Current Concept & Treatment of Multiple Myeloma

Name : Dr. Pandji Irani Fianza, SpPD-KHOM, Msc

Position : Staff of Department of Internal Medicine, School of Medicine
Padjadjaran University/Hasan Sadikin General Hospital

Education
 1989 : Medical Doctor Padjajaran University
 1993 : MSc Research Methodology University of Aberdeen, UK
 1999 : Internist Padjajaran University
 2006 : Hematology-Medical Oncology Padjajaran University
Current Concept and Treatment of Multiple Myeloma
Pandji Irani Fianza

Division of Hematology-Medical Oncology

Department of Internal Medicine,
Medical Faculty Padjadjaran University/ Dr. Hasan Sadikin Hospital,
Bandung
 Multiple Myeloma (MM)

• A neoplastic plasma cell abnormality that is

characterized by clonal proliferation of malignant
plasma cell in the bone marrow
microenviroment, monoclonal protein in the
blood or urine and associated organ dysfunction

Palumbo A, Anderson K. N Engl J Med 2011; 364: 1046-1060

 MM
• An incurable plasma cell neoplasm accounting
for 1% of all malignancies and 10% of
hematologic malignancies
• The advent of novel treatment paradigms has
improved survival over the past two decades
• The Surveillance, Epidemiology and End Results
(SEER) database:
– a modest increase in 5-year relative survival rates
from 1975 to 2000: from 25 to 32%
– From 2001 to 2007, the 5-year relative survival rate
increased to 41.1%
S Girnius and NC Munshi. Leukemia Supplements (2013) 2, S3 -- S9
 Burden of the disease in Indonesia

• 70 MM patients (Indonesia’s Multiple Myeloma

Study Group, cross-sectional multi-center study,
November 2008-November 2009):
– 65.71% of MM patients : age > 50 years old
– Almost half of the patients : IIIA stage (Durie-Salmon
staging system)
– Melphalan/prednisone was the most chemotherapy
regimen used (59.7%) with a result of partial
response as the most frequent response found (45%)

Tadjoedin H, et al. Indonesian Journal of Cancer. 2011 ;5

 The Biology of Myeloma
• Myeloma arises from an asymptomatic premalignant
proliferation of monoclonal plasma cells that are derived
from post–germinal-center B cells

• Multistep genetic and micro environmental changes lead

to the transformation of these cells into a malignant
neoplasm

• Myeloma is thought to evolve most commonly from a

monoclonal gammopathy of undetermined clinical
significance (MGUS) that progresses to smoldering
myeloma and, finally, to symptomatic myeloma
N Engl J Med 2011;364:1046-60.
Common Cytogenetic Findings
Translocations involving 14q32
 t(11;14)
 t(4;14)
 t(14;16)

Chromosome 13 abnormalities
 Monosomy
 Deletion 13
 13q translocations

17p deletions

Hyperdiploid

He J, et al. Am J Med Sci. 2013;345:88-93.

 FISH
t(4;14) t(14;16)
Natural History of MM
Diagnostic criteria for MM
(Revised IMWG Criteria)

Rajkumar. Lancet Oncol 2014;15:e538-48

Staging and Prognosis
 Durie-Salmon Staging System
Stage Criteria

I All the following:

Hb> 10 g/dL
Calcium < 12 mg/dL
No lytic lesions
M-protein: < 5 g/dL if IgG, <3 g/dL if IgA

II Not fulfilling criteria for Stage I or II

III Any of the following:

Hb < 10 g/dL
Calcium > 12 mg/dL
Multiple lytic lesions
M-protein: > 7 gr/dL if IgG, > 5 g/dL if IgA

Stages I, II, and III of the Durie-Salmon staging system can be divided into
A or B depending on serum creatinine:
A: serum creatinine < 2 mg/dL (< 177 μmol/L)
B: serum creatinine > 2 mg/dL (> 177 μmol/L)
 International Staging System

Stage Criteria Median Survival

(months)

I Serum b2-microglobulin < 3.5 mg/L AND 62

Serum albumin > 3.5 g/dL

II Not stage I or stage III* 44

III Serum b2-microglobulin > 5.5 mg/L 29

* There are two categories for stage II: serum β2-microglobulin < 3.5 mg/L
but serum albumin < 3.5 g/dL; or serum β2-microglobulin 3.5 to < 5.5 mg/L
irrespective of the serum albumin level.

