MM 2024 Update - Diagnosis & Risk Stratification PDF

Multiple Myeloma:-2024 update on diagnosis and risk stratification Supervised by Assistant Prof. Dr.Bassam Mohammed Done by Dr. ala’a Kadhim Abbas 3rd stage Haematopathology board student ١ MM 2024 update - ٢٠٢٤ ،‫ تشرين ا...

Multiple Myeloma:-2024 update on diagnosis and risk stratification Supervised by Assistant Prof. Dr.Bassam Mohammed Done by Dr. ala’a Kadhim Abbas 3rd stage Haematopathology board student ١ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧ Contents : Disease overview Diagnostic criteria for multiple myeloma Approach to diagnosis of multiple myeloma Other plasma cells disorders related to MM Molecular classification of MM Prognosis and risk stratification ٢ ٢ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧ Disease overview:- Multiple myeloma is a clonal plasma cell proliferative disorder characterised by the abnormal increase of monoclonal immunoglobulins. Multiple Myeloma accounts for 1% of all cancers and approximately 10% of all haematological malignancies. ٣ ٣ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧  MM is slightly more common in men than in women, and it twice as common in African-Americans compared with Caucasians. The median age of patients at the time of diagnosis is about 65 years. ٤ ٤ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧  Unlike other malignancies that metastasize to bone, the osteolytic lesions in MM exhibit No new bone formation. Bone disease is the main cause of morbidity. Other major clinical manifestations are anaemia,hypercalcemia ,renal failure, and an increased risk of infections. Approximately 1% to 2% of patients have extramedullary disease (EMD) at the time of initial diagnosis, while 8% develop EMD later on in the disease course. ٥ ٥ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧  ‫‪٦‬‬ ‫‪٦‬‬ ‫‪ ٧‬تشرين الثاني‪MM 2024 update - ٢٠٢٤ ،‬‬. Almost all patients with multiple myeloma evolve from an asymptomatic pre-malignant stage termed monoclonal gammopathy of undetermined significance (MGUS). MGUS is present in approximately 5% of the population above the age of 50, and the prevalence is approximately two-fold higher in blacks compared with whites. ٧ ٧ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧ MGUS progresses to multiple myeloma or related malignancy a rate of 1% per year. Since MGUS is asymptomatic, over 50% of individuals who are diagnosed with MGUS have had the condition for over 10 years prior to the clinical diagnosis. In some patients, an intermediate asymptomatic but more advanced pre-malignant stage referred to as smoldering multiple myeloma (SMM) can be recognized clinically. ٨ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧ SMM is prevalent in approximately 0.5% of the general population 40 years of age or older, and progresses to multiple myeloma at a rate of approximately 10% per year over the first 5 years following diagnosis, 3% per year over the next 5 years, and 1.5% per year thereafter. This rate of progression is influenced by the disease burden and the underlying cytogenetic type of disease; patients with t(4;14) translocation, del(17p), and gain(1q) are at a higher risk of progression from MGUS or SMM to multiple myeloma. ٩ ٩ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧  ‫‪١٠‬‬ ‫‪١٠‬‬ ‫‪ ٧‬تشرين الثاني‪MM 2024 update - ٢٠٢٤ ،‬‬ Diagnosis:- The diagnosis of multiple myeloma requires the presence of one or more myeloma defining events (MDE) in addition to evidence of either 10% or more clonal plasma cells on bone marrow examination or a biopsy-proven plasmacytoma. MDE consists of established CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features as well as three specific biomarkers:- ١١ ١١ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧ 1.clonal bone marrow plasma cells ≥60%. 2.serum free light chain (FLC) ratio ≥100 (provided involved FLC level is ≥100 mg/L and urinary monoclonal protein excretion is ≥200 mg per 24 ). 3. more than one focal lesion on MRI. Each of the new biomarkers is associated with an approximately 80% risk of progression to symptomatic end- organ damage in two or more independent studies. ١٢ ١٢ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧ International myeloma working group diagnostic criteria for multiple myeloma Both criteria must be met: 1.Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma. 2.Any one or more of the following myeloma defining events: a.Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: Hypercalcemia: serum calcium >0·25 mmol/L (>1 mg/dl) higher than the upper limit of normal or >2·75 mmol/L (>11 mg/dl). Renal insufficiency: creatinine clearance 177 μmol/L (>2 mg/dl). ١٣ ١٣ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧  Anemia: hemoglobin value of >2 g/dl below the lower limit of normal, or a hemoglobin value 1 focal lesions on magnetic resonance imaging (MRI) studies (at least 5 mm in size). ١٤ ١٤ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧  ‫‪١٥‬‬ ‫‪١٥‬‬ ‫‪ ٧‬تشرين الثاني‪MM 2024 update - ٢٠٢٤ ،‬‬ CBC & Peripheral blood smear :- Normochromic normocytic anemia Variable WBC count & differential Platelets count Normal or low. Rouleaux formation is the most striking feature on the PB smears ,and is related to the quantity and type of the M protein,a Leucoerythroblastic picture may be seen in some cases. Circulating plasma cells can be found,usually in small numbers. ١٦ ١٦ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧  Bone marrow study :- Usually hypercellular B.M. Morphology of PCs varies from mature looking to immature ,plasmablastic and pleomorphic variants(Including multinucleated and mutilobulated forms). Classical PCs are oval shaped with an eccentric nucleus and spoke well or clock face chromatin without nucleolus,there is abundant basophilic cytoplasm with a peri ١٧ nuclear hot. ١٧ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧  