The authors examine in a real-world practice setting whether the proteasome inhibitor bortezomib and immunomodulatory drugs lenalidomide and thalidomide are effective in prolonging overall survival in newly diagnosed multiple myeloma. Chen Y, Lairson DR, Chan W, Du XL. Med Oncol 2017;34:153. doi:10.1007/s12032-017-1001-7

This review discusses current multiple myeloma treatment options, effective symptom management approaches, and practical strategies for supportive care. Summary points Recent therapeutic advances have significantly improved overall survival in patients with multiple myeloma (MM), with a concomitant increase in susceptibility to disease- and treatment-related symptoms. Current therapeutic regimens for relapsed/refractory MM include proteasome inhibitors (eg, bortezomib, carfilzomib) and immunomodulatory agents (eg, thalidomide, lenalidomide, pomalidomide), alone or in combination with chemotherapy or corticosteroids. Toxicities associated with agents and combination regimens used in the treatment of MM include myelosuppression, venous thromboembolism, peripheral neuropathy, infections, fatigue, gastrointestinal disorders, and/or cardiac events. Treatment-specific tools and clinical assessments can be useful for optimizing dosing and schedule adjustments to increase therapy duration, and implementing supportive care strategies (such as growth factors, transfusional support, intravenous hydration, bisphosphonates, and antiviral therapies) to manage treatment-related symptoms. Effective management of the patient with MM requires knowledge of the disease and of treatment-associated adverse events in addition to preventative measures, supportive care strategies, and management of comorbidities. Patient education and individualized survivorship plans can play a role in achieving maximal patient responses to treatment. Improved survival after MM diagnosis has led to increased patient susceptibility to other diseases and comorbidities due to advanced age, thus optimal symptom management will be important to maximize quality of life for patients in addition to disease control and survival. Colson K. Support Care Cancer 2015; 23: 1431–1445. doi:10.1007/s00520-014-2552-1

Here, Guillerey et al. review the immunological microenvironment in myeloma and highlight the numerous promising immune-targeting strategies approved or in clinical trials for the treatment of myeloma. Summary points Multiple myeloma (MM) is a tumor localized at various sites within the bone marrow (BM). With over 20,000 new cases diagnosed per year in the United States, MM represents 1% of all cancers and approximately 10% of all hematological malignancies. Early studies established the role of the BM microenvironment in MM pathology but the immune component of this microenvironment has not received full attention until recently. MM is a multistep progressing disease that starts with an asymptomatic premalignant lesion called monoclonal gammopathy of undetermined significance (MGUS) and develops to an escape phase in which active MM can be observed. Several lines of evidence indicate that changes in the immune responses may drive the development from MGUS to MM progression. Along with genetic changes in plasma cells the BM microenvironment is believed to play a crucial role in disease progression to symptomatic myeloma. Therapeutic options such as autologous stem cell transplant, thalidomide, immunomodulatory drugs, and proteasome inhibitors can restore and enhance anti-myeloma immune responses. However, in spite of the clinical success of these therapies, MM remains largely incurable and most patients relapse. Research is currently ongoing to design new therapeutic strategies able to eradicate residual disease, trigger the immune elimination of myeloma cells, and prevent relapse. Harnessing the immune system is an appealing solution and new approaches such as immunotherapy with natural killer cell-based therapies or immune checkpoint modulation hold great promise for MM patients. Guillerey C, Nakamura K, Vuckovic S, Hill GR, Smyth MJ.  Cell Mol Life Sci  2016; 73:1569–1589. doi: 10.1007/s00018-016-2135-z

