1. Soft-Tissue Plasmacytomas in Multiple Myeloma: Incidence, Mechanisms of Extramedullary Spread, and Treatment Approach Joan Blade´, Carlos Ferna´ndez de Larrea, Laura Rosin˜ol, Marı´a Teresa Cibeira, Raquel Jime´nez, and Ray Powles J Clin Oncol 29:3805-3812 R3 김태영 /Prof. 윤휘중

2. INTRODUCTION MM more than one and a half centuries ago ( London. In 1844) MM are preceded by a MGUS proportion of BMPCs and the size of the M-protein increase CRABsymptoms (hyperCalcemia, Renal insufficiency, Anemia, and/or Bone lesions) soft-tissue extramedullary plasmacytomas (EMPs) - arise as direct extensions from skeletal tumors - from hematogenous metastatic spread

3. INTRODUCTION The focuses of this review - the frequency, location, types of extramedullary myeloma growth - BM myeloma homing and mechanisms in extramedullary myeloma spread - tumor characteristics at extramedullary sites - prognosis and response to therapy deals with extramedullary involvement as soft-tissue plasmacytomas

4. EXTRAMEDULLARY DISEASE IN MM Concept and Incidence Types and Location Bone Marrow Homing and Extramedullary Spread Tumor Characteristics at Extramedullary Sites Prognosis and Response to Therapy

5. EXTRAMEDULLARY DISEASE IN MM Concept and Incidence Autopsy studies have shown extraskeletal involvement in approximately 70% of patients with MM (Thomas et al) Pasmantier studied 57 autopsied patients with MM stage I- intraskeletal stage II- paraskeletal, tumor masses arising directly from bones stage III- extraskeletal, resulting from metastatic spread. In two recent studies 68% and 85% of EMPs - adjacent to bone lesions 32% and 15% of EMPs - hematogenous spread

6. EXTRAMEDULLARY DISEASE IN MM Concept and Incidence The incidence of EMD of newly diagnosed MM :7% to 18% additional 6% to 20% of patients develop plasmacytomas later course 45% of patients with extramedullary involvement at diagnosis had developed EMPs by the time of relapse. (Varettoni et al) allogeneic transplantation-higher extramedullary relapse (37%, 20.4%) ASCT - lower extramedullary relapse(9% to 14%) - younger patients, poor risk factors, clinically aggressive disease - graft-versus-myeloma is more effective on BM than at extramedullary sites extramedullary relapse is more frequent in patients with novel drugs bortezomib, thalidomide, lenalidomide- not associated with higher risk presence of EMD at diagnosis - only significant predictor of extramedullary recurrence

7. EXTRAMEDULLARY DISEASE IN MM Types and Location Most common

8. Local growth

9. Hematogenous spread

10. CNS involvement occurs in approximately 1% of patients Prognosis is poor,with a median survival of 3 months Several imaging techniques MRI, CT, PET-CT

11. EXTRAMEDULLARY DISEASE IN MM Bone Marrow Homing and Extramedullary Spread HGF

12. EXTRAMEDULLARY DISEASE IN MM Bone Marrow Homing and Extramedullary Spread VCAM -> BM homing Migration, Adhesion Loss of CD56 anti–P-selectin antibody, the pan–selectin inhibitor(GMI-1070) => prevent BM homing Increase autonomy of MM tumor

13. EXTRAMEDULLARY DISEASE IN MM Bone Marrow Homing and Extramedullary Spread -Thalidomide exposure induces downregulation of CXCR4 and its ligand SDF-1 =>thalidomide could facilitate extramedullary myeloma growth - CXCR4 inhibitor AMD 3100 :not induce either an increase in tumor progression or engraftment at extramedullary sites

14. EXTRAMEDULLARY DISEASE IN MM Tumor Characteristics at Extramedullary Sites PCs from metastatic EMPs - immature or plasmablastic morphology Myeloma cells from direct extensions are less undifferentiated paired intramedullary and extramedullary PCs have identical Ig heavy chain gene (IgH) sequences RAS mutations were only observed in PCs from extramedullary tumors Extramedullary tumor- CD56 negativity ( Katodritou et al) t(4;14) or t(14;16), 13q deletion in BMPCs, 17q deletion high-risk cytogenetics was similar with and without extramedullary involvement (24% v 21%, respectively) genetic abnormalities of BM myeloma cells are not associated with extramedullary spread

15. EXTRAMEDULLARY DISEASE IN MM Prognosis and Response to Therapy The Pavia group -presence of extramedullary involvement =>shorter progression-free and overall survival. The Royal Marsden group- presence of EMPs at diagnosis => poorer prognosis in patients treated with conventional chemotherapy patients who received highdose melphalan/ASCT => similar outcomes high-dose therapy can overcome the negative impact of EMD

16. EXTRAMEDULLARY DISEASE IN MM Prognosis and Response to Therapy Dimopoulos et al- macrofocal myeloma - age younger than 40 years with MM - multiple skeletal lesions with or without soft-tissue masses - less than10% BMPCs low tumor burden favorable outcome - with an expected median survival exceeding 8 years The Pavia group - 72% of patients with EMPs at least a partial response to initial therapy The Royal Marsden group - conventionally treated, similar response rate irrespective of the presence or absence of EMPs (52% vs 50%) - high-dose therapy similar in those with or without EMPs (90% v 91%)

17. EXTRAMEDULLARY DISEASE IN MM

18. Prognosis and Response to Therapy- novel agent lenalidomide - no published experience on EMPs a more potent immunomodulator than thalidomide Spanish PETHEMA trial- lowest progressive disease rate observed with VTD intensive induction regimen VTD followed by high-dose therapy/ASCT to be the best first-line therapy for younger patients with MM& EMPs.

19. FUTURE RESEARCH DIRECTIONS extramedullary involvement more frequent in the era of novel agents why? different clinical pattern? patients are living longer? frequency of EMD after allogeneic VS autologous transplantation Distinctions between extraskeletal and skeletal EMD remain a key area patients with EMD benefit from combination approaches -combination approaches, consolidation,maintenance

20. FUTURE RESEARCH DIRECTIONS Concerning future research, crucial questions -could genomic studies identify MM with extramedullary potential? -what are the mechanisms involved in hematogenous myeloma dissemination -are these mechanisms different from local extension from bone lesions? -which are the mechanisms of myeloma cell growth and cell survival at extramedullary sites In drug sensitivity studies in mice - the PC growth pattern in experimental mice is consistent with the clinical behavior of myeloma cells in donor patients - each tumor has reproduced the patient pattern of drug sensitivity These experimental models provide an opportunity not only for pathophysiology and molecular studies but also for new drug development