Bone metastases in hematology

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Giles King
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Botziekte bij hematologische tumoren Prof. Dr.

hematology The bone marrow is the source of many

associated with particular hematological malignancies o

$lymphoma develop a pathological fracture independent$ unfavorable prognostic factor R/chemo- plus radiotherapy

Osteosclerotic lesions in myelofibrosis The CRAB criteria

Mayo Clin Proc 2003;78:21 Bone disease in multiple

Criteria according to the IMWG* Some illustrations of

Oncol 2014; 15:e538 Skeletal Related Events (SRE s) are

1 Botziekte bij hematologische tumoren Prof. Dr. Michel Delforge Hematologie, UZ Leuven Bone metastases in hematology The bone marrow is the source of many hematological malignancies However, bone damage is only associated with particular hematological malignancies o Primarily multiple myeloma o Occasionaly Non-Hodgkin lymphoma: ~10% of patients with diffuse large B-cell lymphoma develop a pathological fracture independent unfavorable prognostic factor R/chemo- plus radiotherapy o Osteoporosis in patients with systemic mastocytosis o Osteosclerotic lesions in myelofibrosis The CRAB criteria for symptomatic multiple myeloma Kyle et al. Mayo Clin Proc 2003;78:21 Bone disease in multiple myeloma How to diagnose bone disease in multiple myeloma Criteria according to the IMWG* Some illustrations of myeloma bone disease Br J Haematol 2003;121:749 Lancet Oncol 2014; 15:e538 Skeletal Related Events (SRE s) are an important cause of morbidity and mortality in multiple myeloma * historical data IMWG: International Myeloma Working Group 1

Imaging in multiple myeloma RX Kahler is becoming obsolete Low-dose whole body CT MRI o spine -/+ pelvis o whole body PET-CT Bone remodeling cycle: a delicate balance between osteoblasts and

MIP-1β, IL-3, OPN, SDF-1α RANK IL-6, IL-11, IL-1β, OPG TNF-α, M-CSF activated osteoclasts osteoclast precursor TRACP-5b Seeman et al.

$Ann Oncol 2009:20:1303 Therapy of myeloma bone disease anti-myeloma therapy bisphosphonates novel drugs Fractures or impending fractures o radiotherapy o vertebro-/balloon kyphoplasty o surgery$

2 Imaging in multiple myeloma RX Kahler is becoming obsolete Low-dose whole body CT MRI o spine -/+ pelvis o whole body PET-CT Bone remodeling cycle: a delicate balance between osteoblasts and osteoclasts Pathogenesis of myeloma bone disease myeloma cells osteoblasts balp, osteocalcin Dkk-1, sfrp-2 Sclerostin, activin-a IL-6, IGF-1 stromal cells BAFF, APRIL VCAM-1, α4β1 HGF, MIP-1α, RANKL MIP-1β, IL-3, OPN, SDF-1α RANK IL-6, IL-11, IL-1β, OPG TNF-α, M-CSF activated osteoclasts osteoclast precursor TRACP-5b Seeman et al. N Engl J Med 2006;354:2250 Collagen type-1 degradation products CTX, NTX, ICTP bone resorption Terpos et al. Blood 2007;110:1098; Terpos et al. Ann Oncol 2009:20:1303 Therapy of myeloma bone disease anti-myeloma therapy bisphosphonates novel drugs Fractures or impending fractures o radiotherapy o vertebro-/balloon kyphoplasty o surgery Chemical structure and potency of bisphosphonates Bisphosphonates in multiple myeloma Clinical use Product Category Admin. Route dose clodronate ATP-analogue IV/oral 1600 mg/d orally pamidronate N-containing IV 90 mg IV 2-4h zoldedronic acid N-containing IV 4 mg/15 min Santini et al. Biodrugs 2004 Green, J Bone Miner Res 1994;9:745 2

Zoledronic acid versus pamidronate: efficacy Mode of action of amino bisphosphonates In vitro anti-tumoral activity of zoledronic acid Phase III

treated > 10 mo) comparable safety Rosen et al. J Cancer 2001, and Cancer 2003 Green JR. Oncologist. 2004;9(suppl 4):3-13. 2 Yuasa T, et al.