Greipp PR, et. J Clin Oncol 2005;23: 3412-20

ISS: staging by geographic region

A is Asia; B is Europe; C is North America

Greipp PR, et. J Clin Oncol 2005;23: 3412-20
Survival by ISS Stage, Age, and Treatment Modality

Stage Median OS: Median OS:

Age < 65 yrs (months) Age > 65 yrs (months)

I 69 47
II 50 37
III 33 24

Stage Median OS: Median OS:

High-Dose Chemotherapy Conventional-Dose
(months) Chemotherapy (months)
I 111 55
II 66 40
III 45 25

Orlowski R, et al. Hematology Am Soc Hematol Educ Program. 2006:338-347.

 Prognostic markers
( IMWG Consensus on Risk Stratification in MM)

• Host factors: age

• Tumor related factors:
– Plasma cell labelling index not widely adopted or
– Presence of circulating plasma cells not easily reproducible
– Plasmablastic morphology
– Genetic aberrations
– Gene expression profiles
• Tumor burden/stage:
– ISS
– MRI, PET-CT require further confirmation
• Tumor Responsiveness to Treatment :  at least PR
http;//online.myeloma.org/NetCommunity.
Genetic Abnormalities Detected by FISH

Abnormalities Frequencies Prognosis

t(4;14) 15-20% Poor

t(11;14) 15% Good/Neutral

t(14;16) 5-7% Poor

1q21 Gain 30-35% Poor

13q14 del 45-50% Poor

17p13 del 10% Poor

Segges P, Braggio E. Genet Res Int 2011;2011

 The prognostic risk factors of MM

Poor Risk Favorable Risk

Deletion 13 (del 13q14): by • t (11;14)

karyotyping • t(6;14)
• t (4;14)
• t (14;16)
• t (14;20)
Del 17p13 Hyperdiploidy

Hypodiploidy Normal and other cytogenetic

abnormalities

Pingali SR, et al. Dis Mon 2012;58: 195-207

Prognostic impact of t (4;14)/del(17p) with
ISS

Avet-Ioiseau et al. ASH 2009

Treatment
What is the GOAL of treatment in MM?
• Prolong Survival (OS) Cure in subset of
• Delay Disease Progression (PFS) Patients ?
• Ensure good quality of Life (QOL)
What is needed to
achieve this ?

Efficacy Toxicity

Maximal eradication of tumor clone through achievement of

best possible response balanced with acceptable toxicity
Important to assess the impact of CR on
time to progression and survival

• MM remains incurable, but therapeutic advances

have improved survival
• High-dose therapy followed by ASCT has
improved the outcome of MM patients
• Novel agents are increasing response rates,
particularly CR rates
VISTA Trial (in elderly population)

San Miguel et al. N Engl J Med 2008; 359:906-17

Impact of CR on time to progression and
survival

San Miguel et al.. N Engl J Med 2008; 359:906-17

Association between maximal response and OS in
patients with newly diagnosed MM treated with HDT

Van de Velde et al. Haematologica 2007;92:1399

Depth of response is related to Time to Progression

Adaptd from Niesvizky et al. Br J Haematol 2008;143:46-53

Prognostic influence of 6 response categories
obtained after HDC/ASCT

Martinez-Lopez J et al. Blood 2011;118:529-34

Impact of treatment response on OS

Morgan G et al. IMW Paris 2011

New Response Criteria of MM Treatment

San Miguel et al.. N Engl J Med 2008; 359:906-17

New Response Criteria of MM Treatment

San Miguel et al.. N Engl J Med 2008; 359:906-17

New Response Criteria of MM Treatment

San Miguel et al. N Engl J Med 2008; 359:906-17

MM treatment phases
• Therapeutic objective :
 to obtain increasing
depth of response.
• Induction phase  rapid
reduction of tumor load : at
least VGPR
• Consolidation (high-dose
melphalan with stem cell
rescue + a few cycles of post
transplant combination
treatment)  to further deepen
the response
• Maintenance  to maintain
achieved response for as long
as possible
 Mayo Stratification for Myeloma and Risk-
adapted therapy classification (mSMART)