Bone marrow plasmacytosis ١٨ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧  Immature forms have more dispersed nuclear chromatin ,high N/C ratio and prominent nucleolus.As nuclear immaturity and pleomorphism rarely occurs in reactive PCs, these are reliable indicators of malignancy. the cytoplasm of myeloma cells has abundant endoplasmic reticulum, may contain condensed or crystallised cytoplasmic Ig producing variety of morphologically distinctive findings, including:- ١٩ ١٩ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧  multiple pale bluish-white,grape like accumulations(Mott cells,Morula cells). cherry red refractive round bodies(refractive bodies). Vermilion staining glycogen rich IgA(flame cells). overstuffed fibrils (Gaucher like cells) and crystalline rods. However, these changes are not pathognomonic of myeloma. ٢٠ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧  ‫‪٢١‬‬ ‫‪٢١‬‬ ‫‪ ٧‬تشرين الثاني‪MM 2024 update - ٢٠٢٤ ،‬‬  Numbers of plasma cells varies from barely increased to upwards of 90%. A few MM cases may show less than 10% PCs in the aspirate smear ,likely due to suboptimal BM aspirate or focal distribution of myeloma in the marrow. In such instances, trephine biopsy sections may show more PCs with or without focal clusters /nodular aggregates or sheets of PCs. ٢٢ ٢٢ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧  It is advisable to stain and examine all aspirate smears as well as touch imprints for a more reliable evaluation of PCs numbers. Rarely they may be seen as bare nuclei(degenerating cells). Normal PCs are found in trephine biopsy as small clusters around arterioles. Myeloma PCs may occur as interstitial clusters, focal nodules, broad bands/diffuse sheets, even packed marrow. ٢٣ ٢٣ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧  It may be vary from classical PC morphology to lymphoid, immunoblastic, spindle/oval to signet ring cells. Normal haematopoiesis is generally preserved, however in diffuse involvement it may be suppressed.scattered osteoclasts and fibrosis may be seen in a few cases. A trephine biopsy is useful in assessing suspected light chain- associated amyloidosis and may show vascular or interstitial amyloid deposition. ٢٤ ٢٤ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧ Bone marrow trephine biopsy section showing bone -Bone marrow trephine biopsy shows marrow infiltration by clusters of plasma cells and diffuse and massive infiltration by some plasma cells with multiple cytoplasmic plasma cells with cytologic atypia. vacuolation (mott cells). H&E x600. Hematoxylin & eosin, ×400. ٢٥ ٢٥ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧ Signet ring plasma cell myeloma ٢٦ ٢٦ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧ Serum protein electrophoresis Serum immunofixation electrophoresis ٢٧ ٢٧ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧ Other tests : 24 hours urine collection for protein electrophoresis and immunofixation electrophoresis is recommended at least once every 3-6 months ,to follow the urine M protein level as well as to detect other renal complications that may be result in albuminuria. The Serum free light chain assay is particularly useful in patients who lack a measurable M protein, provided the FLC ratio is abnormal and the involved FLC level is ≥100 mg/L. ٢٨ ٢٨ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧ Note / The M protein is considered to be measurable if it is ≥1 gm/dl in the serum and or ≥200 mg/day in the urine. The M protein level is monitored by SPEP and serum FLC assay to assess treatment response every month while on therapy, and every 3–4 months when off-therapy. Biochemical tests :- S. Ca ,RFT ,LFT , ESR , LDH ,albumin & B2M ٢٩ ٢٩ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧ Imaging study:- The extent of bone disease is best assessed by low-dose WB-CT or PET/CT imaging. MRI scans are useful in patients with suspected SMM to rule out focal bone marrow lesions that can be seen before true osteolytic disease occurs. MRI imaging is also useful in assessing extramedullary disease, suspected cord compression, or when detailed imaging of a specific symptomatic area is needed. ٣٠ ٣٠ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧ Conventional skeletal survey is less sensitive than low-dose WB-CT and PET/CT and recommended only if resources for more advanced imaging are not available. Serum CrossLaps to measure carboxy-terminal collagen crosslinks (CTX) may be useful in assessing bone turnover and to determine adequacy of bisphosphonate therapy. ٣١ ٣١ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧  ‫‪٣٢‬‬ ‫‪٣٢‬‬ ‫‪ ٧‬تشرين الثاني‪MM 2024 update - ٢٠٢٤ ،‬‬  ‫‪٣٣‬‬ ‫‪٣٣‬‬ ‫‪ ٧‬تشرين الثاني‪MM 2024 update - ٢٠٢٤ ،‬‬  ‫‪٣٤‬‬ ‫‪٣٤‬‬ ‫‪ ٧‬تشرين الثاني‪MM 2024 update - ٢٠٢٤ ،‬‬  Bivariate ow cytometry dot plots the plasma cells (blue and red dots) out of >10 × 106 bone marrow cells (grey events) using a conventional PC gating strategy. Please note the de nition of the phenotypically aberrant plasma cell (clonal PC) population (red dots) as distinct from normal residual PC (dark blue dots) in this case was mainly based on CD56 expression and lack of CD19, con rmed by light chain (CyIgκ) restriction. Other residual leukocyte populations are depicted as grey dots. ٣٥ ٣٥ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧ fi fi fl * Conventional karyotyping to detect Hyperdiploid and deletion 13. * fluorescent in situ hybridization (FISH) probes designed to detect t(11;14), t(4;14), t(14;16), t(6;14), t(14;20), trisomies, and del(17p). * Gene expression profiling (GEP) if available can provide additional prognostic value. ٣٦ ٣٦ MM 2024 update - ٢٠٢٤ ،‫ تشرين الثاني‬٧ Other plasma cell disorders related to MM Non-IgM monoclonal gammopathy of undetermined significance (MGUS): All 3 criteria must be met: 1. Serum monoclonal protein (non-IgM type)