BIOLOGICAL INSIGHTS INTO MGUS AND SMOLDERING MYELOMA

1. MONOCLONAL GAMMOPATHY OF
UNDETERMINED SIGNIFICANCE AND
SMOLDERING MULTIPLE MYELOMA:
BIOLOGICAL INSIGHTS AND TREATENT
STRATEGIES.
-FAHEEMA HASAN, MD
SR DM, HEMATO ONCOLOGY,
SANJAY GANDHI POST GRADUATE INSTITUTE OF
MEDICAL SCIENCES.

3. PRECURSOR STATES OF MYELOMA
MGUS and SMM were first described by Kyle and Greipp in 1978
and 1980 as the
 presence of an M-protein in the serum and/or
 excess BM plasma cells in the absence of clinical evidence of
either multiple myeloma or another lymphoproliferative disorder.

4. 1ST DEFINITIONS
First consensus definitions of MGUS and SMM
were put forth by the IMWG in 2003.
 MGUS was defined as the presence of
serum M-protein < 3 g/dL with fewer than
10% monoclonal plasma cells in the BM.
 SMM was defined as either serum M-
protein ≥ 3 g/L or ≥ 10% monoclonal plasma
cells in the BM.

5. Kyle R et al. N Engl J Med 2006;354:1362-1369
MONOCLONAL GAMMOPATHY OF UNDETERMINED
SIGNIFICANCE.
Kyle RA et al. N Engl J Med 2006; Volume 354:1362-1369
• 3% of general population
>50 years
• 1.7% in 50-59
• >5% in over 70
• M>F
• Race
• rate of progression from
MGUS to MM is
approximately 1% of
patients per year
All three criteria must be met:
•Serum monoclonal protein <30 g/L
•Bone marrow plasma cells <10%
•Absence of myeloma defining events or amyloidosis

6. SUBTYPES OF MGUS
1) IgM MGUS( Lymphoplasmacytic)
can progress to smoldering WM and to symptomatic WM
or NHL or even very rarely to MM
2) Non–immunoglobulin M MGUS( plasma cell type)
a risk of progression to MM or solitary plasmacytoma;
3) Light-chain MGUS ( plasma cell type)
a risk of progression to the light-chain type of MM.

7. SECONDARY MGUS
• Development of a new monoclonal protein during the course
of multiple myeloma that has an isotype (heavy and/or light
chain) distinct from the original clone (eg, IgM MGUS in a
patient with IgG multiple myeloma).
• In a series 6.6% at a median of 12 months from the diagnosis
of myeloma .
• More than one isotype occurred in approximately 30% of
patients.
• More common among patients who had undergone
hematopoietic cell transplantation and was associated with
superior survival.
• The MGUS commonly resolved without treatment with a
median duration of approximately six months.

8. RISK FACTORS CONTRIBUTING TO
PROGRESSION FROM MGUS TO MM
• Serum M protein > 1.5 g/dL.
• Non-IgG MGUS (ie, IgA, IgM, IgD MGUS).
• Abnormal FLC ratio (ie, ratio of kappa to lambda free light chains <0.26 or
>1.65).
Lifestyle and environmental risk factors - obesity, immune dysfunction,
and agricultural, chemical, and radiation exposure.

9. SMOLDERING MYELOMA
Heterogeneous disease entity that includes patients with
higher disease burden than in MGUS but remain
asymptomatic.
- Serum M protein (IgG or IgA) ≥3 g/dL or Urinary M
protein ≥500 mg/24 h and/or
-Clonal BMPCs 10%-60%
and
Absence of MDEs or amyloidosis

10. Kyle R et al. N Engl J Med 2007;356:2582-2590
WHY SMOLDERING?
An overall risk of progression of 10% per year for the first 5 years, 3%
per year for the next 5 years, and 1% per year for the last 10 years

