1. Diagnosis and Treatment of
High-risk SMM
Institute of Hematology, Peking University
Peking University People's Hospital
Lu Jin
2.
3. In the treatment of
other malignancies
(breast, colon or
prostate cancer), the
early intervention is
not only appropriate,
but also essential for
successful treatment
and cure.
Treatment concept of
early intervention
Curr Opin Oncol. 2014 Nov;26(6):670-6
4. Early intervention provides a possibility
for curing myeloma
Curr Opin Oncol. 2014 Nov;26(6):670-6
Haematologica December 2014 99: 1769-1771
Clin Cancer Res. 2013 Mar 1;19(5):985-94
The treatment philosophy in
multiple myeloma patients has
been focused on symptomatic
patients.
As extrapolated from other medical
conditions, including other solid
and hematologic malignancies, one
may conjecture that early
intervention has the potential to
provide a path to a cure in
myeloma.
It can be inferred that in the early
(e.g. SMM) stage of the disease
fewer genetic changes cause
higher cure possibility due to lower
disease burden.
7. SMM is a heterogeneous
plasma cell disease
Clinical Lymphoma Myeloma and Leukemia Volume 10, Issue 4, Pages 248-57
8. The risk of SMM progressing to
active MM
Are there any risk factors predicting
progression to active disease?
N Engl J Med 2007;356(25):2582-2590.
9. Risk Stratification Model
J Clin Oncol. 2015 Jan 1;33(1):115-23
Mayo model is mainly dependent on
the serum protein levels
PETHEMA model uses bone marrow
cells
10. Mayo and PETHEMA Risk
Stratification Models
Follow-up time (years) Time from the
diagnosis (months)
11. Two risk stratification models
currently lack of consistency
A study recently integrated Mayo and PETHEMA risk
stratification models .
77 patients with SMM were prospectively risk-stratified based on the
two models .
There was distinct difference between the two models that only 22/77
patients had the same stratified result (consistency: 28.6%)
Leukemia and Lymphoma 2013 ； 54 (10), pp. 2215-2218
12. Lancet Oncol. 2014 Nov;15(12):e538-48
Not CRAB but now SLiM CRAB
•S (60% increase in plasma cells)
•Li (Light chain I/U >100)
•M (1 or multiple focal lesions on MRI)
•C (Elevated serum calcium)
•R (Renal insufficiency)
•A (Anemia)
•B (Osteopathy)
13. BMPC≥60% should be
considered as MM requiring
treatment
N Engl J Med 2011;365(5):474-475.
Leukemia 2013;27(4):947-953
95% progressed
to MM in 2 years
All progressed to
MM in 2 years
14. FLC ratio≥100 should be
considered as MM Requiring
treatment
Leukemia (2013) 27, 941–946
Leukemia 2013;27(4):947-953
72% progressed
to MM in 2 years
98% progressed
to MM in 18
months
15. The predictive value of focal lesion
>1 on MRI
J Clin Oncol 2010; 28: 1606–10.
Leukemia2014;28(12):2402-2403
The median time to progression of
focal lesion >1 on MRI was 13 months
The progression rate of MM in 2 years
was 70%
The median time to progression of focal
lesion >1 on MRI was 15 months
The progression rate of MM in 2 years was
69%
16. Diagnostic Criteria of MM that
may be added in the future
Lancet Oncol. 2014 Nov;15(12):e538-48
17. The predictive value of cytogenetic
abnormalities
JCO VOLUME 31 NUMBER 34 DECEMBER 1 2013
High-risk VS No high-risk cytogenetics 3yearTTP
45% VS 24% (HR, 2.00; P=.001).
18. The diagnosis of MM will
continue to move forward
Blood, 122 (26) , pp. 4172-
19.
20. Why observe and wait ?
High drug toxicity
The protocol contained alkylating agents (which can cause a second tumor)
The enrolled patients were not
risk-stratified
21. Risk stratification and more safe and
effective new drugs bring hope for
early intervention
• Selective treatment in high-risk
patients.
• The toxic side effects of new drugs
are smaller and more effective
22. QUIREDEX:QUIREDEX: 来那度胺来那度胺 ++ 地塞米松治疗地塞米松治疗 SMMSMM 的的
33 期研究期研究
a
Spain: 19 sites; Portugal: 3 sites.
b
DEX (20 mg, D1-4) could be added when the patient had developed to asymptomatic biological progression (M protein increased)
D: day; DEX: dexamethasone; LEN: lenalidomide; ORR: overall response rate; OS: overall survival; TTP: time to disease progression.