High Risk Intermediate Standard Risk

20% Risk 20% 60%**
Genetic • Del 17p • t (4;14)* • Trisomies
abnormaltiy • t (14;16) • Cytogenetic (Hyperdiploid)
• t (14;20) deletion 13 • t(11;14)
• High risk or • t(6;14)
gene hypodiploidy
expression • PCLI > 3%
profiling
signature
Median OS <2-3 years 5 years 6-7 years

* Prognosis is worse when associated with high beta 2 M and anemia

** LDH >ULN and beta 2 M > 5.5 in standard risk may indicate worse prognosis
*** t(11;14) is associated with plasma cell leukemia

Rajkumar SV. Am.J. Hematol 2014;89:999-1009

 Risk Stratification of MM

High Risk Standard Risk Low

Risk
Parameters • ISS II/III and • Others • ISS I/II and
t (4;14) or Absence of
17p13 del
t(4;14),17p13del
and +1q21 and
age < 55 yrs

Median OS 2 years 7 years > 10 years

% Patients 20% 60% 20%

Chng WJ, et al. Leukemia 2014;28:269-77

 Risk Stratification - Therapeutic Questions

High Risk Standard Risk Low

Risk
Parameters • ISS II/III and t • Others • ISS I/II and Absence of
(4;14) or 17p13 t(4;14),17p13del and
del +1q21 and age < 55 yrs

Median OS 2 years 7 years > 10 years

% Patients 20% 60% 20%

Therapeutic Need Novel ? Do these patients
Questions Approaches benefit from maintenance
?Allogeneic SCT or ? Is VGPR a good
immune therapy enough response in these
appoaches patients i.e. can maintain
a MGUS state long term

Chng WJ, et al. Leukemia 2014;28:269-77

 Risk-adapted therapy
• At the present time:
– no recommendation of different treatments for
patients in the different risk groups

– except for patients with t(4;14)  bortezomib-based

treatments for induction and maintenance since
different trials showed that bortezomib-based
treatment improved outcome of these patients
 Treatment of MM
Traditional therapy Novel Agents
• Steroids: • Immunomodulatory drugs:
– Dexamethason – Thalidomide
– Prednisone – Lenalidomide
– Pomalidomide
• Alkylating agents:
– Melphalan, cytoxan • Proteasome Inhibitors:
– High dose with ASCT – Bortezomib
– Carfilzomib
• Other: – Oral PI (Ixazomib,
– Doxil, Cisplatn Oprozomob)
Treatment Guideline
Treatment Guideline
Initial Approach to Treatment of MM
General eligibility requirements for
autologous HCT in MM
• Autologous HCT in MM  as consolidation therapy
following initial response to chemotherapy or for the
treatment of relapsed or refractory disease
• Eligibility requirements varies across countries and
institutions
• In most European countries:
– Offered primarily to patients < 65 years of age
• In US, not considered eligible for autologous HCT in MM:
– Age > 77 years
– Direct bilirubin > 2 mg/dL
– ECOG performance status 3 or 4 unless due to bone pain
– NYHA fucntional status class III or IV
Newly Diagnosed Myeloma
Eligible for Transplantation

*Prefer Rd for trisomies and VCD for t(11;14) or t(6;14)

**For patients who choose delayed ASCT, dexamethason usually
discontinued after 12 months, and continued long-term lenalidomide is
an option for patients who are tolerating treatment well
Rajkumar SV. Am.J. Hematol 2014;89:999-1009
Newly Diagnosed Myeloma
Not Eligible for Transplantation

*Prefer Rd for trisomies and VCD for t(11;14) or t(6;14)

**For patients who choose delayed ASCT, dexamethason usually
discontinued after 12 months, and continued long-term lenalidomide is
an option for patients who are tolerating treatment well
Rajkumar SV. Am.J. Hematol 2014;89:999-1009
 VGPR/CR Postinduction and Post-ASCT in
Phase III Trials of Novel Therapies vs VAD
CR/VGPR
CR/VGPR 100%
100% P < .0001
Doublet Triplet
87%
P = .44

