(PA-139) Romosozumab for Patients with Multiple Myeloma with Skeletal Events on Zoledronic Acid

Myeloma bone disease (MBD) is found in 80% of patients with newly diagnosed multiple myeloma (MM) and is associated with substantial morbidity and mortality.  Bisphosphonates and denosumab, which inhibit bone resorption, are standard of care for treatment and prevention of myeloma bone disease. However these treatments do not replace lost bone or repair bone lesions and 45% of patients will experience a skeletal related event (SRE) despite these therapies.


Sclerostin is a protein produced by osteocytes embedded in bone and inhibits bone formation. Anti-sclerostin antibodies alone, and in combination with bisphosphonates, have been demonstrated to improve bone mineral density and fracture resistance in MM mouse models. Furthermore, romosuzumab, an anti-sclerostin antibody, has been demonstrated in Phase III trials to decrease fracture rates in post-menopausal women with osteoporosis. We aim to evaluate the safety and efficacy of romosuzumab in patients with MM who have had a SRE despite bisphosphonate therapy.

Methods: This is a single arm, pilot study of romosuzumab 210mg subcutaneously monthly for 12 months in twelve patients who have had a SRE despite bisphosphonate therapy. The primary objective is to determine safety of romosozumab and its impact on bone turnover markers (P1NP and beta-CTx). Secondary objectives are to assess effect of romosuzumab on bone mineral density (BMD) at 6 and 12 months, SRE and myeloma progression free survival (PFS).  Patients will have bone marrow biopsies at baseline, cycle 3 and cycle 12 to explore changes in the bone marrow microenvironment and describe interactions between the bone microenvironment and tumour cells. 

Results: At the time of abstract submission, 8 patients have been recruited to this study with a median age of 71.  The median line of myeloma therapy at time of consent was 2 (range 1-8).  At screening, median T score was 0.6 at the lumbar spine and -1 for mean total hip.  Number of lytic lesions on CT skeletal survey was none (n = 1), 1 (n = 1), 1-3 (n = 1) or >3 (n = 5).  Two patients experienced local injection site reactions but there have been no other treatment emergent adverse events.  Assessment of bone turnover markers demonstrate an increase in the bone-formation marker P1NP with the greatest increase seen four weeks after dose 1 (median % change 185%, range -54% to 350%). and a sustained decrease in the bone-resorption marker beta-CTX. BMD measured at total hip and lumbar spine increased at six (n = 1, 8%) and 12 months (n = 1, 19%) of treatment relative to baseline. There have been no new SREs in participants.

Conclusions: In this interim analysis romosozumab has demonstrated an increase in bone formation in patients with multiple myeloma previously treated with bisphosphonates.  There have been no safety concerns. Further recruitment and analysis will add to this dataset prior to presentation at IMS.