This article provides an overview of the challenges in the care of patients with relapsed/refractory multiple myeloma, current and emerging treatment options, and the possible role of hematopoietic stem cell transplantation. Summary points The use of modern therapies such as thalidomide, bortezomib, and lenalidomide coupled with upfront high-dose therapy and autologous stem cell transplant (ASCT) has resulted in improved survival in patients with newly diagnosed multiple myeloma (MM). However, patients with relapsed/refractory  MM (RRMM) present a therapeutic challenge as they often have poorer clinical outcomes. These patients have a median survival of only 1.5 years, and their clinical course is typified by decreasing response duration with an increasing number of salvage regimens. Current treatment standards for RRMM include (1) salvage chemotherapy, (2) salvage autologous stem cell transplant (ASCT), (3) allogeneic hematopoietic stem cell transplant (allo-SCT), and (4) post-transplant consolidation/maintenance therapy. Emerging therapies that target different mechanisms of action including immunotherapy, deacetylase inhibitors, monoclonal antibodies, and new proteasome inhibitors are promising and may change the therapeutic landscape in RRMM. Their favorable safety profiles as monotherapy in patients with RRMM will enable combinatorial use with ASCT/allo-SCT to further improve long-term disease control. Improvement in transplant outcomes has re-ignited a debate on the timing and possible role for salvage ASCT and allogeneic stem cell transplant in RRMM. As the treatment options for management of patients with RRMM become increasingly complex, physicians must consider both disease- and patient-related factors in choosing the appropriate therapeutic approach, with the goal of improving efficacy while minimizing toxicity. Enrolment of patients in clinical trials designed to answer unresolved issues in the treatment of patients with RRMM is highly recommended. Cornell RF & Kassim AA. Bone Marrow Transplant  2016; 51: 479–491. doi: 10.1038/bmt.2015.307

The focus of this review is a critical analysis of combinations of novel agents in the treatment of newly diagnosed multiple myeloma in both transplant eligible and ineligible patients. Summary points Multiple myeloma (MM) is the second most common hematologic malignancy, accounting for 1% of neoplastic diseases and 13% of hematologic cancers, and predominantly affects the elderly. The introduction of novel therapies such as thalidomide, lenalidomide, and bortezomib for the treatment of MM in the last 15 years has drastically improved progression-free survival (PFS), overall survival (OS), and quality of life for patients with MM. In transplant-eligible patients, the three-drug regimens CyBorD, RVD, and BiRD appear to be the most effective with tolerable adverse effect profile and PFS benefit. Carfilzomib in combination with lenalidomide and dexamethasone has been shown to induce deep responses to the point of negative minimal residual disease state on flow cytometry. In transplant-ineligible patients, continuous use of two-drug regimens bortezomib/dexamethasone or lenalidomide/dexamethasone has shown superior overall response and PFS with enhanced tolerability compared with three-drug regimens. New agents for the treatment of MM are under investigation in the relapsed or refractory disease state. As these agents are approved and move to the upfront setting, more exciting and promising results for both the transplant eligible and ineligible patient population will be seen. Runcie KD & Mark TM. Curr Hematol Malig Rep 2015; 10: 388–394. doi:10.1007/s11899-015-0282-1

Subsequent analysis demonstrated improved health-related QOL for patients treated with lenalidomide and dexamethasone vs MPT. 23  The recent studies E1A06 and HOVON 87/NMSG 18 have compared thalidomide maintenance to lenalidomide-based maintenance. 24,   25  Both trials randomized patients to melphalan, prednisone and thalidomide with thalidomide maintenance (MPT-T) vs MPR-R.

Immunomodulatory agents Lenalidomide This is a second generation thalidomide analog and immunomodulatory agent that has shown encouraging results in CLL/SLL patients with del17p [52].

This articles reviews the clinical efficacy of immunomodulatory drugs, their structure-function relationship, molecular mechanisms of action, and associated second primary malignancies and thrombosis. Holstein SA & McCarthy PL. Drugs 2017; 77: 505–520. doi:10.1007/s40265-017-0689-1

An expert review of current treatment options for relapsed/refractory multiple myeloma, the mechanism of action of panobinostat, and how panobinostat fits into the current therapeutic landscape. San-Miguel JF, Einsele H, & Moreau P. Adv Ther 2016; 33: 1896–1920. doi:10.1007/s12325-016-0413-7

Lenalidomide is a more potent thalidomide derivative.

The authors review the plethora of novel agents currently in development or recently approved for the treatment of patients with multiple myeloma. Naymagon L & Abdul-Hay M. J Hematol Oncol 2016; 9: 52. doi:10.1186/s13045-016-0282-1

Thalidomide was the first novel drug to be tested for its efficacy in high-risk patients either as induction (TD, TAD and CTD) or as maintenance therapy, and in both settings high-risk patients did significantly poorer than standard risk. 34, 38, 39 Moreover, studies derived from the UK group (MRC IX intensive, MRC IX non-intensive and MRC IX maintenance) indicate that thalidomide is not superior to conventional chemotherapy in patients with high-risk cytogenetic abnormalities. 39, 40, 41 Accordingly, it could be concluded that thalidomide neither improves nor overcomes the poor prognosis of high-risk patients.