Bone Remodeling in Patients with Relapsed/Refractory Multiple Myeloma Who Receive Lenalidomide-Based Regimens.

Lenalidomide in combination with dexamethasone is very effective for the management of refractory/relapsed multiple myeloma (MM). However, there is very little information for the effect of lenalidomide on bone metabolism in MM. We evaluated bone remodeling in 36 patients (22M/14F; median age 64 years) with refractory/relapsed MM who received lenalidomide-based regimens: 27 received the combination of lenalidomide at the standard dose of 25mg/day x 21 days, every 28 days, with either high (n=18) or low (n=9) dose dexamethasone, while 9 patients received the combination of lenalidomide/low dose dexamethasone plus bortezomib (BDR) at a dose of 1 mg/m², iv, on days 1, 4, 8, 11 every 28 days. The following serum indices of bone turnover were measured on day 1 of cycle 1, and then on day 28 of cycle 3:

• osteoblast inhibitor dickkopf-1 (Dkk-1);

• osteoclast regulators: soluble RANKL (sRANKL) and osteoprotegerin (OPG);

• bone resorption markers: C-telopeptide of collagen type-I (CTX) and tartrate-resistant acid phosphatase type-5b (TRACP-5b); and

• bone formation markers: bone-specific ALP (bALP) and osteocalcin (OC).

We also studied 20 healthy controls of similar gender and age. The median number of previous therapies was 3 (range: 2–7). At baseline, 9 patients had no lytic lesions (group A), while 3 patients had 1–3 lytic lesions (group B) and 24 patients had more than 3 lytic lesions and/or a pathological fracture (group C) in plain radiography of the skeleton. After 3 cycles of therapy the objective response (CR+PR) rate was 77% (21/27) in lenalidomide/dexamethasone patients and 55% (5/9) in BDR patients. MM patients at baseline had increased levels of Dkk-1 (p=0.002), sRANKL (p=0.04), and both markers of bone resorption (p<0.01) compared to controls. In contrast, bone formation as assessed by serum bALP and OC was significantly reduced (p<0.01). Patients with advanced bone disease (group C) had increased levels of CTX (p<0.001), TRACP-5b (p<0.01), Dkk-1 (p=0.04) and reduced levels of OC (p=0.04) compared with all others. Moreover, serum levels of DKK-1 correlated with TRACP-5b (r=0.614, p<0.0001), CTX (r=0.29, p=0.03), sRANKL (r=0.423, p=0.001) and OPG (r=0.572, p<0.0001). The administration of lenalidomide-based regimens produced only a reduction of Dkk-1 (p=0.04) and TRACP-5b (p=0.03) after 3 cycles of therapy. Interestingly, patients who received BDR showed a dramatic reduction of sRANKL (p=0.02), sRANKL/OPG ratio (p=0.03) and Dkk-1 (p=0.02), which associated with an increase in both markers of bone formation (p=0.04). The % reduction of sRANKL and TRACP-5b and the % increase of bALP and OC was higher in BDR patients compared with others. There was no correlation between response to therapy and bone markers’ changes. In conclusion, the combination of lenalidomide plus dexamethasone seems not to have a clear effect on bone metabolism after 3 cycles of therapy, possibly due to administration of high dose dexamethasone in the majority of patients. BDR patients had a beneficial effect mainly on bone formation, reflecting the bone anabolic effect of bortezomib and/or the lower dose of dexamethasone given in these patients. Longer follow-up is needed to exact final conclusions for the effect of lenalidomide on bone metabolism in relapsed/refractory MM.