Should we treat smoldering myeloma?

Is the data convincing?

Prof. Prantar Chakrabarti

Head

Department of Haematology

NRS Medical College, Kolkata, India

•What is smoldering myeloma ?

•Why do we call it “smoldering” ?

• Is it a homogenous group ?

•Why do we want to start treating it ?

•Who benefits from the treatment ?

•At what cost ?

ACTIVE MULTIPLE MYELOMA AND ITS PRECURSOR

N Engl J Med 2007;356:2582-90.

Diagnostic Criteria of Smoldering Myeloma in Different Reported Series

IMWG CONSENSUS CRITERIA-2010

Leukemia (2010) 24, 1121–1127

Why do we call it “smoldering” ?

• 10% average annual risk of progression to MM for

the first 5 years after diagnosis,

• Decreasing to 3% annually for the following 5

years

• Becoming the same 1% annual rate of progression

as MGUS thereafterKyle RA, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007;

356:2582-90.

• Approximately 15% of all

cases with newly diagnosed

multiple myeloma

J Clin Oncol 28:690-697; 2009

IS IT UNIFORM?IS IT UNIFORM?

A. BMPC >10%; M band > 30gm/LB. BMPC >10%; M protein > 30gm /L and involved/uninvolved FLC >/= 8C. Involved / uninvolved FLC >/= 100D. Abnormal Immunophenotype with immunoparesisE. > 1 focal bone lesion on whole body MRIF. Based on FISH reportG. High risk interphase FISH and high tumor burden (M protein > 20 g/L)H. M protein > 30 g/L; abnormal FLC; heavy chain IgA or IgM

RISK FACTOR FOR PROGRESSION FROM SMM TO MYELOMA

RISK FACTOR FOR PROGRESSION FROM SMM TO MYELOMA

BLOOD 2013

“It is critical to recognize that in a disease such

as multiple myeloma, in which defining

criteria rely on the presence or absence of

end-organ damage, diagnosis is only as good

as the tools and technology able to detect

end-organ damage”

-- Ola Landgren

How good are our tools ?

• Based on the presence of end-organ damage, including bone

lytic lesions

• Radiological skeletal survey used for the initial workup

• But, 30% to 50% of the bone mass has to be destroyed

before conventional radiography is able to detect the

damage

• New imaging techniques allow detection of myeloma

manifestations earlier than conventional radiography

Trying to define multiple myeloma

• Hillengass et al reported recently that 30% of patients with SMM have BM

infiltration patterns similar to multiple myeloma when using whole body

MRI.

• So these patients should have been classified as Multiple myeloma, and

should get benefit of earlier therapy.

• SMM patients with > 1 focal BM lesion have a significantly (P <0.001)

shorter time (median time to progression: 13 months vs not reached) to

develop multiple myeloma

Seminars in Hematology, Vol 48, No 1, January 2011

• In SMM, MRI of the spine and pelvis can detect occult lesions

• Between 30% and 50% of patients with SMM have an abnormal

MRI

• Diffusion- weighted whole-body MRI (DWI-MRI), dynamic contrast-

enhanced MRI (DCE-MRI), may be able to identify myelomatous

bony involvement at an earlier stage.

• So improved diagnostic technique can enhance our diagnosis of

symptomatic multiple myeloma, earlier than conventional imaging

methods

• Renal impairment is a defining criterion of MM.

• Aside from a serum creatinine 2.0 mg/dL attributable to the plasma cell

dyscrasia, the current guidelines do not define the renal disease any

further.

Acute tubular necrosis resulting from hypercalcemia or nonsteroidal anti-

inflammatory drugs,

Monoclonal immunoglobulin deposition disease

Light chain proximal tubulopathy

• So organ damage apart from CRAB may indicate symptomatic MM

Is CRAB enough ?

• In one recent study, among patients with

symptomatic MM, 74% presented with CRAB

symptoms, 20% presented with non-CRAB

manifestations, and 6% had both clinical features.

• Should we use only CRAB criteria to determine MM ?

Time to modify CRAB ?

Talamo G, et al:  Clin Lymphoma Myeloma Leuk. 2010;10(6)

“The definition of myeloma-related symptomatology

should also be refined to consider the novel imaging

assessments

and

those patients who would currently be considered high- or

ultra-high-risk SMM based on the presence of focal

lesions in MRI or PET/CT and tomorrow be reclassified as

symptomatic MM.”

All that glitters is not gold !

Curr Hematol Malig Rep (2013) 8:270–276

Clinical Lymphoma, Myeloma & Leukemia August 2010

• The linear model of progression is

now challenged.

• The branching model is now

accepted, as different clones of

myeloma cells acquire different

genetic changes and may progress

differentially to MM

• So, all MGUS/SMM patients do not

behave similarly

Progression of MGUS to MM

Different cytokines concentrations show that SMM falls within the continuum of progression of disease biology from MGUS to MM.

A. Zingone et al. / Cytokine 69 (2014) 294–297

• The patient at other end of the spectra

are candidates for early treatment

• The presence of several prognostic

factors are able to discriminate

subgroups of patients with different

degrees of risk of progression to active

disease

Who would benefit most ?

• Numerous studies have

been done to identify the

SMM patients with higher

risk of progression.

Risk stratification schemes for MGUS and Smoldering Myeloma

• Landgren’s team prospectively evaluated this two most widely accepted risk

models, the Mayo and Salamanca criteria, in a series of 77 patients with SMM

• Patients were categorized as low, standard or high risk according to the two

criteria.

• There was significant discordance in overall patient risk classification (28.6%

concordance)

• Significant discordance was also in classifying patients as low versus high

(P .0001), low versus non-low (P .0007), and high versus non-high (P .0001) risk.