1997;57(18):3890-3894; Shipman CM, et al. Br J Haematol. 1997;98(3):665-672. Fournier P, et al. Cancer Res. 2002;62(22):6538-6544. Wood J, et al.

In vivo anti-tumoral activity of zoledronic acid MRC Myeloma IX study Zoledronic acid versus clodronate: efficacy 1. Aviles A, et al. Med Oncol.

3 Zoledronic acid versus pamidronate: efficacy Mode of action of amino bisphosphonates In vitro anti-tumoral activity of zoledronic acid Phase III randomized study in MM patients showed: non-inferiority of zoledronic acid 4 mg for all SRE treatment during 13 or 25 mo (but limited nr of patients treated > 10 mo) comparable safety Rosen et al. J Cancer 2001, and Cancer 2003 Green JR. Oncologist. 2004;9(suppl 4): Yuasa T, et al. Curr Med Chem. 2007;14(20): van der Pluijm G, et al. J Clin Invest. 1996;98(3): Boissier S, et al. Cancer Res. 1997;57(18): ; Shipman CM, et al. Br J Haematol. 1997;98(3): Fournier P, et al. Cancer Res. 2002;62(22): Wood J, et al. J Pharmacol Exp Ther. 2002;302(3): ; Boissier S, et al. Cancer Res. 2000;60(11): ; Kunzmann V, et al. Blood. 2000;96(2): In vivo anti-tumoral activity of zoledronic acid MRC Myeloma IX study Zoledronic acid versus clodronate: efficacy 1. Aviles A, et al. Med Oncol. 2007;24(2): Berenson J, et al. Presented at: ASH Abstract McCloskey EV, et al. Br J Haematol. 2001;113(4): Morgan et al. Lancet Oncol 2011;12:743 Morgan et al. Lancet Oncol 2011;12:743 3

Role of bisphosphonates: regardless of bone lesions at diagnosis Significant survival benefit with zoledronic acid Survival according to the presence of bone lesions Morgan et al.

Blood 2012;119:5380 Survival according to the depth of response Partial response post transplant: Complete response post transplant: Hazard Ratio 0.53, Hazard Ratio 0.98 95% Confidence Interval 0.

4 Role of bisphosphonates: regardless of bone lesions at diagnosis Significant survival benefit with zoledronic acid Survival according to the presence of bone lesions Morgan et al. Lancet Oncol 2011;12:743 Morgan et al. Lancet Oncol 2011;12:743 Morgan et al. Blood 2012;119:5380 Survival according to the depth of response Partial response post transplant: Complete response post transplant: Hazard Ratio 0.53, Hazard Ratio % Confidence Interval , p= % Confidence Interval , p=0.91 Bisphosphonates in MM optimal use in 2013 bisphosphonates remain essential in the treatment of patients with multiple myeloma all patients requiring anti-myeloma treatment should receive bisphosponates irrespective of the presence of bone lesions (<-> reimbursement criteria) zoledronic acid is the bisphosphonate of choice because of: practical reasons: short infusion time its potent activity on bone disease Its positive impact on progression-free and overall survival in patients with bone lesions on conventional X-rays Question two: how long do you give bisphosphonates in multiple myeloma? A. Indefinitively B. For two years C. For one year D. On an individual basis Morgan et al. Blood 2013;122:2974 Terpos et al, J Clin Oncol 2013;31:2347 4

disease o For at least two years in all other patients o After 2 years: continue only if incomplete response and symptomatic bone disease LOTUZ: Long-term use of zoledronic acid in myeloma 2y ZOL

