Myeloma Bone Disease. Evangelos Terpos, MD, PhD. National & Kapodistrian University of Athens, School of Medicine, Athens, Greece

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1 Evangelos Terpos, MD, PhD National & Kapodistrian University of Athens, School of Medicine, Athens, Greece Myeloma Bone Disease Disclosure of Conflict of Interest (List) Honoraria Advisor Steering Committee Educational grants Novartis, Amgen, Celgene Amgen Amgen, Janssen-Cilag Amgen, Janssen-Cilag, Celgene

2 Myeloma Bone Disease Evangelos Terpos, MD, PhD Department of Clinical Therapeutics University of Athens School of Medicine Athens, Greece

$increased bone resorption and impaired bone formation Sequelae Pathological fractures Osteoporosis Hypercalcemia Bone pain Spinal cord compression Kyle. Mayo Clin Proc.$

3 Bone Disease in Multiple Myeloma A burdensome and frequent complication in MM Present in up to 80% of patients at diagnosis Characterized by osteolytic bone lesions secondary to increased bone resorption and impaired bone formation Sequelae Pathological fractures Osteoporosis Hypercalcemia Bone pain Spinal cord compression Kyle. Mayo Clin Proc. 1975;50:29-40

4 Bone metabolism: a balance between osteoblasts and osteoclasts Seeman E, et al. N Engl J Med. 2006;354: van Bezooijen RL, et al. Cytokine Growth Factor Rev. 2005;16:

5 Regulation of osteoblast function Logothetis CJ, et al. Nat Rev Cancer. 2005;5:21-8.

6 Wnt Signaling and Osteoblasts Piters E, et al. Arch Biochem Biophys. 2008;473:112-6.

7 RANK ligand: an essential mediator of osteoclasts RANKL RANK CFU-M Prefusion osteoclast Growth factors Hormones Cytokines Multinucleated osteoclast Mature osteoclast Osteoblast lineage Bone CFU-M = colony forming unit macrophage. Boyle WJ, et al. Nature. 2003;423:

8 Increased bone density associated with absence of RANKL Preclinical experiments Normal RANKL knockout Li J, et al. Proc Natl Acad Sci. USA. 2000;97:

Osteoprotegerin: the decoy receptor of RANKL Osteoclast formation, function, and survival inhibited by OPG RANKL RANK OPG CFU-M Prefusion osteoclast Growth

9 Osteoprotegerin: the decoy receptor of RANKL Osteoclast formation, function, and survival inhibited by OPG RANKL RANK OPG CFU-M Prefusion osteoclast Growth factors Hormones Cytokines Multinucleated osteoclast Inactive osteoclast Osteoblast lineage Bone OPG = osteoprotegerin. Boyle WJ, et al. Nature. 2003;423:

Reduced bone density associated with absence of OPG BV%TV 100 50 40 30 20 10 0 10 * * OPG

10 Reduced bone density associated with absence of OPG BV%TV * * OPG +/+ OPG +/ OPG / * P < (compared with OPG +/+) Bucay N, et al. Genes Dev. 1998;12:

11 RANKL/OPG balance drives osteoclast activity Alterations of the RANKL ligand/opg ratio are critical in the pathogenesis of bone diseases that result from increased bone resorption Promotes OC activation Osteoclast activity Prevents OC activation OC = osteoclast. Hofbauer LC, et al. JAMA. 2004;292: Lacey DL, et al. Cell. 1998;93: Boyle WJ, et al. Nature. 2003;423:

Myeloma Microenvironment and Bone Disease Myeloma cells RANKL OPG

activin-a IL-6, IGF-1 BAFF, APRIL a4b1 integrin RANKL RANKL OPG

BMSCs Terpos E, et al. Ann Oncol. 2005;16(8):1223-1231.