VGPR 73.7%
P < .001 P < .0001 67%
64%
18.6%
P < .001 P = .03
61% 62.3% 66% 32% 60%
CR/nCR 54.3% 54%
P = .87 P < .001 P < .0001 23%
50% P < .001 44% 31% 21.4%
44.4% P = .004 19.3% 42% 43.2%
P = .002 41.7%
37.7% 37.2% 37% 36% 35%
34.7% 55.1%
27.2% 28% 55% TD
40% 27.5%
22.9% 18.8% 21%
35.0% 18% 32% 31% 40.9% CR/nCR
12.6% 15.1% 34% 17%
17.1% 31% 41% 43%
30%
16% 15% CR/nCR
14.8% 8.7% 18.4% 15% 16% 11% 33%
6.4% 3% 2% 14% 12% 11% 5% 10.4%
0%
TD VAD TD VAD VD VAD VD VAD TAD VAD TAD VAD PAD VAD PAD VAD CTD CVAD CTD CVAD VTD TD VTD TD CyBorD RVD
Pre-HDT Post-HDT Pre-HDT Post-HDT Pre-HDT Post-HDT Pre-HDT Post-HDT Pre-HDT Post-HDT Pre-HDT Post-HDT
Macro IFM2005-01 HOVON 50 HOVON 65 MRC IX GIMEMA

Macro M, et al. Blood. 2006;108:57-62. Harousseau JL, et al. J Clin Oncol. 2010;28:4621-4629. Lokhorst
HM, et al. Blood. 2010;115:1113-1120. Sonneveld P, et al. IMW 2010. Abstract 40. Cavo M, et al. Lancet.
2010;376:2075-2085. Reeder CB, et al. Blood. 2009;114: abstract 616. Richardson PG, et al. Blood.
2009;114: abstract 1218. Kumar SK, et al. Leukemia. 2010;24:1352-1356.
Bortezomib

• A proteasome inhibitor
• Has shown good efficacy as a single agent and in
combination in patients
– with relapsed multiple myeloma
– as initial treatment, including prior to autologous stem
cell transplantation
• Has been studied as monotherapy and in combination
with standard treatments, such as dexamethasone,
chemotherapy, and with newer agents such as the
IMiDs, thalidomide and lenalidomide
• Is well-tolerated, including in combination
Bortezomib: a potent first-in-class
proteasome inhibitor
Dipeptidyl boronic acid Cross-section of b-ring
derivative
b1 Post- b2
Tryptic
glutamyl
site
site

O OH b7 b3
H
N N B
N OH Bortezomib
H b6 b4
O Chymo-
N tryptic
b5 site

(reversible inhibitor of chymotryptic active site

of proteasome b subunit)

Janssen-Cilag 2003
 Single-agent bortezomib active in
newly diagnosed MM
Richardson et al.
RR (CR+PR), n=28 45% (67% including MR)
Jagannath et al.*
RR (CR+nCR+PR) 41% (after 2 cycles), 11% CR+nCR
(23 pts evaluable) 85% (after addition of Dex),
20% CR+nCR

• Well tolerated: safety profile similar to previous studies

– Neuropathy frequently prevalent at baseline

*Stem cells successfully harvested from 13 patients: 12 received transplants

Richardson et al. Blood 2004;104:100a (abstract 336)

Jagannath et al. Haematologica 2005;90(Suppl 1):148 (abstract P0.725)
 IFM2005-01 Trial:
Bortezomib + dexamethasone vs VAD
in newly diagnosed MM

Harousseau et al. J Clin Oncol 2010;28:4621-29

 IFM2005-01 Trial:
Bortezomib + dexamethasone vs VAD
in newly diagnosed MM

Harousseau et al. J Clin Oncol 2010;28:4621-29

 Bortezomib combination protocols
in previously untreated patients
Study N Regimen CR/nCR CR+PR Toxicity
Gr 1-2 PN 16%, no Gr 3-4 PN
PAD 6 Gr3 events: abnormal liver
Cavenagh
19 VEL (1.0 mg/m2) + Adria + 17% 89% function; thrombocytopenia,
(25541)
Dex → SCT neutropenia, hyperglycemia,
sepsis, anxiety
HD Dex
Harousseau
48 VEL + high dose Dex → 21% 67% 1 Gr3 PN, others ≤ Gr2
(14902)
SCT
VTD Infection (3), orthostatic
Wang (7841) 36 31% 89% hypotension (1), DVT (2) Gr 3
VEL+ Thal + Dex → SCT PN (reversible) (3)
TT3
81% 6 treatment related deaths,
Barlogie (11541) VEL + DT-PACE → SCT x2
162 at 12 NA Other toxicity not different
→ VDT-PACE + from DT-PACE
mos
Thal dex
VMP Gr 3-4: GI <15%; PN 15%;
Mateos (7861) 60 39% 85% anemia 12%, neutropenia
VEL + M + P (Days 1 – 4) 39%, thrombocytopenia 46%