Engl J Med. 2013;369:438-47
• Primary endpoint: TTP to symptomatic disease
• Secondary endpoints: ORR, OS, safety
– Cutoff date for final analysis: October 15, 2012
– Median follow-up: 40 months
N = 119a
•SMM
•Stratified by
time since
diagnosis
(≤ 6 vs. > 6 mo)
Early Treatment (n = 57):
LEN: 25 mg, D1-21
DEX: 20 mg, D1-4,12-15
Nine 28-day cycles
Observation (n = 62):
(No treatment until
progression to
symptomatic MM)
R 1:1
LEN: 10 mg, D1-21b
(Protocol amendment
limits total treatment
duration to 2 y)
Maintenance
23. Eligibility Criteria
BMPC: bone marrow plasma cell; MC: monoclonal component; PC: plasma cell; SMM: smoldering multiple myeloma.
Engl J Med. 2013;369:438-47
• Key inclusion criteria:
– Diagnosed with SMM within the past 5 yrs
– High-risk of progression to symptomatic disease, defined as:
• BMPC infiltration ≥ 10% and increased monoclonal component (IgG ≥ 3 g/dL, or IgA
≥ 2 g/dL, or Bence-Jones proteinuria > 1 g/24 hours)
OR
• 1 of 2 criteria above and ≥ 95% phenotypically aberrant BMPC with immunoparesis
• Key exclusion criteria:
– Presence of CRAB symptoms
• Hypercalcemia
• Renal failure (creatinine ≥2 mg/dL)
• Anemia (hemoglobin <10 g/dL or 2 g/dL below lower limit of normal)
• Bone lesions
24. Response rate up to 90%
for Rd treatment
a
7 patients didn’t receive maintenance treatment: withdrawal of informed consent t (4); Grade 4 pneumonia (1); DEX-related delirium (1); adjudication by investigator (1).
Engl J Med. 2013;369:438-47
• 50 of 57 pts (88%) completed 9 cycles of induction therapy and received LEN maintenance
• 12 pts (24%) had an improvement in the quality of response after a median of 15 cycles of LEN
maintenance
25. Significant prolongation
of TTP by Rd treatment
Median TTP
Treatment NR
Observation 21 months
Dx: diagnosis; HR: hazard ratio; NR, not reached; TTP: time to progression; Tx: treatment.
Engl J Med. 2013;369:438-47
• Early Tx was associated with significantly longer TTP vs observation
– 76% in the observation group developed symptomatic MM requiring Tx initiation vs.
23% in the Tx group
– Time between Dx and study entry (≤ 6 mos vs. > 6 mos) did not affect TTP
26. Significant prolongation of OS
by Rd treatment （ since
enrollment ）
3-year OS
rate (%)
Treatment 94
Observation 80
HR: hazard ratio;
• Median follow-up time of 40 months
• Compared with observation group, early treatment could significantly increase 3-year survival rate since
enrollment
Engl J Med. 2013;369:438-4
27. Significant prolongation of OS
by Rd treatment （ since
diagnosis ）• • Median follow-up time of 46 months
• • Compared with observation group, early treatment could siginicanlty increase OS since diagnosis
• • In Rd group, 44% patients with the time from diagnosis to enrollment of ≤6 months, 56% patients
with the time of ＞ 6
a Median follow-up time: 46 months
5-year OS
rate (%)
Treatment 94
Observation 78
Engl J Med. 2013;369:438-4
28. Good Safety- Induction Phase
AE, n (%)
Treatment (n = 62)
Observation (n =
63)
Gr 1 Gr 2 Gr 3 Gr 1 Gr 2
Hematology
Neutropenia
Thrombocytopenia
Anemia
3 (5)
6 (10)
11 (18)
8 (13)
1 (2)
4 (6)
3 (5)
1 (2)
1 (2)
0
0
0
0
0
0
Non-hematology
Infection a
Rash
Asthenia
Constipation
Diarrhea
DVT b
19 (31)
12 (19)
6 (10)
4 (6)
9 (15)
1 (2)
6 (10)
6 (10)
5 (8)
6 (10)
4 (6)
2 (3)
4 (6)
2 (3)
4 (6)
0
1 (2)
0
7 (11)
0
5 (8)
0
1 (2)
0
7 (11)
0
1 (2)
1 (2)
1 (2)
0
a
1 patient had Grade 5 infection during the early treatment.
b
Of the 3 patients, 1 received aspirin (100 mg/day), the second received warfarin with low INR, the third didn’t receive prophylactic treatment.
