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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 effıcacy 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; 361:489–491.
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 profondità
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 2–3 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.
IgAκ IgAλ
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 λ
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(10):1819-1823
AcMve MulMple Myeloma
Diagnosis • Screening for osteoly3c lesions by WBXR or low-‐dose CT is mandatory for every pa3ent with MM. • MRI may be considered a complementary examina3on given its excellent imaging of the axial skeleton and poten3al iden3fica3on of spinal cord or nerve root compression.
AcMve MulMple Myeloma
Staging and prognosis • The results of MRI and FDG PET/CT give prognos3c informa3on on both progression-‐free survival and overall survival. • The presences of more than 3 focal lesions, extramedullary disease and high SUV values on FDG PET/CT have an independent nega3ve prognos3c value. • A diffuse infiltra3on or an increased number (>7) of focal lesions are MR findings associated with a worse prognosis
AcMve MulMple Myeloma
Role of FDG PET/CT and MRI in response assessment
• Two large prospec3ve studies confirmed the prognos3c value of FDG PET/CT results aWer induc3on treatment and aWer ASCT in transplant-‐eligible pa3ents. • In this seXng, incomplete FGD suppression is associated with a worse overall and progression-‐free survival. • MRI may be useful for the follow up of diffuse BM infiltra3on. Focal lesions may remain hyperintense, and the correla3on with biological responses is only weak
IMAGING FUNZIONALE attività di malattia
risposta alla terapia
• DWI (SENZA MdC)
RM PET • METABOLISMO
IMAGING IBRIDO PET/MRI
KEY POINTS
ConvenMonal morphology, protein electrophoresis, and skeletal survey remain the standard of care in the diagnosis and treatment of paMents with myeloma, but novel cellular, serologic, and imaging assays have found their way into the clinic.
Serum-‐free light chain and the new heavy/light chain assays are
parMcularly valuable for diagnosis and follow-‐up of oligosecretory myelomas; however, these are not currently a subsMtute for the 24-‐hour urine assay.
Fluorescence in situ hybridizaMon (FISH) analysis on purified plasma cells is mandatory at baseline for paMent risk straMficaMon and should only be repeated at relapse/ progression for those paMents iniMally classified as geneMc standard risk.
KEY POINTS
Flow cytometry immunophenotyping and allele-‐specific oligonucleoMde polymerase-‐chain reacMon have contributed to the evaluaMon of minimal residual disease (MRD), which translated into definiMon of high-‐quality responses (immunophenotypic and molecular remission) associated with longer survival and with the possibility of monitoring consolidaMon and maintenance therapies.
Novel imaging techniques (e.g., MRI or PET/CT) have progressively been
incorporated into rouMne pracMce and might become a new standard in the future, parMcularly for idenMficaMon of occult bone disease in smoldering myeloma and to exclude extramedullary disease for definiMon of complete response outside of the bone marrow.