5 Question two: how long do you give bisphosphonates in multiple myeloma? A. Indefinitively B. For two years C. For one year D. On an individual basis Bisphosphonates in MM Duration of treatment Every 3 to 4 weeks For newly diagnosed patients: o For one year in patients reaching complete response and without active bone disease o For at least two years in all other patients o After 2 years: continue only if incomplete response and symptomatic bone disease LOTUZ: Long-term use of zoledronic acid in myeloma 2y ZOL therapy Inclusion 18 mos n=298 n=218 Baseline Dose and regimen of zoledronic acid at treating physician s discretion Treatment patterns of zoledronic acid 2. Skeletal related events (SREs) 3. Renal deterioration 4. Osteonecrosis of the jaw (ONJ) 6 Terpos et al, J Clin Oncol 2013;31:2347 Van den Wijngaert et al. Supp Cancer Care 2013; 21:3483 LOTUZ: Flow of myeloma patients LOTUZ: Skeletal related events in MM Bisphosphonates and osteonecrosis of the jaw 2002: FDA received reports of 9 cases of ONJ in cancer patients treated with zoledronic acid (ZA) : 104 cancer patients with ONJ reported and BP suspected as potential cause : warnings about BRONJ disseminated by manufacturers, national regulatory agencies epidemiological studies: o manufacturer sponsored: incidence between 0.1 and 1.8% o investigator driven: incidence between 5 and 10% from 2006 : independent clinical recommendations for diagnosis, prevention and treatment of BRONJ Van den Wijngaert et al. Supp Cancer Care 2013; 21:3483 Van den Wijngaert et al. Supp Cancer Care 2013; 21:3483 Edwards et al. Lancet Oncology 2008;9:

Product: BRONJ: general recommendations o Zoledronic acid > pamidronate > clodronate Related to treatment duration and cumulative dosis Risk factors: o Dental problems invasive dental procedures

6 Product: BRONJ: general recommendations o Zoledronic acid > pamidronate > clodronate Related to treatment duration and cumulative dosis Risk factors: o Dental problems invasive dental procedures extractions dentures o Poor dental hygiene, smoking o Anti-cancer treatment? Prevention = dental controls before and during treatment Vahtsevanos et al. J Clin Oncol 2009;27:5356 American Association of Oral and Maxillofacial Surgeons. J Oral Maxillofac Surg 2007;65:369 Pathogenesis of myeloma bone disease myeloma cells osteoblasts balp, osteocalcin Dkk-1, sfrp-2 Sclerostin, activin-a IL-6, IGF-1 stromal cells BAFF, APRIL VCAM-1, α4β1 HGF, MIP-1α, RANKL MIP-1β, IL-3, OPN, SDF-1α RANK IL-6, IL-11, IL-1β, OPG TNF-α, M-CSF activated osteoclasts osteoclast precursor TRACP-5b Collagen type-1 degradation products CTX, NTX, ICTP bone resorption Terpos et al. Blood 2007;110:1098; Terpos et al. Ann Oncol 2009:20:1303 Bone disease in MM: role of anti-tumoral therapy proteasome inhibitors Delforge et al, Eur J Haematol 2011;86:372 Denosumab (anti-rankl) in multiple myeloma Randomized, double-blind study between denosumab 120 mg SC and zoledronic acid 4 mg IV Adults with solid tumors and bone metastases or multiple myeloma Post hoc analysis of myeloma subset (n = 180) o No difference in skeletal related events o Dmab increased the risk of death by 2,3 fold vs ZOL (HR = 0,44; p < 0,05) Ongoing prospective comparative study between Dmab and ZA in newly diagnosed multiple myeloma patients (NCT ) Henry et al. J Clin Oncol 2011;29:1125 Other novel agents in development for MM bone disease BHQ880 1 o neutralizing anti-dkk monoclonal antibody o phase II study recently published o can be combined with zoledronic acid Activin A 2,3 o Activin A is primarily produced by bone marrow stromal cells o Promotes osteoclasts and inhibits osteoblast differentiation o Sotatercept (ACE-011) sequesters activin receptor increases bone formation reduces tumor growth increases erythropoiesis 1. Swaminathan et al. Br J Haematol 2014;167: Terpos et al. Ann Oncol 2012;23: Fields et al. Expert Opin Invest Drugs 2013;22:87, Conclusions Bone disease in hematology primarily relates to multiple myeloma Bone disease is the most frequent clinical complication in myeloma Every patient with symptomatic myeloma should be taken into consideration for treatment of skeletal-related events IV bisphosphonates remain the cornerstone of treatment of myeloma bone disease Novel agents targeting osteoclasts and osteoblasts are in different phases of clinical development 6

Bone Health in Patients with Multiple Myeloma

Bone Health in Patients with Multiple Myeloma Amrita Y. Krishnan, MD Director Judy and Bernard Briskin Myeloma Center City of Hope Comprehensive Cancer Center Bone Health Bisphosphonates in Space Bone