*VEL: Bortezomib – VELCADE®

1. Abstracts in Blood 2005;106 (ASH 2005) 2. Abstract in Blood 2004;104 (ASH 2004)
Maintaining CR is important
 Bortezomib-Melphalan-Prednisone Followed by
Maintenance With Bortezomib-Thalidomide (VMP-VT)
Compared With Bortezomib-Melphalan-Prednisone
(VMP) for Initial Treatment of Multiple Myeloma

N=511

Palumbo A et al. JCO 2014;32:634-640

 Survival outcomes in the intention-to-treat
population, according to study group.

TNT
PFS

OS after
OS Relapse

Palumbo A et al. JCO 2014;32:634-640

 VT-Maintenance for Non-Transplant Patients

VMP vs. VMPT-VT:

• 3-year PFS: 41% vs 56%
• median PFS: 24.8 vs 35.3 months (P .001)
• TNT 27.8 vs 46.6 months (P .001)
• 5-year overall survival (OS) was greater with VMPT-VT (61%)
than with VMP (51%; HR, 0.70; P .01).

VMPT-VT group, more grade 3 to 4 adverse events including

neutropenia (38%), thrombocytopenia (22%), peripheral
neuropathy (11%), and cardiologic events (11%).

Conclusion
Bortezomib and thalidomide maintenance significantly improved
OS in multiple myeloma patients

Palumbo A et al. JCO 2014;32:634-640

 Summary of bortezomib data
in relapsed/refractory MM
Regimen Phase n CR + PR CR + nCR Reference

Single-agent bortezomib Richardson

III 331 43% 16%
(APEX) (25471)

+ low-dose IV melphalan I/II 22 53% 5% Popat (25551)

+ oral cyclophosphamide II 50 82% 12% Kropff (25491)

Suvannasankha
+ steroids II 30 60% 6%
(25621)
+ pegylated
liposomal doxorubicin I 42 73% 36% Orlowski2

1. Abstracts in Blood 2005;106 (ASH 2005) 2. Blood 2005;105:3058–65

 Response to bortezomib by
prognostic factor and line of treatment

CR+PR 34%
CR+PR 45%

n is shown by the number on each bar

>1 prior treatment and MM refractory to prior treatment resulted in

lower responses to bortezomib
Richardson et al. ASCO 2005; Sonneveld et al. IMW 10, Sydney, 2005
 Bortezomib: higher response rates in
second-line therapy than later therapy
CR nCR PR
100
P=0.0035
Proportion of patients (%)

80 P<0.0001

60
45
40 34
26
32
21
20 13
23 0.5 nCR
6 7
13
6 2 6
0
Bortezomib Dex Bortezomib Dex
1 prior line of therapy >1 prior line of therapy

Sonneveld et al. IMW 10, Sydney, 2005

ONCE WEEKLY Cybord (VCD)

Reeder et al. Blood 2009; 114: Abstract 616 (Oral Presentation)

 ONCE WEEKLY Cybord (VCD)

ITT Cohort 1 – Twice Cohort 2 – Once All (N=63)

Weekly (n=33) Weekly (n=30)
ORR 88% 93% 90%
CR/nCR 39% 43% 41%
≥VGPR 61% 60% 60%

After 4 Cycles Cohort 1 – Twice Cohort 2 – Once All (N=55)

Weekly (n=28) Weekly (n=27)
ORR 96% 93% 95%
CR/nCR 46% 48% 47%
≥VGPR 71% 63% 67%

Reeder et al. Blood 2009; 114: Abstract 616 (Oral Presentation)

ONCE WEEKLY Cybord (VCD)
Survival & PFS

Reeder et al. Blood 2009; 114: Abstract 616 (Oral Presentation)

 Summary
• MM is a neoplastic plasma cell abnormality that is
characterized by clonal proliferation of malignant plasma
cell in the bone marrow microenviroment, monoclonal
protein in the blood or urine and associated organ
dysfunction
• ISS staging influence survival
• MM remains incurable, but therapeutic advances have
improved survival
• High-dose therapy followed by ASCT has improved the
outcome of MM patients
• Novel agents are increasing response rates, particularly
CR rates
• Maintaining CR is important
Genomics-driven cancer medicine
Thank You