11. CLINICAL PREDICTORS OF PROGRESSION
• BMPC levels ≥10%,
• serum M protein levels≥3 g/dL, and
• abnormal sFLC ratios (< 0.125 or > 8)

12. COMPARISON OF THE TWO POPULAR
RISK STRATIFICATION MODELS IN SMM

13. OTHER NAMED RISK STRATIFICATION
SYSTEMS

14. CRITERIA FOR HIGH RISK SMOLDERING
MULTIPLE MYELOMA
A)Bone marrow clonal plasma cells 10%
B) And any one or more of the following
• Serum M protein >30 g/L
• IgA SMM
• Immunoparesis with reduction of two uninvolved immunoglobulin isotypes
• Serum involved/uninvolved free light chain ratio 8 (but less than 100)
• Progressive increase in M protein level (Evolving type of SMM)
• Bone marrow clonal plasma cells 50%-60%
• Abnormal plasma cell immunophenotype (95% of bone marrow plasma
• cells are clonal) and reduction of one or more uninvolved immunoglobulin
• isotypes
• t (4;14) or del 17p or 1q gain
• Increased circulating plasma cells
• MRI with diffuse abnormalities or 1 focal lesion
• PET-CT with focal lesion with increased uptake without underlyingosteolytic bone
destruction
(Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma. Blood. 2015.)

15. THE STORY ALL ALONG AND WHY?
The current 5-
year survival rate
does not exceed
50%

16. THE MOLECULAR MAKEUP OF MYELOMA
AND ITS PRECURSOR DISEASE STATES.
• Existence of a well-defined clinical spectrum of premalignant
states provides the opportunity to study premalignant cells in
their clonal evolution.
• Genetic events detected at the MGUS stage are likely to be
primary events.
• Events present at the MM stages that were absent in MGUS
are probably secondary events leading to tumour progression
.
• NO MORE LINEAR PROGRESSION BUT A DARWINIAN MODEL.

17. The transition of MGUS to plasma cell leukemia has been traditionally represented as a linear
pathway .
But the progression myeloma is through branching pathways similar evolution of species .
This simple branching model clearly has implications for targeted treatment because the
multiple distinct subclones could lead todifferential responses to treatment.
Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma. Nat Rev Cancer. 2012

18. FROM PLASMA CELL TO MGUS
Cytogenetic aberrations that occur in this transition is mainly of
2 types.
1) hyperdiploid (approximately 50%) - with extra copies of the
odd-numbered chromosomes.
2) nonhyperdiploid (approximately 40%)- associated with
translocations IgH locus.
• Less than 10% of patients are nonhyperdiploid and are negative
for known translocations.
• Hyperdiploid MM is associated with a relatively better
prognosis.

19. Pathogenesis of Multiple Myeloma
TWO MAJOR PATHWAYS
non-hyperdiploidHyperdiploid
IgH TranslocationsInfrequent IgH
Translocations
4p16
FGFR3+
MMSET
11q13
(cyclin D1)
6p21 (cyclin
D3)
20q11
(mafB)
16q23 (c-
maf)
Multiple trisomies of
chromosomes 3, 5, 7, 9,
11, 15, 19 and 21
Hideshima et al, Blood, August 2004, 607-618
PRIMARY EVENTS
Overexpression of a
cyclin D gene is present in
both hyperdiploid
and nonhyperdiploid MM
and is an initiating event.
Hideshima et al, Blood, August 2004, 607-618

20. TRANSLOCATIONS INVOLVED IN
MULTIPLE MYELOMA
S Manier et al, Nature Reviews Clinical Oncology ; 2016.

21. SECONDARY EVENTS INVOLVED IN
PROGRESSION
Copy number variations.
Genetic mutations
Epigenetics
Tumour microenvironment

22. COPY NUMBER VARIATIONS
• CNVs are more frequently found in MM than
MGUS by SNP basedarrays
• more common in nonhyperdiploid MM.
• Gain of 1q21, Deletion of 1p, Del(13), Del
(17p) are seen more commonly in MM than
MGUS and can be implicated in the
progression.

