SD or better
Mean duration of response 12 months
CR IF-
CR IF+ PR MR SD - +
Prior treatment had no significant effect on response rate
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

62. Treatment plan – APEX Bortezomib Dexamethasone Randomization Induction
8 cycles
4 cycles
1.3 mg/m2 IV push
Days 1, 4, 8, 11 Q3W cycle
40 mg po
Days 1–4, 9–12, 17–20 Q5W cycle
Maintenance
3 cycles
5 cycles
1.3 mg/m2 IV push
Days 1, 8, 15, 22 Q5W cycle
40 mg po
Days 1–4 Q4W cycle
273 treatment days
280 treatment days
Richardson et al. NEJM 2005

63. APEX: Time to Progression (n=669)
78% improvement in median TTP with bortezomib
Median TTP: Bortezomib 6.2 months vs dexamethasone 3.5 months
Richardson et al. NEJM 2005

64. APEX: Response rates (CR, PR)
100
Median time to response (TTR)
43 days in both arms
Duration of response
Bortezomib 8.0 months
Dexamethasone 5.6 months
Median follow-up ~8.3 months 90 80
P<.0001 70 60
Response (%) 50
38% 40 30
25% PR
18%
<1% nCR 20 10
7% nCR
16% PR
<1% CR
6% CR
Bortezomib
Dexamethasone
Richardson et al. NEJM 2005

65. APEX: 1-year survival (n=669)
80%
66%
The Kaplan-Meier plot for survival censored at one year in both arms for the entire intent-to-treat population. Data for survival analysis were censored on or before January 13, 2004, with P values from stratified log-rank tests.
41% decreased risk of death with bortezomib
Richardson et al. NEJM 2005

66. APEX: Overall survival (n=669)
This is a Kaplan-Meier plot of overall survival in the entire intent-to-treat population
The survival curves cross at ~500 days, because of the death of one patient on the bortezomib arm at 504 days.
At that time, the curve had accounted for 330 of the 333 patients (with 50 deaths and 280 patients censored), with only the one patient death and 2 censored data points after the cross.
Median duration of follow-up 8.3 months
Richardson et al. NEJM 2005

67. Conclusion Phase III APEX:
Bortezomib demonstrated superior efficacy to high-dose dexamethasone in relapsed MM
Significant TTP benefit (P<.0001)
Response rate advantage (P<.0001)
Superior 1-year survival (P=.0005, HR=.53)
Superior overall survival (P=.0013, HR=.57)
Richardson et al. NEJM 2005

68. Most common adverse events from Phase I, SUMMIT, CREST and APEX trials
Toxicities were predictable and manageable
Adverse event Phase I1 SUMMIT2 CREST3 APEX4
(%) (%) (%) (%) Thrombocytopenia
Fatigue
Nausea
Diarrhea
Constipation
Vomiting NR 35
Peripheral neuropathy
NR = not recorded
1Orlowski et al. J Clin Oncol 2002;20:4420; 2Richardson et al. N Engl J Med 2003;348:2609;
3Jagannath et al. Br J Hematol 2004;127:165; 4Richardson et al. ASH 2004 (abstract 336.5)

69. Combinations therapies in Multiple Myeloma
Bortezomib + Thalidomide
+/- cytotoxic drugs
induction
relapse
M-COMPONENT
High dose
remission

70. Multiple Myeloma Studies in Development: Front Line
Dana Farber
Richardson
Phase II VELCADE alone in 1st line tx
CHU de Nantes
Harousseau
Phase II VELCADE + high-dose dexamthasone 1st line, pre-transplant
Location PI
Study
ECOG/CTEP
Dispenzieri
Phase II VELCADE in high risk myeloma, 1st line
U. Maryland
Badros
Phase I/II VELCADE + DT-PACE, 1st line
CALGB
Orlowski
Phase II VELCADE + Doxil
U. Arkansas
Barlogie
Phase II VELCADE + Total Therapy III in high risk myeloma 1st line
Salick Group
Jagannath
Phase II VELCADE monotx
Dex after 2 cycles for less than optimal response

71. MULTIPLE MYELOMA cure AUTOLOGOUS FIRST STEP Proteasome inhibitors
Thalidomide
Mini allo
AUTOLOGOUS FIRST STEP
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72. MULTIPLE MYELOMA chronic Chemo Thalidomide Proteasome inhibitors
Lanilomide
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