A Phase IB multicentre dose-determination study of BHQ880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events

British Journal of Haematology

Volumn 167, Issue 3, 2014, Pages 366-375

  Iyer, Swaminathan P ^a   Beck, Joseph Taddeus ^b   Stewart, A Keith ^c   Shah, Jatin ^d   Kelly, Kevin R ^e   Isaacs, Randi ^f   Bilic, Sanela ^f   Sen, Suman ^f   Munshi, Nikhil C ^g  

^a WEILL CORNELL MEDICAL COLLEGE   (United States)

^b PA   (United States)

^c MAYO CLINIC   (United States)

^d UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^e UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO   (United States)

^f NOVARTIS PHARMA AG   (Switzerland)

^g HARVARD MEDICAL SCHOOL   (United States)

Author keywords

BHQ880; Multiple myeloma; Phase I; Skeletal related event

Indexed keywords

ANTINEOPLASTIC AGENT; BHQ 880; BISPHOSPHONIC ACID DERIVATIVE; BORTEZOMIB; CALCIUM; CREATININE; DICKKOPF 1 PROTEIN; IMMUNOMODULATING AGENT; PAMIDRONIC ACID; PHOSPHATE; UNCLASSIFIED DRUG; ZOLEDRONIC ACID; ANABOLIC AGENT; BHQ880; BONE DENSITY CONSERVATION AGENT; DKK1 PROTEIN, HUMAN; IMIDAZOLE DERIVATIVE; MONOCLONAL ANTIBODY; SIGNAL PEPTIDE; TUMOR PROTEIN;

ADULT; AGED; ANTINEOPLASTIC ACTIVITY; ARTICLE; BONE DENSITY; BONE DISEASE; BONE LESION; BONE RADIOGRAPHY; BONE STRENGTH; CALCIUM METABOLISM; CANCER GROWTH; CANCER MORTALITY; CANCER RECURRENCE; CLINICAL ARTICLE; CREATININE BLOOD LEVEL; DOSE RESPONSE; DRUG DOSE ESCALATION; DRUG PROTEIN BINDING; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; FEMALE; HIP; HUMAN; HYPERTENSION; IMMUNOGENICITY; MALE; MAXIMUM TOLERATED DOSE; MULTICENTER STUDY; MULTIPLE CYCLE TREATMENT; MULTIPLE MYELOMA; NUCLEAR MAGNETIC RESONANCE IMAGING; PHASE 1 CLINICAL TRIAL; PHOSPHATE METABOLISM; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; SPINE; THROMBOCYTOPENIA; TREATMENT DURATION; ANTAGONISTS AND INHIBITORS; BLOOD; CHEMICALLY INDUCED; CLINICAL TRIAL; COMPLICATION; DRUG COMBINATION; DRUG THERAPY; ETIOLOGY; FRACTURES, SPONTANEOUS; IMMUNOLOGY; MIDDLE AGED; MOLECULARLY TARGETED THERAPY; OSTEOLYSIS; PREVENTION AND CONTROL; RECURRENT DISEASE; SPINAL CORD COMPRESSION;

AGED; ANABOLIC AGENTS; ANTIBODIES, MONOCLONAL; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; BONE DENSITY CONSERVATION AGENTS; BONE RESORPTION; DIPHOSPHONATES; DRUG THERAPY, COMBINATION; FEMALE; FRACTURES, SPONTANEOUS; HUMANS; HYPERTENSION; IMIDAZOLES; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; MALE; MAXIMUM TOLERATED DOSE; MIDDLE AGED; MOLECULAR TARGETED THERAPY; MULTIPLE MYELOMA; NEOPLASM PROTEINS; OSTEOLYSIS; RECURRENCE; SPINAL CORD COMPRESSION;

EID: 84911996275     PISSN: 00071048     EISSN: 13652141     Source Type: Journal    
DOI: 10.1111/bjh.13056     Document Type: Article

References (35)