AE: adverse event; DEX: dexamethasone; DVT: deep vein thrombosis; Gr: grade; LEN: lenalidomide; Ph: phase; pts: patients; SMM: smoldering multiple myeloma.
Engl J Med. 2013;369:438-47
30. Rd treatment didn’t increase risk
of SPM occurence
• 4 patients (6%) in treatment group had second primary tumor a
• Of which, 3 patients had early signs of malignant tumor at
enrollment
• 1 patient (2%) in observation group had MDS
• 5-year cumulative incidence of SPM between the two groups
was comparable (20% vs.25%; P= 0.42)
a
At the time of the writing of this report, one additional patient in the treatment group had received a diagnosis of concomitant incidental prostate cancer
(confirmed by a preplanned biopsy 6 weeks after randomization).
MDS: myelodysplastic syndromes; PSA: prostate-specific antigen; SPM: second primary malignancy; Tx: treatment.
Engl J Med. 2013;369:438-47
31. Long-term follow-up results
provided further evidence of the
efficacy of Rd
Engl J Med. 2013;369:438-47
Maria-Victoria Mateos et al. ASH 2014 #3465
Proportion of
patients with
disease
progression to
symptomatic
disease
Proportion of
patients with 5-
year survival
after
progressed to
symptomatic
MM a
TTP
(Months)
OS
(Survival rate ，
%)
SPM
(cases)
Early follow-
up results
（ median
follow-up
time of 40
months ）
Rd group vs.
observation
group: 23% vs.
76%
Not reported Rd group vs.
observation
group: Not
reached vs. 21
(HR=0.18
P<0.001)
Rd group vs.
observation
group:
94%vs.80%
(HR=0.31
P=0.03)
Rd group vs.
observation group:
4 vs. 1
Long-term
follow-up
results （ me
dian follow-
up time of 64
months ）
Rd group vs.
observation
group: 23% vs.
85%
Rd group vs.
observation
group: 83% vs.
58%
Rd group vs.
observation
group: Not
reached vs. 21
(HR= 6.21,
p<0.0001)
Rd group vs.
observation
group: 93% vs.
67% (HR= 4.35,
p=0.008)
Rd group vs.
observation group:
4 vs. 1
No new SPM cases
a:>25% of increase in monoclonal component with no symptoms
37. SMM: ongoing primary studies
a
Trials may include additional objectives not listed in the table.
BORT: bortezomib; BSC: best supportive care; CFZ: carfilzomib; DEX: dexamethasone; DoR: duration of response; ECOG: Eastern Cooperative Oncology Group; ELO: elotuzumab; Gr: grade;
IV: intravenous; LEN: lenalidomide; NK: natural killer; ORR: overall response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; qd: once daily; QoL: quality of life;
SMM: smoldering multiple myeloma; THAL: thalidomide; TTP: time to progression.
http://clinicaltrials.gov/. Accessed Jan 7, 2015
Phase Study Population
Planning
enrollment
Protocol Main purpose a
Status
3
ECOG E3A06
(NCT01169337)
High-Risk SMM
FLC(< 0.26 or >
1.65 ）
N = 380
Lenalidomide qd for
21 days of 28 day
cycles or BSC until
PD
≥ Grde 3 non-heme
toxicity, PFS, ORR,
OS, QoL, safety
Enrolling
2
HCI33979
(NCT00983346)
SMM N = 20
Bortezomib IV (0.7
mg/m2
) D1, 8, 15, 22
of 42-day cycles
（ 9 cycles ）
Bone effects,
impact on SMM
natural history
Completed
2
12-C-0107
(NCT01572480)
SMM
N = 14
Carfilzomib +
lenalidomide +
dexamethasone
ORR, PFS, DoR,
safety, correlative
studies
Enrolling
2
CA204-011
(NCT01441973)
High-risk SMM
（ Mayo
criteria ）
N = 40
ELO 10 or 20 mg/kg
IV
Change in M-
protein and NK
cells, ORR, PFS
Ongoing
2
UARK 98-036
(NCT00083382)
SMM N = 100
Disodium
Pamidronate +
thalidomide +
Zoledronic acid
ORR, TTP, OS Completed
38. SMM: ongoing primary studies
a
Trials may include additional objectives not listed in the table.