MIP-1a, MIP-1b, SDF-1a, IL-3, HGF, OPN Osteoclast precursor

12 Myeloma Microenvironment and Bone Disease Myeloma cells RANKL OPG (-) CD138 Osteoblasts Dkk-1, sfrp-2 balp, osteocalcin sclerostin, activin-a IL-6, IGF-1 BAFF, APRIL a4b1 integrin RANKL RANKL OPG VCAM-1 VCAM-1 (-) RANKL RANK IL-6 IL-11, IL-1b, bfgf TNFa, M-CSF BMSCs Terpos E, et al. Ann Oncol. 2005;16(8): Moreaux J, et al. Blood. 2011;117(4): MIP-1a, MIP-1b, SDF-1a, IL-3, HGF, OPN Osteoclast precursor Collagen type-1 degradation products: NTX, ICTP, CTX TRACP-5b Activated osteoclasts Bone resorption Bone matrix

13 Osteoclasts: Key for Myeloma Cell Growth Without Osteoclasts With Osteoclasts Myeloma cell culture after 14 days Abe M, et al. Blood 2004;104(8):

14 Sclerostin in multiple myeloma Sclerostin (pg/ml) p = 0.03 p = * p = * * p = 0.02 * p < p < Controls (n = 20) MM diagnosis (n = 147) MM plateau (n = 29) MM relapse (n = 88) Asymptomatic MM (n = 20). Terpos E, et al. Int J Cancer. 2012;131:

15 Sclerostin and bone disease in multiple myeloma Sclerostin (pg/ml) p < Controls (n = 20) MM no fractures (n = 113) MM with fractures (n = 34). Terpos E, et al. Int J Cancer. 2012;131:

Activin and bone growth Activin A a promoter

osteoblast differentiation in MM Osteoclast

receptor type IIA Increased bone resorption

16 Activin and bone growth Activin A a promoter of osteoclastogenesis and also a inhibitor of osteoblast differentiation in MM Osteoclast Activin stimulates osteoclasts Activin inhibits osteoblasts Osteoblast Activin Activin receptor type IIA Activin Activin receptor type IIA Increased bone resorption Reduced bone formation Vallet S, et al. Proc Natl Acad Sci. 2010;107:

17 Activin A promotes multiple myeloma-induced osteolysis Activin A (pg/ml) Activin A levels are increased in bone marrow plasma of MM patients MM 0 1 OL NS * * MM > 1 OL Average levels of activin A MM 0 1 OL: pg/ml MM > 1 OL: pg/ml Non-MM: 30.6 pg/ml *p < 0.05 Non-MM Activin A (pg/ml) 3,500 3,000 2,500 2,000 1,500 1, Activin A is mainly produced by BMSCs and osteoclasts induced by MM cells via JNK pathway activation Mean 1,300 OC NS Mean 1,884 Mean 299 **p < 0.01 Mean8.2 BMSC OB MM BMSCs secreted high levels of activin A (average 1.8 ng/ml); activin A secretion by OC was variable over a wide range ** OL = osteolytic lesion. Vallet S, et al. Proc Natl Acad Sci. 2010;107:

18 Circulating Activin-A in multiple myeloma 2500 p < * 2000 p < * Activin-A (pg/ml) * p = NS p = NS * Controls (n = 17) MGUS (n = 10) MM asymptomatic (n = 13) MM diagnosis (n = 85) MM relapse (n = 15) Terpos E, et al. Ann Oncol 2012;23:

19 Activin-A and bone disease in multiple myeloma Terpos E, et al. Ann Oncol 2012;23:

20 SREs Are a Serious Problem for Patients With Multiple Myeloma Patients (%) 60% 50% 40% 30% 20% 51% 37% 34% Total SREs Pathologic fracture Radiation therapy Surgical intervention Spinal cord compression 10% 5% 3% 0% n = 179 SRE, skeletal-related event. a. 21-month data (including osteolytic lesions) except for surgical intervention and spinal compression, for which only 9-month data are available from placebo arm of randomized study. Berenson JR, et al. J Clin Oncol. 1998;16:

21 SREs Are a Serious Problem for Patients With Multiple Myeloma (our experience) SREs at diagnosis 5.2% 5% n = 284 Terpos et al. ASH 2013

22 Therapies for Myeloma-related Bone Disease multiple myeloma plasma cell VCAM1 CD40 MUC1 VLA-4 CD40L ICAM1 bone marrow stromal cell MLN3897 WNT rec eptor BAFF MIP-1a VEGF IL-6 RUNX-2 B-catenin mesenchymal cell RANK fms MAPK ERK TRAF6 p38 JNK p50/p52 AP-1 Osteoblasts Integrin osteoclast osteoblasts Bisphosphonates Activin A Bone Sotatercept

