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UOC Ematologia e CTMO Ospedale Oncologico A. Businco - Cagliari

Daniele Derudas

I nuovi strumenti laboratoristici e di imaging nella gestione clinica del Mieloma Multiplo

Cagliari, 30 maggio 2014

prognosis and follow-up of monoclonal gammapathy of undetermined significance ( MGUS)

"dangerous" MGUS

prognosis and follow-up of asymptomatic multiple myeloma (MM)

diagnostic work-up and management of symptomatic MM

SUMMARY

Diagnostic assays have three main objectives:

to contribute to the diagnosis and differential diagnosis of monoclonal gammopathies to yield information about prognostic factors in order to facilitate the therapeutic decision-making process to provide appropriate tools to monitor treatment effcacy It should be noted that many of the laboratory parameters contribute to more than one objective.

Diagnosis

Disease definitions for the non-IgM monoclonal gammopathies

Essential procedures for the diagnosis and follow-up of multiple myeloma

Serum Free Light Chain Assays: Polyclonal Ab to sequestered Light Chain epitopes

Approximate diagnostic sensitivity of tests for monoclonal gammopathies.

Light Chain Myeloma

Bradwell et al. Lancet. 2003; 361:489491.

Nonsecretory Myeloma Less than 3% of all patients with myeloma No paraprotein detectable on SPEP, UPEP 85% of NSMM have cytoplasmic M-protein in plasma cells by IHC 68% of NSMM detectable by sFLC testing Patients now been reclassified as hyposecretory or oligosecretory

Drayson et al. Blood, 2001

Multiple Myeloma: - glomerulus undamaged -tubule damaged Proteinuria: only FLC

LCDD: - glomerulus dameged -tubulus very damaged Proteinuria: albumin and FLC

AL Amyloidosis : - glomerulus damaged -tubulo little dameged Proteinuria: albumin, few FLC

Glomerulus

Tubule

NEPHRON

Examination of PROTEINURIA

C. Pozzi, Web Simposium 2012

MCR

ICR

sCR

CR IF- CR

Ridurre il tumor burden

Aumentare la profondit

della risposta

CR IF-: CR immunofixation negative

sCR: Stringent CR

ICR:immunofphenotipic complete response

MCR: molecular complete response

CR : complete response

International Myeloma Working Group uniform response criteria: CR and other response categories

International Myeloma Working Group uniform response criteria: CR and other response categories

Serum Free Light Chain assays predict CR earlier than SPEP

Stage II/III MM, N = 42 at Memorial Sloan Kettering1 Dox/Dex 23 cycles thal/dex 2 cycles Serum free light chain assays performed q cycle RR 91% 7 CR, 9 nCR, 22 PR Normalization of serum free light chain ratio after 1 or 2 cycles was significantly associated with subsequent CR or nCR (p = 0.003) May allow addition of alternative treatment at an early stage if free light chain ratio remains abnormal Univ of Arkansas monitoring q cycle2 1Hassoun et al. Br J Haematol 2005. 2 van Rhee et al. Blood. 2007.

Serum Free Light Chain Assays

Monitoring response to therapy Shorter half-life of FLC provides more rapid response indicator than monitoring intact Ig Abnormal ratio can detect underlying disease when SPE or IFE normalize

Minimal Residual Disease

31% of pts have SPE negative but abnormal FLC ratio

Normal FLC ratio : stringent complete response

Free light chain escape

A: Kaplan-Meier curves of survival from first relapse for IgG patients relapsing with whole paraprotein secretion (PO), both paraprotein and light chains (PLC) or patients with FLC escape phenomenon; B: Kaplan-Meier curves of survival from first relapse for IgA patients relapsing with whole paraprotein secretion (PO), both paraprotein and light chains (PLC) or patients with FLC escape phenomenon

A: Kaplan-Meier curves of overall survival from diagnosis for patients relapsing with whole paraprotein secretion (PO), both paraprotein and light chains (PLC) or patients with FLC escape phenomenon; B: Kaplan-Meier curves of survival from first relapse for patients relapsing with whole paraprotein secretion (PO), both paraprotein and light chains (PLC) or patients with FLC escape phenomenon

Model of Darwinian evolution in MM assessed by the type of paraprotein secreted: one clone is able to produce a complete antibody, while the other secretes only a FLC. Chemotherapy is differentially active against the different clones, as different is the impact of other evolutionary bottlenecks such as microenvironment or competition for the stem cell niche. The different selective pressures applied will determine which of the clone(s) will survive and give rise to the relapse. The different clonal composition at relapse will ultimately impact on the different sensitivities to subsequent treatments and therefore on survival.