23. EPIGENETICS AND miRNAS
• The most important epigenetic changes during
the transformation from MGUS to multiple
myeloma are global DNA hypomethylation and
gene specific DNA hypermethylation.
• miRNAs are noncoding, single-stranded RNA
molecules known to influence various tumor
behavior by regulating gene expression.
• miR-32 and the miR-1792 cluster among multiple
myeloma patients & is not found in MGUS
patients.

24. RECURRENT MUTATIONS
• Upto eight driver genes that are recurrently
mutated on progression from MGUS to MM
KRAS, NRAS, BRAF, TP53 etc by NGS in one
study.
• ? Contamination by normal plasma cells?
• GEP of MYC showed MYC activation in the
majority of MM (67%), whereas little to no
activation was demonstrated in healthy
controls and MGUS

25. THE BM MICROENVIRONMENT
• GEP of BM Endothelial cells in MGUS and MM
patients revealed differential expression genes
involved in resistance to apoptosis, ECM
formation, bone remodeling, cell adhesion, and
angiogenesis.
• Proteomic analysis-Annexin A2 (ANXA2) and
Galectin-2 were identified in the BM ECM of MM
but were absent in BM from healthy donors or
MGUS patients.
• Increased circulating endothelial progenitor cells-
? Target for therapy.

27. PROPOSED MODEL OF CLONAL
EVOLUTION IN MULTIPLE MYELOMA
EXPANSION OF
ALTERED
CLONES THAT
ARE ALREADY
PRESENT –
DARWINIAN
MODEL
S Manier et al, Nature Reviews Clinical Oncology ; 2016.

28. • WHAT DOES THE ONGOING RESEARCHES SAY?

29. PCROWD ANALYSIS AT DFCI-
GHOBRIAL LABS

30. PCROWD CONTINUED..

31. DFCI

33. MANAGEMENT OF MGUS
• Management of MGUS requires an
understanding of the risk of progression to
symptomatic disease requiring therapy.
• Therefore Risk stratify.

34. MANAGEMENT OF MGUS

35. MANAGEMENT OF SMOLDERING
MYELOMA
• Baseline investigations should include SPEP, CBC, serum
creatinine, serum calcium, UPEP with immunofixation, FLC
ratio, and bone marrow biopsy.
• Imaging skeletal survey + (low-dose whole-body CT or
PET/CT, MRI) of the whole body or spine and pelvis)
• Repeat in 2 to 3 months .
• If the results of these tests are stable, the span of time
between testing can be lengthened to every four to six
months for one year, then to every 6 to 12 months

36. TO TREAT OR NOT TO TREAT
SMOLDERING MYELOMA??
• Before 1990, in the Melphalan based trials conducted there
were no benefit but therapy was rather detrimental
• Post 1990 era, Thalidomide , Bisphosphonates were tried still,
no absolute increase in OS, or reduction in TTP was noted,
and most patients discontinued due to neuropathy.
• As we develop therapies that have lower toxicities and have
increasingly higher efficacy for the disease in which they are
intended,including the possibility of cure, the number of
patients willing to undergo such treatments will also increase.

37. TREATMENT STRATEGIES
Ola Landgren, haematologica | 2014; 99(11)

39. Treatment of high risk SMM: first randomized trial
showing benefit in treatment arm--QuiReDex
High risk
SMM*
Lenalidomide 25 mg/d D1-21
Dexamethasone 20 mg/d
D1-4, 12-15
Lenalidomide 10 mg/d
D1-21 every 2 mos
Observation
Induction phase
28d cycles x 9 cycles
Maintenance
*High risk SMM
Both BMPC≥10% AND M-protein≥ 3 gm/dL
OR
one of the above plus aPC >95% and immunoparesis
Mateos M et al. N Engl J Med 2013;369:438-447.
119 high risk SMM patients
randomized
-

40. Mateos M et al. N Engl J Med 2013;369:438-447.
Len/Dex versus Observation in High Risk SMM: TTP

41. Mateos M et al. N Engl J Med 2013;369:438-447.
Len/Dex versus Observation in High Risk SMM: OS

42. Spanish Trial Conclusions
• Early intervention in high risk SMM
– Prolongs TTP
– Improves OS
– Does not result in appreciable toxicity
• Prevents irreversible damage to kidneys and bones
“on our watch!”

