No abstract

Although interactions with bone marrow stromal cells are essential for multiple myeloma (MM) cell survival, the specific molecular and cellular elements involved are largely unknown, due in large part to the complexity of the bone marrow microenvironment itself. The T-cell costimulatory receptor CD28 is also expressed on normal and malignant plasma cells, and CD28 expression in MM correlates significantly with poor prognosis and disease progression. In contrast to T cells, activation and function of CD28 in myeloma cells is largely undefined. We have found that direct activation of myeloma cell CD28 by anti-CD28 mAb alone induces activation of PI3K and NFB, suppresses MM cell proliferation, and protects against serum starvation and dexamethasone (dex)-induced cell death. Coculture with dendritic cells (DCs) expressing the CD28 ligands CD80 and CD86 also elicits CD28-mediated effects on MM survival and proliferation, and DCs appear to preferentially localize within myeloma infiltrates in primary patient samples. Our findings suggest a previously undescribed myeloma/DC cell-cell interaction involving CD28 that may play an important role in myeloma cell survival within the bone marrow stroma. These data also point to CD28 as a potential therapeutic target in the treatment of MM. IntroductionMultiple myeloma (MM) remains an incurable clonal B lymphoid neoplasm of plasma cells, second only to non-Hodgkin lymphoma in incidence. 1 Despite significant initial responses to chemotherapy, more than 90% of patients with MM relapse with resistant disease, 2 underscoring the need to identify novel therapeutic targets that affect myeloma survival and resistance pathways. Given that MM cells are critically dependent on normal elements of the bone marrow stroma for cell growth and survival, these interactions are attractive targets. One such interaction is stromal production of soluble growth factors, such as IL-6 and TRANCE. 1,3 Another important set of interactions involves direct myeloma cell contact with extracellular matrix (ECM) and/or stromal cells. Such direct contact up-regulates stromal cell IL-6 and VEGF production, induces NFB signaling, drops myeloma cells out of cell cycle, and enhances resistance to chemotherapy. [4][5][6] However, the specific molecular (eg, integrins 4,7 ) and cellular components (eg, osteoclasts 8 ) of these direct interactions within the complex bone marrow microenvironment are only beginning to be described. As important, the characteristic progression of myeloma to stromal independence marks a clinically worse disease, 9 yet the mechanisms that underlie this transition are also poorly understood.Identification of prosurvival receptors typically expressed on myeloma cells may point to the stromal cells expressing the receptor ligands. One potential receptor is CD28. CD28 has a restricted lineage expression, found predominantly on T cells but also on normal plasma cells, primary myeloma isolates, and myeloma cell lines at levels comparable with T cells. [10][11][12][13] In T cells, CD28 recep...

BackgroundRuxolitinib, a Janus kinase 1 and 2 inhibitor, demonstrated improvements in spleen volume, symptoms, and survival over placebo and best available therapy in intermediate-2 or high-risk myelofibrosis patients with baseline platelet counts ≥100 × 109/L in phase III studies. The most common adverse events were dose-dependent anemia and thrombocytopenia, which were anticipated because thrombopoietin and erythropoietin signal through JAK2. These events were manageable, rarely leading to treatment discontinuation. Because approximately one-quarter of MF patients have platelet counts <100 × 109/L consequent to their disease, ruxolitinib was evaluated in this subset of patients using lower initial doses. Interim results of a phase II study of ruxolitinib in myelofibrosis patients with baseline platelet counts of 50-100 × 109/L are reported.MethodsRuxolitinib was initiated at a dose of 5 mg twice daily (BID), and doses could be increased by 5 mg once daily every 4 weeks to 10 mg BID if platelet counts remained adequate. Additional dosage increases required evidence of suboptimal efficacy. Assessments included measurement of spleen volume by MRI, MF symptoms by MF Symptom Assessment Form v2.0 Total Symptom Score [TSS]), Patient Global Impression of Change (PGIC); EORTC QLQ-C30, and safety/tolerability.ResultsBy week 24, 62% of patients achieved stable doses ≥10 mg BID. Median reductions in spleen volume and TSS were 24.2% and 43.8%, respectively. Thrombocytopenia necessitating dose reductions and dose interruptions occurred in 12 and 8 patients, respectively, and occurred mainly in patients with baseline platelet counts ≤75 × 109/L. Seven patients experienced platelet count increases ≥15 × 109/L. Mean hemoglobin levels remained stable over the treatment period. Two patients discontinued for adverse events: 1 for grade 4 retroperitoneal hemorrhage secondary to multiple and suspected pre-existing renal artery aneurysms and 1 for grade 4 thrombocytopenia.ConclusionsResults suggest that a low starting dose of ruxolitinib with escalation to 10 mg BID may be appropriate in myelofibrosis patients with low platelet counts.Trial registrationClinicalTrials.gov: NCT01348490.

Early mortality (EM; death ≤ 6 months from diagnosis) has been reported in several newly diagnosed multiple myeloma (NDMM) trials. Before the era of novel agents, the incidence was 10%‐14%. Causes of death included infections/pneumonia, renal failure, refractory disease, and cardiac events. Staging systems, such as the revised International Staging System (r‐ISS), and prognostic factors including cytogenetics, lactate dehydrogenase levels, and myeloma‐specific factors, are useful to assess overall prognosis; however, they cannot predict EM. We evaluated patients treated with novel agents in the Connect MM® Registry and identified risk factors of the EM cohort. Eligible patients were enrolled in the registry within 60 days of diagnosis. Univariate and multivariate analyses were conducted to evaluate associations between baseline characteristics and EM. Prediction matrices for EM were constructed from a logistic model. Between September 2009 and December 2011, 1493 patients were enrolled in the registry and had adequate follow‐up. Of these patients, 102 (6.8%) had EM and 1391 (93.2%) survived for > 180 days. Baseline factors significantly associated with increased EM risk included age > 75 years, higher Eastern Cooperative Oncology Group performance status, lower EQ‐5D mobility score, higher ISS stage, lower platelet count, and prior hypertension. Renal insufficiency trended toward increased EM risk. These risk factors were incorporated into a prediction matrix for EM. The EM prediction matrix uses differential weighting of risk factors to calculate EM risk in patients with NDMM. Identifying patients at risk for EM may provide new opportunities to implement patient‐specific treatment strategies to improve outcomes.

• Lenalidomide (vs no) maintenance therapy post-ASCT improved survival outcomes in patients with NDMM.• Using unselected registry patients, this study reproduced the survival benefits of lenalidomide maintenance observed in clinical trials.