BHQ880: Fully Human, Anti-Dickkopf1 (DKK1) Neutralizing Antibody; IV: intravenous; KIR: killer-cell immunoglobulin–like receptor; ORR: overall response rate; PD: progressive disease;
PK: pharmacokinetics; q2m: every 2 months; qd: once daily.
http://clinicaltrials.gov/. Accessed Jan 7, 2015
Phase Study Population
Planning
enrollment
Protocol Main purpose a
Phase
2
11-C-0024
(NCT01248455)
SMM N = 9
IPH2101 (anti-KIR):
IV q2m for 6 cycles
ORR, safety, PK Ongoing
2
IPH2101-203
(NCT01222286)
SMM N = 30
IPH2101 (anti-KIR)
0.2 or 2 mg/kg IV for
6 cycles
ORR, safety,
pharmacodynamics
Completed
2
CBHQ880A2204
(NCT01302886)
High-risk SMM
（ Mayo
Criteria ）
N = 58 BHQ880A
ORR, safety, PK,
effects on bone
metabolism/density
Completed
2
2009-015
(NCT01589887)
MGUS and/or
SMM
N = 17
Polyphenon E
800mg qd for up to
6 × 28-day cycles or
until PD
Sustained
reduction in M-
protein
Ongoing
2
WSU-2009-015
(NCT00942422)
MGUS and/or
SMM
N = 8
Polyphenon E 800
mg qd for up to
6 × 28-day cycles or
until PD
Changes in M-
protein levels
Ongoing
39. SMM: ongoing primary studies
Phase Study Population
Planning
enrollment
Protocol Main purpose a
Status
2
NCI-2009-00866
(NCT00099047)
MGUS /SMM N=36
Celecoxib or PBO;
BID for 6 mos until
PD, toxicity
Changes in M-protein, IL-6,
β2-microglobulin, IL-1β,
CD4+/CD8+ ratio, COX-2
staining
Ongoing
2
CR100755
(NCT01484275)
High-risk
SMM （ May
o criteria ）
N=100
Siltuximab or PBO;
IV q4w until PD, AE,
or study end
1-y PFS rate, PFS, PD, QoL,
safety, OS
Enrolling
2
12-BI-505-02
(NCT01838369)
SMM N=10 BI-505
Change in M-protein,
safety, PK
Enrolling
1/2
City of Hope
04064 b
(NCT00112827)
MM/progress
ed SMM
requiring
treatment
N=86
Tandem SCT+TMI,
with lenalidomide
for maintenance
treatment
Safety, ORR, PFS, OS Ongoing
1
CR017452
(NCT01219010)
MGUS /SMM
/indolent MM N=30
Siltuximab 15mg/kg
IV q3w for 4 cycles
and maint, for 2 y
QTc interval, safety,
efficacy, PK,
pharmacodynamics
Complete
d
a
Trials may include additional objectives not listed in the table. b
MM pts included.
AE: adverse event; BI-505: Human Anti-Intercellular Adhesion Molecule 1 monoclonal antibody; BID: twice daily; IL: interleukin; IV: intravenous; LEN: lenalidomide; MM: multiple myeloma;
ORR: overall response rate; OS: overall survival; QOL: quality of life; PBO: placebo; PD: progressive disease; PFS: progression-free survival; PK: pharmacokinetics; q3w: every 3 weeks; q4w:
every 4 weeks; SCT: stem cell transplant; TMI: total marrow irradiation.