IgA IgA

Heavy Light Chains

HLCR detects relapse 1st

IFE and HLC ratio normal at the same time HLC ratio became abnormal indicating relapse when IFE was still normal IFE remained normal for further 5.5 months Laboratory relapse was confirmed by IFE Later clinical relapse was noted.

Ludwig Leukemia 2013

Paziente IgA

Hevylite anMcipano la recidiva di 2 mesi

Lim. Inf. HLCr

Lim. Inf. FLCr

Modificata da Astolfi et al., BC October 2013

ReacMve plasmacells Monoclonal plasmacells

Number Not pathognomonic Not pathognomonic

Morphological maturity Not pathognomonic

Not pathognomonic

Morphology of immaturity Rare Reliable indicator

Russel bodies Not pathognomonic

Not pathognomonic

Immunophenotyping CD19+, CD27+, CD45+, CD28-, CD38+,CD138+/-, CD56-

Mainly CD19-, CD27-,CD45-, CD28+, CD38+, CD138+, CD56+/-

IgG Policlonal Monoclonal

Origin Expansion of normal plasma cell progenitors (plasmablasts CD38+, CD138-) and plasma cell precursor (CD38+, CD138+) keeping differenMaMon capacity

Expansion of a clone of differenMated B cells Ig-secreMng terminals to heavy chain with the "Switch" isotypic

Additional response criteria and updates

Andy C. Rawstron et al.

Minimal Residual Disease

Prognostic Significance of Cytogenetics Abnormality Prognosis Non hyperdiploid karyotype Adverse Cytogenetic 13/del(13) Adverse FISH Del(17p) Adverse FISH t(11;14) Adverse FISH t(4;14) Favorable FISH t(14;16) Adverse FISH deletion 1 q Adverse FISH amplification 1 p Adverse

PFS and OS estimates (4-year) for ISS-iFISH categories group I, group II and group III. (a) PFS and (b) OS for the three groups derived from recursive partitioning.

Risk stratification and possible therapeutic questions within each risk categories

Risk classifica3on Baseline

The risk of death within 2 years of the start of therapy was related to 3 independent variables in a mul=variate analysis:

LDH>normal (p=0.0014) ISS-3 (p=0.0097) presence of t(4;14) or 17p dele=on (p=0.0002) Method

These 3 variables were then used to create a scoring system from zero to 3 to predict survival for the overall popula=on in the IFM2005-01 trial.

Score Zero = neither LDH, nor ISS-3, nor t(4:14) or del 17p. Found in 57% of IFM pa=ents Score One = 1 adverse factor, either LDH, ISS-3, t(4;14) or del 17p. Found in 32% of IFM

pa=ents Score Two = high LDH plus ISS-3, without t(4;14) or del 17p. Found in 6% of IFM pa=ents Score Three= presence of t(4;14) and/or 17p dele=on with(in addi=on) either ISS-3 or high

LDH. Found in 5% of IFM pa=ents Based on these scores they found the 4 year OS was:

Score Zero = 84% Score One =73% Score Two = 68% Score Three = 19 months

Moreau et al Abstract 598, ASH 2012

Prognostic Factors in Myeloma

Risk Stratification of Active Multiple Myeloma

Incidence and Median Overall Survival by Risk Group

Essential procedures for the diagnosis and follow-up of multiple myeloma

INDICATIONS FOR SPINE AND PELVIS MRI MRI is mandatory in pts with a presumed diagnosis of solitary plasmacytoma MRI should be considered in patients with smoldering myeloma. MRI is strongly recommended in non secretory MM MRI should be considered in patients as routine evaluation at diagnosis because (1) unsuspected focal lesions and soft tissue plasmacytomas can be visualized and (2) pattern of MRI abnormality may have prognostic significance MRI is mandatory in MM with a suspicion of cord compression and/or collapsed vertebras.

IMW Consensus, Blood 2011

Kaplan Mayer OS from starting therapy according to MRI Focal Lesions

Walker et al, JCO 2007

P< .0001

Diagnostic studies on magnetic resonance imaging

Diagnostic studies on FDG PET and FDG PET/CT

PROGNOSTIC SIGNIFICANCE OF CT-PET

PET-CT as tool of response assessment after/during therapy

Zamagni et al, Blood 2011

TTP AND PFS ACCORDING TO BASELINE FDG-PET/ CT: NUMBER OF LESIONS

TTP, PFS AND OS ACCORDING TO BASELINE FDG-PET/CT: SUV VALUE

TTP, PFS AND OS IN PATIENTS WITH EXTRAMEDULLARY DISEASE

Zamagni et al, Blood 2011

Blood. 2013;121(10):1819-1823

Blood. 2013;121(