43. Interpretation
This study is, to our knowledge, the first randomised trial in which early treatment
has been assessed in selected patients with high-risk smouldering multiple
myeloma. Positive results from ongoing trials would support the use of early
treatment for patients with high-risk disease in the near future.

44. Current Studies in High-Risk Smoldering MM
•Biomarker study of elotuzumab (phase II)[2]
•Siltuximab (anti IL6) or no treatment (phase II)[3]
•Lenalidomide or observation (phase III)[1]
•Elotuzumab-Lenalidomide-dex
•Daratumumab single agent at different doses (Centaurus trial)
•Carfilzomib, lenalidomide, and dexamethasone (phase II)[5]:
1. ClinicalTrials.gov. NCT01169337.
2. ClinicalTrials.gov. NCT01441973.
3. ClinicalTrials.gov. NCT01484275.
4. ClinicalTrials.gov. NCT01302886.
5. ClinicalTrials.gov. NCT01572480.

45. When Should Treatment Be Initiated?
Potential New Myeloma or Smoldering Myeloma
Observation
Rajkumar SV, Landgren O, Mateos MV. Blood 2015
Any Myeloma Defining Events?
• CRAB,
• >60% PC,
• FLC >100,
• MRI >1 focal
No Myeloma Defining Events (SMM)
Treat as Myeloma
High Risk SMM
(Median TTP ~2 years)
Low Risk SMM
Consider
Treat as Myeloma
Evolving, or
Many high risk
factors
Clinical Trials
Rajkumar SV, Landgren O, Mateos MV. Blood 2015

46. What if your friend is walking towards a
cliff?
• Wait until they are falling to rescue them?
• What if they are running?
• What if they are enjoying the walk?

47. IDEAL STATE!!

48. SUMMARY
• MGUS and SMM are precursor states of MM.
• MGUS IS NO MORE ‘US’.
• Management of both these states depends on the risk stratification.
• MYC and mutations involving the MAPK pathways seems to predict
progression to MM
• Future goals should be to provide molecularly based predictions and use
these molecular markers to counsel.
• No place of treatment for MGUS and low risk smoldering myeloma .
• Observation is still the standard of care for SMM; however, selected high
risk SMM patients with multiple risk factors can be considered for therapy.

49. REFERENCES:
• Niels N, Ingrid S, Reinier R, Victor P. From MGUS to Multiple Myeloma, a
Paradigm for Clonal Evolution of Premalignant Cells. Cancer Res; 78(10)
May 15, 2018
• Rajkumar SV. Multiple myeloma: 2018 update on diagnosis, risk-
stratification, and management. Am J Hematol, 2018
• Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma.
Blood. 2015;125(20):3069–3075.
• Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF,Offord JR, et
al. Prevalence of monoclonal gammopathy of undetermined significance. N
Engl J Med 2006;354:1362–9.
• Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield
JM, et al. Clinical course and prognosis of smoldering (asymptomatic)
multiple myeloma. N Engl J Med 2007;356:2582–90.
• Landgren O, Kyle RA, Pfeiffer RM, et al. Monoclonal gammopathy of
undetermined significance and smoldering multiple myeloma: biological
insights and early treatment strategies. Hematology 2013.
• Salomon Manier, Karma Z. Salem, Jihye Park, Dan A. Landau, Gad Getz
and Irene M. Ghobrial . Genomic complexity of multiple myeloma and its
clinical implications . Nature Reviews Clinical Oncology 2016.