Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed, refractory, or ineligible, to an IMiD (Immunomodulatory Drug), with measurable disease and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T0). The median age at diagnosis was 58 years and time from diagnosis to T0 was 3.3 years. Following T0, 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T0 in 94 patients (51%) including >=partial response in 69 (38%). The median overall survival and event free survival from T0 were 9 and 5 months respectively. This study confirms the poor outcome once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.

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Multiple myeloma (MM) is a plasma cell malignancy, characterized by the localization of the MM cells in the bone marrow (BM), where they proliferate and induce osteolysis. The MM cells first need to home or migrate to the BM to receive necessary survival signals. In this work, we studied the role of CCR1 and CCR5, two known chemokine receptors, in both chemotaxis and osteolysis in the experimental 5TMM mouse model. A CCR1-specific (BX471) and a CCR5-specific (TAK779) antagonist were used to identify the function of both receptors. We could detect by RT-PCR and flow cytometric analyses the expression of both CCR1 and CCR5 on the cells and their major ligand, macrophage inflammatory protein 1alpha (MIP1alpha) could be detected by ELISA. In vitro migration assays showed that MIP1alpha induced a 2-fold increase in migration of 5TMM cells, which could only be blocked by TAK779. In vivo homing kinetics showed a 30% inhibition in BM homing when 5TMM cells were pre-treated with TAK779. We found, in vitro, that both inhibitors were able to reduce osteoclastogenesis and osteoclastic resorption. In vivo end-term treatment of 5T2MM mice with BX471 resulted in a reduction of the osteolytic lesions by 40%; while TAK779 treatment led to a 20% decrease in lesions. Furthermore, assessment of the microvessel density demonstrated a role for both receptors in MM induced angiogenesis. These data demonstrate the differential role of CCR1 and CCR5 in MM chemotaxis and MM associated osteolysis and angiogenesis.

Serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor (TNF)-alpha were frequently measured during the first 30 days after allogeneic bone marrow transplantation (BMT) in 84 consecutive adult patients. Major transplant-related complications (MTCs) occurred in 33% of cases and included veno-occlusive liver disease, idiopathic pneumonia syndrome, severe endothelial leakage syndrome and 4grade II acute graft-versus-host disease. Compared with patients having minor complications, those with MTCs developed higher levels at times of maximal clinical signs (all cytokines, Po0.001), between days 0-5 post-BMT (IL-6 and IL-8, Po0.05) and days 6-10 (L-6, Po0.001; IL-8 and TNF, Po0.01) post-BMT. We could not discriminate patterns of cytokine release that were specific for any subtype of MTC. Higher levels of IL-8 during days 0-5 were associated (P ¼ 0.044) with early (o40 days) death. Multivariate analysis including patient and transplant characteristics as well as post-BMT levels of C-reactive protein showed that high average levels of one or more of the cytokines within the first 10 days post-BMT were independently associated with MTC (Odd's ratio: 2.3 [1.2-4.5], P ¼ 0.011). This study shows that systemic release of proinflammatory cytokines contributes to the development of MTC and provides a rationale for pre-emptive anti-inflammatory treatment in selected patients.

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