Discordance in risk score

Cherry BM, et al. Modeling progression risk for smoldering multiple

myeloma: results from a prospective clinical study. Leuk Lymphoma.

“ Identification and validation of other

biomarkers will be needed before clinicians can

determine whether initiation of early treatment

is beneficial to patients with high-risk SMM. ”

-- Ola Landgren

Expertspeak

Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: biological insights and early treatment strategies; Hematology 2013

• Flow cytometry of abberant plasma

cells

• The serum FLC monomer-dimer

patterns.

• Estimated doubling time of less

than 3 months

Newer markers of Risk stratification

American Journal of Hematology, Vol. 89, No. 9, September 2014

Clinical Lymphoma, Myeloma & Leukemia February 2014

Relative risk of progression

Rajkumar, S. V. & Kyle, R. A. Nat. Rev. Clin. Oncol. 10, 554–555 (2013);

• Bone marrow plasmacytosis of >60% affects 2% to

8% of all SMM patients

• The involved FLC/ uninvolved FLC of >100 or

greater captures approximately 7% to 15% of the

SMM population

• More than 1 focal lesion on whole-body MRI, which

affects 15% of SMM patients

Ultra high risk SMM

What happens when we treat SMM early ?

• Pre 1990 era. Melphalan based therapy

• Post 1990 era. Thalidomide based therapy

• In the Hjorth study, the response rate was similar (52 % vs. 55

%)

• Thalidomide plus zolendronic acid versus zolendronic acid in

SMM patients,

the rate of ≥PR was 37 % in the thalidomide arm versus 0 %,

but there were no significant differences either in the TTP to

symptomatic MM (4.3 vs. 3.3 years) or in the overall survival.

most of the patients discontinued treatment due to peripheral

neuropathy.

• One should be careful to analyze key end points such as time to

progression and overall survival because partial and complete

responses may not be illustrative of benefit

• Paradoxically, patients who initially displayed at

least a PR to thalidomide had a shorter median time

to treatment (< 2 years) than patients who showed

no improvement (not reached in 8 years).

• This may be a result of selection of aggressive

clones because of treatment

What we learnt ?

• The rate of adverse events, particularly

infection, was much higher in the

treatment group than in the observation

group

• all grade infection: 47% [including a fatal

respiratory infection] vs. 22%.

• Median follow-up of 40 months- not

sufficient to allow assessment of different

consequences of the treatment such as

secondary malignancies and negative

effect on further therapy.

-- N Engl J Med 2013;369:438-47.

• Only patients of high risk SMM taken.

• Bone status of the SMM patients were not

included

• No MRI was performed at baseline and a higher

incidence of MRI signal abnormalities in the

observation group could not be excluded.

Drawbacks

Drawbacks contd..• Although these therapeutic strategies have

facilitated improved survival, cure remains elusive.

• 4 cycle Lenalidomide/ dexamethasone without

transplant in symptomatic myeloma has 3 year

survival of only 55 %.

• So, Lenalidomide/ dexamethasone is generally

given indefinitely until disease progression ( based

on single-institution studies as well as on the

E4A03 trial.)

• On a cautionary note, there is potential for the

development of long-term toxicities with prolonged

novel agent therapy

• This strategy may result in overtreatment of

approximately 40% of patients at 3 years, 30% of

patients at 4 years, and 20% of patients at 5 years

• With the regimens (ie, lenalidomide plus

dexamethasone), the annual cost of therapy is

approximately $100 000 USD, not including the

extra monitoring required for patients on active

therapy and management of adverse events.

Drawbacks contd..

• Addition of DEX was allowed at the time of asymptomatic biologic progression in treatment group but not in the observation group. (‘time varying confounding’ effect) – this might have given a false impression on Overall survival difference

• Trial results only applicable to a subset with SMM (40% diagnosed with a flow based definition – A methodology not available in many institutions)

Drawbacks contd..

• Patients in the observation arm were not only differently managed compared with patients in the treatment arm, but were also not managed according to current “good” clinical practices checking the monoclonal immunoglobulin and other disease markers including MRI for initiating

treatment before the occurrence of symptomatic disease

Drawbacks contd..

• In highly active disease, i.e. ultra high risk, may simulate

the scenario 1, and can benefit from early treatment.

• But other SMM patients will follow scenario 2 or 3, where

therapy will not change the position, rather may be

detrimental.

TRIALS IN PATIENTS WITH SMOLDERING MYELOMA

Swedish Myeloma Registry

NEJM 2013

From January 1, 2008, through December 31, 2011, a total of 2494 patients (median age, 72 years) received a diagnosis of multiple myeloma, of whom 360 (14.4%) had smoldering multiple myeloma. Of the patients with smoldering multiple myeloma, 104 (28.8%) had high-risk disease (defined as an M-protein level of ≥3 g per deciliter and plasma-cell infiltration of ≥10%); these patients accounted for 4.2% of all patients with multiple myeloma. After 2 years, 56.6% of the patients with high-risk smoldering multiple myeloma had progression to symptomatic disease, and after a median follow-up time of 29.8 months, 70.4% had progression.

29% will be considered for early treatment according to criteria.

Rate of progression - >80% at 2-3 years

LEN –DEX based on phase 3 data

HOWEVER, THIS CONCEPT NEEDS TO BE ENDORSED BY IMWG FOR A CONSENSUS

BLOOD, 19 DECEMBER 2013 x VOLUME 122, NUMBER 26

TREATMENT YES / NO

? Second Malignancy

Side effects

Drug resistance

? Quality of life

Less progression to

MM