1. Berenson, J.R. (2005) Myeloma bone disease. Best Practice & Research. Clinical Haematology, 18, 653-672.
2. Berenson, J.R., Rosen, L.S., Howell, A., Porter, L., Coleman, R.E., Morley, W., Dreicer, R., Kuross, S.A., Lipton, A. & Seaman, J.J. (2001) Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer, 91, 1191-1200.
3. Boyden, L.M., Mao, J., Belsky, J., Mitzner, L., Farhi, A., Mitnick, M.A., Wu, D., Insogna, K. & Lifton, R.P. (2002) High bone density due to a mutation in LDL-receptor-related protein 5. The New England Journal of Medicine, 346, 1513-1521.
4. Cockcroft, D.W. & Gault, M.H. (1976) Prediction of creatinine clearance from serum creatinine. Nephron, 16, 31-41.
5. Croucher, P.I., De Hendrik, R., Perry, M.J., Hijzen, A., Shipman, C.M., Lippitt, J., Green, J., Van Marck, E., Van Camp, B. & Vanderkerken, K. (2003) Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival. Journal of Bone and Mineral Research, 18, 482-492.
6. Day, T.F., Guo, X., Garrett-Beal, L. & Yang, Y. (2005) Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Developmental Cell, 8, 739-750.
7. Durie, B.G., Kyle, R.A., Belch, A., Bensinger, W., Blade, J., Boccadoro, M., Child, J.A., Comenzo, R., Djulbegovic, B., Fantl, D., Gahrton, G., Harousseau, J.L., Hungria, V., Joshua, D., Ludwig, H., Mehta, J., Morales, A.R., Morgan, G., Nouel, A., Oken, M., Powles, R., Roodman, D., San Miguel, J., Shimizu, K., Singhal, S., Sirohi, B., Sonneveld, P., Tricot, G., Van Ness, B. & Scientific Advisors of the International Myeloma Foundation (2003) Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation. The Hematology Journal, 4, 379-398.
8. Fulciniti, M., Tassone, P., Hideshima, T., Vallet, S., Nanjappa, P., Ettenberg, S.A., Shen, Z., Patel, N., Tai, Y.T., Chauhan, D., Mitsiades, C., Prabhala, R., Raje, N., Anderson, K.C., Stover, D.R. & Munshi, N.C. (2009) Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood, 114, 371-379.
9. Gentile, M., Recchia, A.G., Mazzone, C. & Morabito, F. (2012) Emerging biological insights and novel treatment strategies in multiple myeloma. Expert Opinion on Emerging Drugs, 17, 407-438.
10. Glass, D.A. 2nd, Bialek, P., Ahn, J.D., Starbuck, M., Patel, M.S., Clevers, H., Taketo, M.M., Long, F., McMahon, A.P., Lang, R.A. & Karsenty, G. (2005) Canonical wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Developmental Cell, 8, 751-764.
11. Gong, Y., Slee, R.B., Fukai, N., Rawadi, G., Roman-Roman, S., Reginato, A.M., Wang, H., Cundy, T., Glorieux, F.H., Lev, D., Zacharin, M., Oexle, K., Marcelino, J., Suwairi, W., Heeger, S., Sabatakos, G., Apte, S., Adkins, W.N., Allgrove, J., Arslan-Kirchner, M., Batch, J.A., Beighton, P., Black, G.C., Boles, R.G., Boon, L.M., Borrone, C., Brunner, H.G., Carle, G.F., Dallapiccola, B., De Paepe, A., Floege, B., Halfhide, M.L., Hall, B., Hennekam, R.C., Hirose, T., Jans, A., Jüppner, H., Kim, C.A., Keppler-Noreuil, K., Kohlschuetter, A., LaCombe, D., Lambert, M., Lemyre, E., Letteboer, T., Peltonen, L., Ramesar, R.S., Romanengo, M., Somer, H., Steichen-Gersdorf, E., Steinmann, B., Sullivan, B., Superti-Furga, A., Swoboda, W., van den Boogaard, M.J., Van Hul, W., Vikkula, M., Votruba, M., Zabel, B., Garcia, T., Baron, R., Olsen, B.R., Warman, M.L. & Osteoporosis-Pseudoglioma Syndrome Collaborative Group (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell, 107, 513-523.