http://clinicaltrials.gov/. Accessed Jan 7, 2015
40. Early intervention to high-risk SMM will lead to
persistent control or cure of disease
Clinical Cancer Research 17 (6), pp. 1243-1252
41. Promising treatment prospects of SMM
draw much attention from investigators
References to Smoldering Multiple Myeloma
1974-1978 1979-1983 1984-1988 1989-1993 1994-1998 1999-2003 2004-2009 2010-2013
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Hits:GoogleScholar
42. Peking University Institute of
Hematology Peking University
People's Hospital
Beijing Key Laboratory of HSCT
Introduction for
PUIH
Hinweis der Redaktion
MGUS的诊断是1978年提出，SMM是1980年提出。MM基本都是由MGUS进展而来，因而认为MM的早期阶段就是MGUS，也就是癌前病变的阶段。2010年IMWG给出的诊断标准数值界定了MGUS和SMM，3个临床研究证实IgM型MGUS、非IgM型MGUS以及轻链型MGUS的临床进程是一致的。
MGUS是最常见的浆细胞疾病。
Kyle等检测MGUS在50岁以上人群中的发生率，发现MGUS in 3.2% of 21,463 patients，随着年龄增加，患者发病率明显增加，例如80岁以上患者是50-59岁患者的4倍，如果加入血清游离轻链作为MGUS的检测标准，Dispenzieri的结果是50岁以上人群4.2%会有MGUS
在台湾、日本、泰国的报道分别为，较欧美为低
MM以及MGUS患者的一级亲属中MGUS发生率是人群的2.6倍
发生MGUS的诱因中可能的有杀虫剂、肥胖、居住在城市
在进展过程中有拷贝数的改变They found copy number abnormalities in all stages. The incidence of genomic imbalance increased from a median of 5 per case for MGUS to 7.5 per case for SMM and 12 per case for multiple myeloma
2010年IMWG首次提出了SMM的危险分层
在SMM的前5年，每年有10%患者进展为MM，在后5年每年进展的比例是5%，再往后5年每年的进展进率是1%，如果SMM的两个标准都达到，TTP的时间是2年，如果M蛋白没有达到而浆细胞在10%以上，TTP是8年，如果M蛋白达到，而浆细胞数没有达到TTP是19年，也就是分泌旺盛的进展会快一些
NCT01441973：elotuzumab is a human IgG1 monoclonal antibody targeting signaling lymphocytic activation molecule family, member 7 (SLAMF7, also known as CS1). SLAMF7 is a glycoprotein, expressed in myeloma and natural killer (NK) cells. But it could not be detected in normal tissues.
NCT00083382：Disodium pamidronate + THAL + zoledronic acid
NCT01222286：The experimental drug anti-KIR has been shown to help NK cells kill multiple myeloma cells. Researchers are interested in determining whether anti-KIR can be given to individuals with smoldering multiple myeloma to improve their abnormal blood test results
NCT01302886：DKK1 can inhibit osteoblast differentiation. It is a soluble inhibitor transduced by wingless (Wnt) signal, and secreted by myeloma cells. DKK1 level is higher in patients with osteolytic destruction. For bone metabolism and tumor growth, the effect of anti-DKK1 monoclonal antibody has been validated in animal model. DKK1 neutralizing antibody can increase the number of osteoblasts expressing osteocalcin and decrease the number of osteoclast, leading to increased BMD and decreased tumor burden.
Studies confirmed that in human MM rat model, BHQ880 (a human IgG1 anti-DKK1 antibody) could inhibit the osteoclastic effect of myeloma cell and the growth of tumor cell. In addition, it also could down-regulate the ability of marrow stroma cell of secreting IL-6, which suggested that DKK1 could promote the growth and survival of myeloma cell by promoting IL-6 release.
NCT01589887：Polyphenon E Green tea extract contains ingredients that may prevent or slow the growth of monoclonal gammopathy of undetermined significance and/or smoldering multiple myeloma
NCT00099047:Celecoxib cox-2 inhibitor
NCT01484275：Siltuximab (Anti- IL 6 Monoclonal Antibody）
NCT01838369：BI-505, a Human Anti-Intercellular Adhesion Molecule 1 Monoclonal Antibody
NCT00112827：Patients with smoldering myeloma are eligible if there is evidence of progressive disease requiring therapy (&gt;= 25% increase in M protein levels or Bence Jones excretion; Hgb =&lt; 10.5 g/dl; frequent infections; hypercalcemia; rise in serum creatinine above normal on two separate occasion)
NCT01219010：Diagnosis of MGUS (measurable serum M-protein &lt; 3 g/dL AND clonal bone marrow plasma cells &lt; 10% without any end organ damage), SMM (measurable serum M-protein = 3 g/dL OR clonal bone marrow plasma cells = 10% without any end organ damage) or IMM (measurable serum M-protein = 3 g/dL OR clonal bone marrow plasma cells = 10% and = 3 lytic bone lesions but no other end organ damage)
Treatment goals in
smoldering myeloma. Under
active surveillance, patients with
high-risk smoldering MM have a
&gt;84% lifetime risk of progression
to full-blown myeloma (52). One
can envision several scenarios
resulting from treatment of SMM.
Aimed at preventing progression,
SMM could be treated as a
chronic disease, with relatively
benign maintenance therapy used
to control the malignant clone.
Alternately, highly active therapy
could be used with the goal
of cure, though this may prove
challenging in the context of
current treatment options.
However, to responsibly do any
such trial, well-designed
correlative studies should be done
to assess for the theoretical
possibility of unexpected longterm
adverse events or selecting
for more aggressive disease.
