Multiple Myeloma and Amyloidosis: An Evolving Treatment Paradigm Toward the Goal of Tailored Therapy

Significant advances over the last 15 years in our understanding of the biology of multiple myeloma (MM) have led to exciting new opportunities for treatment, which have in turn transformed the therapeutic paradigm in the last decade. The successful translation of these derived novel therapies from laboratory bench to bedside with less toxicity and more specific anti-MM activity has dramatically improved patient outcome. The next generation of new molecules has followed, demonstrating exciting responses and improved tolerability, promising further improvements in survival. Combination approaches in particular have generated deep and durable responses that are unprecedented in this disease. In this review, first the molecular heterogeneity of MM and its pathogenesis, prognosis, and therapeutic implications are succinctly reviewed by Avet-Loiseau et al. As Avet-Loiseau et al note, data support that this heterogeneity is primarily related to molecular characteristics of the tumor clone(s), although the contribution of the tumor microenvironment is likely also key. Although genetic changes are the hallmark of the cancer cell, these changes are typically limited in many hematologic neoplasms (such as chronic myeloid leukemia and most acute leukemias). In contrast, solid tumors usually present a wide variety of chromosomal and genomic rearrangements. Myeloma as a genetic entity is probably somewhere in between these two extremes, and a continued improvement in our understanding of this heterogeneity is vital to treatment choices. In this context, current trends in transplant for myeloma in the era of novel therapies are addressed by Moreau et al, who ask a fundamental question: should autologous stem-cell transplantation be used upfront or as salvage treatment as the time of progression in all eligible patients initially treated with novel agents or in specific subgroups? The recent introduction of first-generation novel agents in MM—specifically thalidomide, bortezomib, and lenalidomide—is changing the transplantation scenario in many different ways, and this is broadly discussed by Moreau et al, who also outline future directions. A critical aspect of myeloma management, specifically advances in its imaging and the management of myeloma-related bone disease, is examined by Terpos et al. The combination of novel antimyeloma agents (such as bortezomib, which has potent anabolic effects on bone) with bisphosphonates or with other drugs that enhance osteoblast function (such as anti-Dickkopf-1 agents) may alter our way of managing myeloma-related bone disease in the near future. Novel antiresorptive agents such as denosumab have also demonstrated encouraging results, but additional studies are needed before these agents can be recommended for managing MM-related bone disease. Next, future directions and second-generation novel therapies, together with innovative combinations, are thoughtfully reviewed by Mitsiades et al, who present a clear vision of the future in antimyeloma therapy. They provide a comprehensive review of novel agents for the treatment of myeloma, which is then followed by a critical analysis of clinical research to date and the current translation of these advances into clinical practice. The role of combination regimens in the future of myeloma treatment is addressed as it pertains to individual clinical settings, and then personalized treatment is considered philosophically with a balance between the current state of the art and prospect for the future. Finally, Merlini et al review the increasingly important entity of amyloidosis and provide a state-of-the-art review of its pathogenesis and the impact of new therapeutic options. Given that amyloid, as an entity and as a consequence of MM, is an increasingly important area to better understand in the management of plasma cell dyscrasias overall, this prescient article is especially useful because treatment options are improving for such patients, but major challenges remain. Early and accurate diagnosis is the key to effective therapy, and unequivocal identification of the amyloidogenic protein may require advanced technologies and expertise. Prognosis is dictated by the extent of cardiac involvement, and cardiac staging directs the choice of treatment. The authors emphasize that treatment for light chain amyloidosis is highly individualized on the basis of age, organ dysfunction, and regimen toxicities and should be guided by biomarkers of hematologic and cardiac response. Alkylator-based chemotherapy remains effective in almost two thirds of patients. Novel agents now also prove highly effective, and trials are ongoing to establish their optimal use; the results to date of such studies are then thoughtfully addressed. In summary, this review seeks to provide an overview across both MM and amyloidosis of an evolving treatment paradigm toward the goal of tailored theapy, which will hopefully be useful to clinicians and scientists alike. JOURNAL OF CLINICAL ONCOLOGY O V E R V I E W VOLUME 29 NUMBER 14 MAY 1