12. Grotewold, L. & Ruther, U. (2002) The wnt antagonist dickkopf-1 is regulated by bmp signaling and c-jun and modulates programmed cell death. The EMBO Journal, 21, 966-975.
13. Heath, D.J., Chantry, A.D., Buckle, C.H., Coulton, L., Shaughnessy, J.D. Jr, Evans, H.R., Snowden, J.A., Stover, D.R., Vanderkerken, K. & Croucher, P.I. (2009) Inhibiting dickkopf-1 (Dkk1) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma. Journal of Bone and Mineral Research, 24, 425-436.
14. Heider, U., Kaiser, M., Mieth, M., Lamottke, B., Rademacher, J., Jakob, C., Braendle, E., Stover, D. & Sezer, O. (2009) Serum concentrations of DKK-1 decrease in patients with multiple myeloma responding to anti-myeloma treatment. European Journal of Haematology, 82, 31-38.
15. Kaiser, M., Mieth, M., Liebisch, P., Oberländer, R., Rademacher, J., Jakob, C., Kleeberg, L., Fleissner, C., Braendle, E., Peters, M., Stover, D., Sezer, O. & Heider, U. (2008) Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma. European Journal of Haematology, 80, 490-494.
16. Lemaire, O., Attal, M., Bourin, P. & Laroche, M. (2010) DKK1 correlates with response and predicts rapid relapse after autologous stem cell transplantation in multiple myeloma. European Journal of Haematology, 84, 276-277.
17. Li, J., Sarosi, I., Cattley, R.C., Pretorius, J., Asuncion, F., Grisanti, M., Morony, S., Adamu, S., Geng, Z., Qiu, W., Kostenuik, P., Lacey, D.L., Simonet, W.S., Bolon, B., Qian, X., Shalhoub, V., Ominsky, M.S., Zhu Ke, H., Li, X. & Richards, W.G. (2006) Dkk1-mediated inhibition of wnt signaling in bone results in osteopenia. Bone, 39, 754-766.
18. Macsai, C.E., Foster, B.K. & Xian, C.J. (2008) Roles of wnt signalling in bone growth, remodelling, skeletal disorders and fracture repair. Journal of Cellular Physiology, 215, 578-587.
19. Morgan, G.J., Child, J.A., Gregory, W.M., Szubert, A.J., Cocks, K., Bell, S.E., Navarro-Coy, N., Drayson, M.T., Owen, R.G., Feyler, S., Ashcroft, A.J., Ross, F.M., Byrne, J., Roddie, H., Rudin, C., Cook, G., Jackson, G.H., Wu, P., Davies, F.E. & National Cancer Research Institute Haematological Oncology Clinical Studies Group. (2011) Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC myeloma IX): secondary outcomes from a randomised controlled trial. The Lancet Oncology, 12, 743-752.
20. Morvan, F., Boulukos, K., Clément-Lacroix, P., Roman-Roman, S., Suc-Royer, I., Vayssière, B., Ammann, P., Martin, P., Pinho, S., Pognonec, P., Mollat, P., Niehrs, C., Baron, R. & Rawadi, G. (2006) Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. Journal of Bone and Mineral Research, 21, 934-945.
21. Mukhopadhyay, M., Shtrom, S., Rodriguez-Esteban, C., Chen, L., Tsukui, T., Gomer, L., Dorward, D.W., Glinka, A., Grinberg, A., Huang, S.P., Niehrs, C., Izpisúa Belmonte, J.C. & Westphal, H. (2001) Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. Developmental Cell, 1, 423-434.
22. Padhi, D., Jang, G., Stouch, B., Fang, L. & Posvar, E. (2011) Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. Journal of Bone and Mineral Research, 26, 19-26.