23 Targeting Osteoclasts With Bisphosphonates

24 Breast Cancer and Multiple Myeloma ZOL Multiple Was as Event Efficacious Analysis as PAM Regarding Reduction of SREs in the MM Stratum Zoledronic acid is more effective than pamidronate resulting in an additional 16% reduction in the the risk of developing an SRE Multiple myeloma Risk reduction 7% P value Breast cancer %.025 Total % Risk ratio (zoledronic acid 4 mg versus pam) In favor of zoledronic acid In favor of Pam *Hypercalcemia of malignancy is included as an SRE. Rosen et al. Cancer 2003;98:

25 Pamidronate: 30 mg versus 90 mg Time to skeletal event by planned treatment Patients With SRE (%) Number at risk MP, P MP, P HD, P HD, P Time, months MP, P90 MP, P30 HD, P90 HD, P Event-Free Survival (%) Skeletal event free survival by planned treatment Number at risk MP, P MP, P HD, P HD, P Time, months MP, P90 MP, P30 HD, P90 HD, P Gimsing P, et al. Lancet Oncol. 2010;11:973.

26 MRC Myeloma IX: ZOL SREs vs. CLO in Overall Population P <.0001 Patients with SRE, % P =.070 P < P =.37 P <.001 P =.040 P =.29 Morgan G, et al. Lancet Oncol. 2011;12(8):

MRC Myeloma IX: ZOL Significantly OS vs CLO 100 Survival, % patients 80 60 40 20 Δ 5.5 mo *P =.

27 MRC Myeloma IX: ZOL Significantly OS vs CLO 100 Survival, % patients Δ 5.5 mo *P =.04 ZOL CLO 0 Number at risk: Time, years ZOL CLO Kaplan-Meier analysis adjusted for treatment pathway (intensive vs non-intensive). *Log-rank, stratified by treatment pathway. Abbreviations: CLO, clodronate; OS, overall survival; ZOL, zoledronic acid. Morgan G, et al. Lancet. 2010;376(9757):

28 Among Patients Treated 2 Years, ZOL OS vs CLO 100 Survival, % patients Patients, n CLO ZOL Log-rank P = CLO ZOL Time Since Initial Randomisation, years Abbreviations: CLO, clodronate; OS, overall survival; ZOL, zoledronic acid. Morgan G, et al. Blood 2012;119:

29 ZOL Significantly OS vs CLO in Patients With Bone Disease at Baseline (n = 1,350) Survival Distribution Function Estimate OS, % patients Clodronate (n = 682) Zoledronic acid (n = 668) + Censored P =.0107 HR = 0.82 (95% CI = 0.70, 0.96) ~10 mo ZOL CLO Time Since Initial Randomisation, years Abbreviations: CI, confidence interval; CLO, clodronate; HR, hazard ratio; OS, overall survival; ZOL, zoledronic acid. Morgan G, et al. Blood 2012;119:

30 OS Was Similar for ZOL and CLO in Patients with No Bone Disease at Baseline (n = 578) Survival Distribution Function Estimate OS, % patients Clodronate (n = 276) Zoledronic acid (n = 302) + Censored P =.4690 HR = 1.10 (95% CI = 0.85, 1.40) ZOL CLO Time Since Initial Randomisation, years Abbreviations: CI, confidence interval; CLO, clodronate; HR, hazard ratio; OS, overall survival; ZOL, zoledronic acid. Morgan G, et al. Blood 2012;119:

31 GM MRC Myeloma IX: ZOL SREs vs CLO Regardless of Bone Lesions at Baseline Bone Lesions at Baseline No Lesions at Baseline Cumulative Incidence Function, SREs a /Patient CLO 43% ZOL 34% P =.0038 Cumulative Incidence Function, SREs a /Patient P =.0068 CLO 17% ZOL 9% Time From Randomization, months Time From Randomization, months Highlights the importance of treating all patients regardless of skeletal morbidity at presentation a SREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions or the appearance of new osteolytic bone lesions. Abbreviations: CLO, clodronate; MRC, Medical Research Council; SRE, skeletal-related event; ZOL, zoledronic acid. Morgan G, et al. Lancet Oncol. 2011;12(8):

32 IMWG Guidelines 2013: BPs Treatment Initiation Bisphosphonates should be initiated in MM patients, with (grade A) or without (grade B) detectable osteolytic bone lesions in conventional radiography, who are receiving antimyeloma therapy as well as patients with osteoporosis (grade A) or osteopenia (grade C) due to myeloma. The beneficial effect of ZOL in patients without detectable bone disease by MRI or PET/CT is unknown. Intravenous ZOL and PAM exhibit comparable efficacy in reducing SREs in patients with MM, and are recommended for preventing SREs in patients with active MM (grade A). Terpos E, et al. J Clin Oncol. 2013;31:

33 IMWG guidelines 2013: BPs Treatment Duration Intravenous bisphosphonates should be administered at 3- to 4- week intervals to all patients with active MM (grade A). ZOL improves OS and reduces SREs over CLO in patients who received treatment for more than two years; thus it should be given until disease progression in patients not in CR or a vgpr and further continued at relapse (grade B). There is not similar evidence for PAM. PAM may be continued in patients with active disease at the physician s discretion (grade D), and PAM therapy should be resumed after disease relapse (grade D). For patients in CR/vgPR, the optimal treatment duration of BPs is not clear; the panel agrees that BPs should be given for at least 12 months and up to 24 months and then at the physician s discretion (grade D; panel consensus). Terpos E, et al. J Clin Oncol. 2013;31:

34 Osteonecrosis of the Jaw: a Rare but Sever Complication in MM

ONJ: Update of our Center Experience N= 238 patients who received at least one dose of zolendronic acid (ZA) received only zolendronic acid (ZA) survived at least 6 months after 1 st infusion of ZA

35 ONJ: Update of our Center Experience N= 238 patients who received at least one dose of zolendronic acid (ZA) received only zolendronic acid (ZA) survived at least 6 months after 1 st infusion of ZA Implementation of preventive measures since 2003 All patients were assessed for ONJ by an experienced maxillofacial surgeon and a dental surgeon Median follow up for all patients is 3 years (range ) Median number of infusions was 17 (range 1-107) N= 25 (10.5%) patients developed ONJ

36 Cumulative incidence of ONJ (accounting for death due to MM as a competing event) Cumulative incidence of death Cumulative incidence of ONJ 1-year 2-years 3-years 4-years % OS 97% 88% 79% 67% % ONJ (95%CI) 1% (0.2%-5%) 4.9% (2.5%-8.5%) 8.5% (5%-13%) 11.6% (7.2%-17.1%)

37 Natural History of ONJ in Myeloma ONJ resolved and did not recur in 60/97 (62%) ONJ resolved and then recurred in 12 patients (12%) ONJ healed in ~75% ONJ did not resolve over a follow-up period of at least 9 months in 25 patients (26%) ONJ recurrence followed re-initiation of bisphosphonate in 6 of 12 patients Patients in whom ONJ was precipitated by dental procedures, were less likely to have recurrence or non-healing lesions, after BP reinitiation following ONJ healing, as compared to those who develop spontaneous ONJ lesions (p=0.007) Badros et al. J Clin Oncol 2008;26:5904-9

38 IMWG Guidelines 2013: BPs and ONJ (1) Preventive strategies should be adopted to avoid ONJ. Patients should receive a comprehensive dental examination and be educated regarding optimal dental hygiene (grade C; panel consensus). Existing dental conditions should be treated before initiating bisphosphonate therapy (grade C; panel consensus). After bisphosphonate treatment initiation, unnecessary invasive dental procedures should be avoided and dental health status should be monitored on at least an annual basis (grade C). Patients ongoing dental health status should be monitored by a physician and a dentist (grade D; panel consensus). Dental problems should be managed conservatively if possible (grade C). Terpos E, et al. J Clin Oncol. 2013;31:

39 IMWG Guidelines 2013: BPs and ONJ (2) Temporary suspension of bisphosphonate treatment should be considered if invasive dental procedures are necessary (grade D). The panel consensus is to stop bisphosphonates for 90 days before and after invasive dental procedures (tooth extraction, dental implants and surgery to the jaw). Bisphosphonates do not need to be discontinued for routine dental procedures including root canal. Initial treatment of ONJ should include discontinuation of bisphosphonates until healing occurs (grade C). The decision to restart bisphosphonates should be individualized, until the results of prospective long-term studies are available (grade D). The physician should consider the advantages and disadvantages of continued treatment with bisphosphonates, especially in the relapsed/refractory MM setting (grade D). Terpos E, et al. J Clin Oncol. 2013;31:

40 Other Antiresorptive Agents in Myeloma?

Denosumab (anti-rankl): randomised, doubleblind, active-controlled, phase 3 trial Key Inclusion Adults with solid tumours and bone metastases (excluding breast and prostate) or multiple myeloma Key

