Faculty Bibliography

Over the past two decades, not only treatment options, but also the diagnosis, staging, and risk assessment of multiple myeloma (MM), have undergone significant development, partially due to a deeper understanding of MM pathogenesis. Conventional cytogenetics and fluorescence in situ hybridization are routinely assessed in MM, and when combined with ISS stage may attain an even better predictive potential. In order to achieve even more effective and individualized therapies, one crucial goal is the identification of genes and gene combinations that predict for response or resistance to chemotherapy. High-dose chemotherapy with autologous stem cell transplant (SCT) still remains the standard therapy for younger patients, with novel agents now being included in both pre-transplant regimens and post-transplant consolidation/maintenance approaches. Similarly, novel agents are also being incorporated into allogeneic SCT for selected patients. In the treatment of elderly patients with MM, novel agents have been successfully incorporated into less intensive regimens, including melphalan/prednisone, low-dose dexamethasone, and cyclophosphamide/dexamethasone. While second-generation proteasome inhibitors are currently being intensively investigated, the subcutaneous administration of bortezomib, being equivalent to the established i.v. route, is now entering clinical practice. Supportive care remains a crucial aspect in the management of MM. The European Myeloma Network Trialist Group aims to address these contemporary aspects in MM.

BACKGROUND:As rare myelomas, i.e. the IgD, IgE, IgM and non-secretory forms, constitute only a small proportion of any study, relatively little is known about their prognosis in the era of peripheral stem cell transplantation. DESIGN AND METHODS/METHODS:We used the European Group for Blood and Marrow Transplantation Myeloma Database to compare the outcome following autologous transplantation of over 20,000 patients with common myelomas (IgG, IgA and light chain myeloma) with the outcome of patients with rare myelomas: 379 IgD, 13 IgE, 72 IgM and 976 non-secretory cases. RESULTS:The study confirms the multiple adverse prognostic factors seen in IgD myeloma. Somewhat surprisingly, patients with IgD and non-secretory myeloma both had higher complete remission rates before and after transplantation than patients with common myelomas. However, while the overall survival of patients with non-secretory myeloma was similar to that of the patients with common myelomas, the survival of patients with IgD myeloma was significantly worse (although better than survival rates reported for non-transplanted patients); this was due to higher transplant-related mortality and relapse/progression rates. The post-transplantation survival of patients with IgE or IgM myeloma appears to be very poor. CONCLUSIONS:This study provides data on the biological features of rare myelomas. The overall survival of patients with IgD, IgE or IgM myeloma is poor following autologous transplantation but substantially better than that reported for patients who were not transplanted.

Bisphosphonates are firmly entrenched in the treatment of metastatic bone disease secondary to several tumor types, including breast cancer, prostate cancer, and myeloma. More recently, an emerging body of preclinical and clinical evidence indicates that bisphosphonates might also exhibit antitumor activity. This expanded role for bisphosphonates in the adjuvant setting might have profound clinical implications in many cancer types, particularly in the context of prevention of bone metastasis. Increased understanding of the mechanistic basis of the antitumor effects indicates that these might occur via direct mechanisms such as induction of apoptosis and inhibition of tumor cell adhesion and invasion, as well as indirect mechanisms such as inhibition of angiogenesis. There is also considerable evidence to suggest that nitrogen-containing bisphosphonates might exert additive or synergistic interactions with standard cytotoxic agents. However, mature clinical data with bisphosphonates are limited and, thus far, provide conflicting evidence regarding the antitumor role of bisphosphonates, but have mostly been conducted with first-generation bisphosphonates such as clodronate that are not as effective as next-generation bisphosphonates. Several large randomized clinical trials are ongoing with the next-generation bisphosphonate zoledronic acid to prospectively confirm an antitumor role for bisphosphonates in various tumor types. This review assesses the current body of preclinical and clinical evidence in favor of an antitumor effect of bisphosphonates in different cancer types.

The introduction of thalidomide, lenalidomide, and bortezomib has changed the way that multiple myeloma (MM) is treated and has greatly improved survival outcomes. These novel agents are often used in combination with conventional drugs, such as dexamethasone, to optimize clinical responses; however, they are also being evaluated as part of novel treatment combinations to build upon the success of available treatment regimens. Lenalidomide-based combinations are a focus of clinical research due to the high efficacy, good tolerability, and lack of cumulative toxicity associated with lenalidomide. Lenalidomide is an IMiDs® immunomodulatory compound with a dual mechanism of action - tumoricidal effects rapidly reduce MM burden while long-term immunomodulatory actions maintain tumor suppression. Several new agents with antimyeloma effects have been identified including: epigenetic agents (e.g. histone deacetylase inhibitors); novel proteasome inhibitors; novel immunomodulatory compounds; cyclin-dependent kinase inhibitors; interleukin-6 inhibitors; and other experimental agents such as heat-shock protein 90 inhibitors and monoclonal antibodies targeting MM cell surface receptors (e.g. anti-CS1 and anti-CD40). Many of these new agents, in combination with lenalidomide, are in early phases of clinical evaluation. Early clinical results are promising, indicating that the novel lenalidomide-based drug combinations are effective and generally well tolerated in patients with MM; future research will continue to evaluate these novel combinations and help to identify the optimal setting (e.g. induction, salvage, or maintenance) in which they may provide the greatest impact on the disease course.