Bone Marrow Fibrosis Is a Negative Predictor for Osteolytic Lesions in Patients with Myeloma.

Multiple myeloma is a clonal lymphoproliferative disorder characterised by proliferation of plasma cells in marrow and is associated with an unbalanced bone remodelling leading to osteolytic lesions. Bone marrow interstitial fibrosis is common in myeloma. Correlation of marrow fibrosis with clinical parameters and survival in patients with myeloma is conflicting. We have analysed the impact of marrow fibrosis at presentation in 83 (F: 45; M: 38) patients with median age 67 yrs on osteolytic lesions and survival. Reticulin silver impregnation is employed as standard matrix stain. H & E slides were reviewed for degree and pattern of plasma cell infiltration. Marrow reticulin was quantified from Grade 0–4. 50 had IgG myeloma, 15 had Ig A myeloma, 13 had LC myeloma, 2 had Ig D myeloma and PCL and one had Ig M myeloma. Median marrow plasma cell count was 60%. 42% had increased marrow reticulin (> grade2). 33 received VAD, 16 melphalan and prednisolone, 7 dexamethasone, 6 cyclophosphamide, thalidomide, dexamethasone, 6 cyclophosphamide, 4 thalidomide, 1 dexamethasone and thalidomide combination and 10 only bisphosphonates as initial therapy.

Haemoglobin < 10 gms/dl was in 47% patients. 67% were positive for BJP. 33% had hypercalcaemia. 51% had >2 osteolytic lesions at diagnosis. 55% had β2-microglobulin >4mg/L and 22% had renal failure at diagnosis. 47% needed more than one line of therapy. Marrow reticulin was a negative predictor for osteolytic lesions (Fisher’s Exact test; p: 0.001). Marrow reticulin didn’t correlate with other laboratory parameters. Marrow reticulin, sex, BJP & number of osteolytic lesions at diagnosis did not impact on OS (Log Rank test p values: 0.6, 0.07, 0.6 & 0.4 respectively). Known poor prognostic markers Hb <10gm/dl, hypercalcaemia, renal failure and elevated β2-microglobulin were associated with poor OS (Log Rank test p values: 0.02, 0.04, 0.004 & 0.002 respectively) with median follow-up 27 months. Number of osteolytic lesions and anaemia at diagnosis had impact on progression free survival (Log Rank test; p values: 0.01 & 0.02 respectively) where as raised β2-microglobulin, marrow reticulin, hypercalcaemia and renal failure (Log Rank test; p values: 0.07, 0.7, 0.9 & 0.35 respectively) had no impact. Marrow reticulin also had no effect on requirement for more than one line of therapy (p value: 0.17).

Marrow reticulin is a negative predictor for osteolytic lesions, even though it does not appear to impact on survival in patients with myeloma. Our study also confirms the poor prognostic role of anaemia, hypercalcaemia, renal failure and raised β2-microglobulin in patients with myeloma. Further study of the hepatocyte growth factor/c-Met interaction may identify the negative correlation between marrow fibrosis and osteolytic lesions. This may enhance understanding of skeletal prophylaxis in patients with myeloma.