41 Denosumab (anti-rankl): randomised, doubleblind, active-controlled, phase 3 trial Key Inclusion Adults with solid tumours and bone metastases (excluding breast and prostate) or multiple myeloma Key Exclusion Current or prior intravenous bisphosphonate administration N = 886 Denosumab 120 mg SC and Placebo IV* Q4W Supplemental Calcium and Vitamin D N = 890 Zoledronic acid 4 mg IV* and Placebo SC Q4W 1 Endpoint Time to first on-study SRE (non-inferiority) 2 Endpoints Time to first on-study SRE (superiority) Time to first-and-subsequent on-study SRE (superiority) *IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine (per zoledronic acid label) Henry D, et al. J Clin Oncol 2011;29(9):

Time to first-and-subsequent on-study SRE (multiple event analysis) Cumulative Mean Number of SREs 1.5 1.0 0.5 0.0 2 - Rate Ratio: 0.90 (95% CI: 0.77 1.

42 Time to first-and-subsequent on-study SRE (multiple event analysis) Cumulative Mean Number of SREs Rate Ratio: 0.90 (95% CI: ) P = 0.14 Denosumab Zoledronic Study Month Acid Total # of SREs Henry D, et al. J Clin Oncol 2011;29(9):

2 1 2 3 10 Hazard ratio (Dmab vs ZOL) In favor of Dmab In favor of ZOL a Excluding patients with breast or prostate cancer.

43 Denosumab vs. ZOL in Patients With Multiple Myeloma In a post hoc analysis of the MM subset (n = 180) Dmab the risk of death by 2.3-fold vs ZOL (HR = 0.44; P <.05) 1 Overall Survival 2.26 P value < Hazard ratio (Dmab vs ZOL) In favor of Dmab In favor of ZOL a Excluding patients with breast or prostate cancer. Abbreviations: CI, confidence interval; Dmab, denosumab; HR, hazard ratio; ST/MM, solid tumors or multiple myeloma; OS, overall survival; ZOL, zoledronic acid. Henry D, et al. Presented at ECCO/ESMO Abstract 20LBA.

Phase III Study of Dmab Versus ZOL in the Treatment of Bone Disease in Patients With MM Key endpoints: Primary: Time to the

event analysis); time to the first on-study SRE (superiority test) Study, N = 1,520 Newly diagnosed MM and plan to receive

prior antimyeloma, denosumab, or IVBP therapy No oral BPs for > 1 year R ZOL (4 mg IV) + placebo SC, q 4 weeks Dmab (120 mg SC)

anticipated to begin March 2012 BP = Bisphosphonate; Dmab = Denosumab; ECOG = Eastern Cooperative Oncology Group; IV =

44 Phase III Study of Dmab Versus ZOL in the Treatment of Bone Disease in Patients With MM Key endpoints: Primary: Time to the first on-study SRE (non-inferiority test) Secondary: Time to the first-and-subsequent SRE (superiority test, using multiple event analysis); time to the first on-study SRE (superiority test) Study, N = 1,520 Newly diagnosed MM and plan to receive primary, frontline antimyeloma therapies 1 bone lesion ECOG performance status = 0, 1, or 2, and adequate organ function No prior antimyeloma, denosumab, or IVBP therapy No oral BPs for > 1 year R ZOL (4 mg IV) + placebo SC, q 4 weeks Dmab (120 mg SC) + placebo IV, q 4 weeks Event-driven (until ~800 patients have 1 on-study SRE) Status: Not yet open for patient recruitment; anticipated to begin March 2012 BP = Bisphosphonate; Dmab = Denosumab; ECOG = Eastern Cooperative Oncology Group; IV = Intravenous; MM = Multiple myeloma; SC = Subcutaneous; SRE = Skeletal-related event; ZOL = Zoledronic acid. Clinical Trials.gov Identifier: NCT

45 Bone Anabolic Agents and Multiple Myeloma

BMD: Pre- and Post-Bortezomib (combined with ZOL) 0-1 P=0.009 BV/TV = 12.85% Tb.Th = 0.