23. Politou, M.C., Heath, D.J., Rahemtulla, A., Szydlo, R., Anagnostopoulos, A., Dimopoulos, M.A., Croucher, P.I. & Terpos, E. (2006) Serum concentrations of dickkopf-1 protein are increased in patients with multiple myeloma and reduced after autologous stem cell transplantation. International Journal of Cancer. Journal International Du Cancer, 119, 1728-1731.
24. Pozzi, S., Fulciniti, M., Yan, H., Vallet, S., Eda, H., Patel, K., Santo, L., Cirstea, D., Hideshima, T., Schirtzinge, L., Kuhstoss, S., Anderson, K.C., Munshi, N., Scadden, D., Kronenberg, H.M. & Raje, N. (2013) In vivo and in vitro effects of a novel anti-Dkk1 neutralizing antibody in multiple myeloma. Bone, 53, 487-496.
25. Qiang, Y.W., Chen, Y., Stephens, O., Brown, N., Chen, B., Epstein, J., Barlogie, B. & Shaughnessy, J.D. Jr (2008a) Myeloma-derived dickkopf-1 disrupts wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma. Blood, 112, 196-207.
26. Qiang, Y.W., Shaughnessy, J.D. Jr & Yaccoby, S. (2008b) Wnt3a signaling within bone inhibits multiple myeloma bone disease and tumor growth. Blood, 112, 374-382.
27. Qiang, Y.W., Chen, Y., Brown, N., Hu, B., Epstein, J., Barlogie, B. & Shaughnessy, J.D. Jr (2010) Characterization of Wnt/beta-catenin signalling in osteoclasts in multiple myeloma. British Journal of Haematology, 148, 726-738.
28. Rajkumar, S.V. (2011) Multiple myeloma: 2011 update on diagnosis, risk-stratification, and management. American Journal of Hematology, 86, 57-65.
29. Rosen, L.S., Gordon, D., Kaminski, M., Howell, A., Belch, A., Mackey, J., Apffelstaedt, J., Hussein, M.A., Coleman, R.E., Reitsma, D.J., Chen, B.L. & Seaman, J.J. (2003) Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer, 98, 1735-1744.
30. Spencer, G.J., Utting, J.C., Etheridge, S.L., Arnett, T.R. & Genever, P.G. (2006) Wnt signalling in osteoblasts regulates expression of the receptor activator of NFkappaB ligand and inhibits osteoclastogenesis in vitro. Journal of Cell Science, 119, 1283-1296.
31. Stewart, J.P. & Shaughnessy, J.D. Jr (2006) Role of osteoblast suppression in multiple myeloma. Journal of Cellular Biochemistry, 98, 1-13.
32. Terpos, E., Kastritis, E., Roussou, M., Heath, D., Christoulas, D., Anagnostopoulos, N., Eleftherakis-Papaiakovou, E., Tsionos, K., Croucher, P. & Dimopoulos, M.A. (2008) The combination of bortezomib, melphalan, dexamethasone and intermittent thalidomide is an effective regimen for relapsed/refractory myeloma and is associated with improvement of abnormal bone metabolism and angiogenesis. Leukemia, 22, 2247-2256.
33. Tian, E., Zhan, F., Walker, R., Rasmussen, E., Ma, Y., Barlogie, B. & Shaughnessy, J.D. Jr (2003) The role of the wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. The New England Journal of Medicine, 349, 2483-2494.
34. Yaccoby, S., Ling, W., Zhan, F., Walker, R., Barlogie, B. & Shaughnessy, J.D. Jr (2007) Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood, 109, 2106-2111.
35. Yao, H., Ashihara, E., Strovel, J.W., Nakagawa, Y., Kuroda, J., Nagao, R., Tanaka, R., Yokota, A., Takeuchi, M., Hayashi, Y., Shimazaki, C., Taniwaki, M., Strand, K., Padia, J., Hirai, H., Kimura, S. & Maekawa, T. (2011) AV-65, a novel Wnt/beta-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model. Blood Cancer Journal, 1, e43.