Skeletal-Related Events In Patients With Multiple Myeloma In The Era Of Novel Agents: Low Incidence Of Pathological Fractures After Treatment

Skeletal-related events (SREs) which include pathological fractures, spinal cord compression (SCC) and a need for radiotherapy or surgery to bone are frequent complications of multiple myeloma (MM). Although, the frequency and characteristics of SREs in MM patients who received conventional chemotherapy (CC) or thalidomide-based regimens along with bisphosphonates (BPs) have been described, there are no data available in the era of proteasome inhibitors or novel IMiDs. Thus, we retrospectively evaluated the records of 400 consecutive patients with symptomatic MM (207M/193F, median age: 63 years) who were diagnosed, treated and followed in a single center. All patients had a whole body skeletal survey using conventional radiography at diagnosis and then at the time of relapse or whenever clinically indicated, while MRI of the spine and pelvis at diagnosis was available for 223 patients. Furthermore, we tested 125 patients for SNPs in genes that are involved in the biology of bone destruction: LRP5 (rs4988321), GC vitamin D (rs4588), TNFRSF11A (rs3018362), DKK1 (rs1569198), RANKL (rs9594759), OPG (rs6469804) and ERS1 (rs1038304).

At diagnosis, the skeletal survey detected osteolytic disease in 284 (71%) patients. In MRI, 34.5% of the patients had focal, 40.5% diffuse, 21% normal, and 4% a variegated pattern of marrow involvement. SREs were observed in 167 (41.7%) patients at diagnosis: 104 (26%) patients presented with pathological fractures (87 with vertebral fractures, 18 with rib fractures and 17 with fractures of the long bones; 22 patients had both vertebral and long bone or rib fractures), while 22 (5.5%) patients required surgery to bone, 21 (5.2%) radiotherapy and 20 (5%) patients presented with SCC. The incidence of SREs was higher in patients with osteolytic lesions (49.5% vs. 24%, p<0.001) or abnormal MRI pattern (49.7% vs. 23.3%, p=0.001). However, we noted that approximately 1/4 patients without lytic lesions in plain X-rays or with normal MRI pattern presented with a SRE at diagnosis. Patients homozygous for RANKL polymorphism had lower incidence of osteolysis at diagnosis (14/28, 50%) versus all others (76%, p=0.009), suggesting that this polymorphism may protect bone loss in MM, as it has been suggested for normal population.

Frontline therapy with IMiD-based regimens was given in 172 (43%) patients, while 80 (20%) patients received bortezomib-based regimens, 111 (27.7%) both IMiD and bortezomib (VTD or VRD) and 37 (9.2%) patients CC. BPs were given in all but 86 patients (21.5%) at diagnosis, mainly due to renal insufficiency; however, almost 60% of them (n=51) received BPs later in the course of their therapy. The vast majority (91%) of patients received zoledronic acid (ZA). Due to renal impairment, ZA was discontinued in 6 patients, while the dose was reduced in 44. During first line treatment, 7 (1.75%) patients developed a SRE: 2 on bortezomib- and 5 on IMiD-based regimens. The rate of SREs was higher in patients who did not receive upfront BPs (4.7% vs. 1%; p=0.021).

The median follow-up was 39 months. At the time of first relapse (data available for 176 patients), 3 patients presented with fractures and 35 patients required local radiotherapy to bone (SRE incidence: 21.6%). Patients who had received only bortezomib-based regimens (VD or VCD, n=20) had lower SRE rate (2/20, 10%) vs. all others (36/156, 22%, p=0.173); the 3 patients with fractures had received MPT (n=2) or RD (n=1). In total, during the course of their disease, 52.8% of the patients presented with at least one SRE. Presentation with SREs at diagnosis did not predispose for SREs during the disease course, regardless of anti-myeloma treatment, possibly due to the low number of fractures and the higher number of radiation needed after frontline therapy.

In summary, our data from the first systematic report on the incidence and characteristics of SREs in the era of novel agents indicate that SREs remain a significant complication in MM. Importantly, despite high response rates after first line therapy more than 20% of patients required radiotherapy at the time of relapse. The fracture rate was very low during first line therapy and at first relapse probably due to the extensive use of potent BPs and bortezomib, which has bone anabolic effects. The use of modern imaging techniques (i.e. PET/CT or LDWBCT) that can detect bone masses earlier and lead to earlier initiation of treatment may reduce the SRE incidence in the near future.