8 Post-Bz BMD L1-L4 pre bortezomib BMD L1-14 post bortezomib 4/27 patients (14%) showed

DXA, had responded to VD therapy (3 PR and one CR), and had received VD as 2nd-line

46 BMD: Pre- and Post-Bortezomib (combined with ZOL) 0-1 P=0.009 BV/TV = 12.85% Tb.Th = 0.1 Tb.Sp. = 0.7 Tb.N. = 1.5 Pre-Bz BV/TV = 90% Tb.Th = 0.7 Tb.Sp. = 0.2 Tb.N. = 2.8 Post-Bz BMD L1-L4 pre bortezomib BMD L1-14 post bortezomib 4/27 patients (14%) showed at least 10% of increase in L1-L4 BMD; all these patients had osteoporosis according to DXA, had responded to VD therapy (3 PR and one CR), and had received VD as 2nd-line treatment Terpos E et al. Ann Oncol. 2010;21:1561. Zangari et al. Haematologica. 2011;96:333.

47 VMP: results in a patient after 9 cycles of therapy Delforge et al. Eur J Haematol 2011; 86(5):372-84

48 VRD versus RD on Bone Metabolism Terpos E, et al. Am J Hematol 2014;89:34-40

49 Phase II: BHQ880, Anti-DKK1 MAb for Patients With Smoldering MM Safety (N = 39) Any grade AE: 74.4%: 30.8% fatigue, 20.5% pyrexia, 17.9% arthralgia, 17.9% back pain Grade 3/4 AE: 1 case each of hypophosphatemia and pneumonia Pharmacokinetics DKK1 saturation reached by Day 8 of cycle 1 and maintained throughout 28-day cycle BHQ880 reached steady state by cycle 4 No evidence of direct antimyeloma activity Bone activity Evidence of bone activity at cycle 6 by qct with finite element analysis Increased bone strength in 9 of 15 patients (60%) completing 6 month qct evaluation Munshi N, et al. ASH Abstract 331.

50 Sotatercept in multiple myeloma phase 1/2 study MPT + 4 cycles of sotatercept, g/kg Placebo Hip BMD, change from baseline (%) 4 Lumbar BMD, maximum change from baseline (%) n Placebo 0.1 mg/kg 0.3 mg/kg 0.5 mg/kg Lumbar BMD, change from baseline (%) All patients 169/ET With 85 Without 169/ET Time from start of treatment (days) bisphosphonates Time from bisphosphonates start of treatment (days) Placebo 0.1 mg/kg 0.3 mg/kg 0.5 mg/kg Placebo 0.1 mg/kg 0.3 mg/kg 0.5 mg/kg Abdulkadyrov KM, et al. Br J Haematol 2014; in press

51 Conclusions ZOL is more effective than clodronate regarding reduction of SREs BPs have shown antimyeloma activity; ZOL OS versus clodronate in MM patients, mainly in those with bone disease at baseline. It is recommended for use in active myeloma (not in CR/vgPR after 2 years) ZOL is at least as equal as denosumab in MM regarding SREs reduction; concerns about denosumab; further studies are needed. Bortezomib is recommended for patients with extended bone disease in combination with BPs. For patients with renal impairment (RI) bortezomib can reverse RI and then can be combined with BPs BHQ880 and sotatercept has shown encouraging bone anabolic effects

52 Acknowledgments Department of Clinical Therapeutics M.A. Dimopoulos, E. Kastritis, M. Roussou, M. Migkou, D. Christoulas, M. Gavriatopoulou, M. Gkotzamanidou, D. Gika, E. Eleutherakis-Papaiakovou, D. Mparmparoussi, C. Matsouka, C. Liakou, T. Bragatuni London, UK A. Rahemtulla, A. Karadimitris Sheffield, UK P. Croucher, R. Coleman Hersey, PA, USA A. Lipton, K. Leitzel Greek Myeloma Study Group K. Zervas, E. Katodritou (Thessaloniki) S. Delimpasi (Athens) E. Michalis (Athens) A. Parcharidou (Athens) A. Zomas (Athens) Z. Kartasis (Halkida) A. Pouli (Athens) C. Tsatalas, E. Spanoudakis (Alexandroupolis) A. Symeonidis (Patras) E. Hatzimichail (Ioannina) M.C. Kyrtsonis (Athens) E. Stefanoudaki (Athens) P. Panayiotidis (Athens) J Meletis (Athens)

53 Thank you

Multiple Myeloma Bone Disease

The 4th World Congress on CONTROVERSIES IN MULTIPLE MYELOMA May 3-5, 2018 Paris, France Multiple Myeloma Bone Disease Evangelos Terpos MD, PhD Plasma Cell Dyscrasias Unit,, National & Kapodistrian, School