Novel agents in Waldenstrom Macroglobulinemia (original) (raw)
Related papers
Disease control should be the goal of therapy for WM patients
Blood Advances, 2017
This article has a companion Counterpoint by Treon and Castillo. Waldenström's macroglobulinemia (WM) is a unique low-grade lymphoma in several aspects: the symptoms and complications of WM are not only related to the tumor burden, but also to the physicochemical and immunologic properties of the monoclonal immunoglobulin M (M-IgM) produced by the lymphoplasmacytic cells. Treatment is aimed at reducing lymphoplasmacytic infiltration and the subsequent decrease of M-IgM to ameliorate symptoms and complications associated with the expansion of the neoplastic cells and of the M-IgM. Setting the strategy of therapy for WM includes weighing the heterogeneity of clinical presentation, symptoms, and complications, whereas, because patients with WM are often of advanced age, treatment decisions may critically depend on patients' comorbid conditions, with toxicity risks often being the primary consideration. 1 The ultimate goal of cancer therapy is to cure; in contrast to high-grade lymphomas, acute leukemias, chronic myeloid leukemia, or myeloma, a complete eradication of the disease is probably not feasible with the current therapies for WM. The term "disease eradication" has not been defined in WM; a more accurate term is complete response (CR), in which no malignant cells or their products (M-IgM) are detected by conventional methods such as immunohistochemistry and immunofixation. 2 This is closer to a disease burden below the limit of detection rather than "disease eradication."
Blood, 2016
In this phase 2 multicenter trial, we evaluated the efficacy of the combination of bortezomib, dexamethasone and rituximab (BDR) in 59 previously untreated symptomatic patients with Waldenström's Macroglobulinemia, most of which were of advanced age and with adverse prognostic factors. BDR consisted of a single 21-day cycle of bortezomib alone (1.3 mg/m(2) IV days 1, 4, 8, and 11), followed by weekly IV bortezomib (1.6 mg/m(2) days 1, 8, 15, and 22) for 4 additional 35-day cycles, with IV dexamethasone (40 mg) and IV rituximab (375 mg/m(2)) on cycles 2 and 5, for a total treatment duration of 23 weeks. On intent to treat, 85% responded (3% complete response, 7% very good partial response, 58% partial response). After a minimum follow-up of 6 years, median progression-free survival was 43 months and median duration of response for patients with at least partial response was 64.5 months. Overall survival at 7 years was 66%. No patient has developed secondary myelodysplasia while t...
Leukemia, 2013
Treatment in medical oncology is gradually shifting from the use of non-specific chemotherapeutic agents towards an era of novel targeted therapy in which drugs and their combinations target specific aspects of the biology of tumor cells. Multiple myeloma (MM) has become one of the best examples in this regard, reflected in the identification of new pathogenic mechanisms, together with the development of novel drugs that are being explored from the preclinical setting to the early phases of clinical development. We review the biological rationale for the use of the most important new agents for treating MM and summarize their clinical activity in an increasingly busy field. First, we discuss data from already approved and active agents (including second-and thirdgeneration-proteasome inhibitors, immunomodulatory agents (IMIDs) and alkylators). Then we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAb), cell cycle specific drugs, deacetylase inhibitors, agents acting on the unfolded protein response, signaling transduction pathway inhibitors, and kinase inhibitors. Among this plethora of new agents or mechanisms some are specially promising: Anti-CD38 MoAb, such as daratumumab, are the first antibodies with clinical activity as single agents in MM. Also the kinesin spindle protein inhibitor Arry-520 is effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients. Immunotherapy against MM is also being explored, and probably the most attractive example of this approach is the combination of the anti-CS1 MoAb elotuzumab with lenalidomide and dexamethasone, that has produced exciting results in the relapsed/refractory setting.
Clinical Cancer Research, 2007
Purpose: Waldenstrom's macroglobulinemia (WM) is a B-cell disorder. Despite advances in the therapy, WM remains incurable. As such, novel therapeutic agents are needed for the treatment of WM. Experimental Design: In this multicenter study, 27 patients with WM received up to eight cycles of bortezomib at 1.3 mg/m 2 on days 1, 4, 8, and 11. All but one patient had relapsed/or refractory disease. Results: Following therapy, median serum IgM levels declined from 4,660 to 2,092 mg/dL (P <0.0001).The overall response rate was 85%, with10 and13 patients achieving minor and major responses, respectively. Responses were prompt and occurred at median of1.4 months.The median time to progression for all responding patients was 7.9 (range, 3-21.4+) months.The most common grade III/IV toxicities occurring in z5% of patients were sensory neuropathies (22.2%), leukopenia (18.5%), neutropenia (14.8%), dizziness (11.1%), and thrombocytopenia (7.4%). Sensory neuropathies resolved or improved in nearly all patients following cessation of therapy.
Innovative Agents in Multiple Myeloma
Journal of the Advanced Practitioner in Oncology, 2014
Multiple myeloma (MM) remains an incurable cancer of the bone marrow plasma cells. However, the overall survival of patients with MM has increased dramatically within the past decade. This is due, in part, to newer agents such as immunomodulatory drugs (lenalidomide, thalidomide, and pomalidomide) and proteasome inhibitors (bortezomib, carfilzomib, MLN9708). These and several other new classes of drugs have arisen from an improved understanding of the complex environment in which genetic changes occur. Improved understanding of genetic events will enable clinicians to better stratify risk before and during therapy, tailor treatment, and test the value of personalized interventions. The ultimate goal in this incurable disease setting is to reduce the impact of cancer- or chemotherapy-related side effects. Nurses and advanced practitioners are integral to the treatment team. Thus, each should be aware of changes to the current drug landscape. Targeted drugs with sophisticated mechanis...
New developments in the treatment of multiple myeloma –
clinical utility of daratumumab
Biologics: Targets and Therapy
Multiple myeloma is a clonal disorder of plasma cells that is currently considered incurable. CD38 is a 46 kDa type II transmembrane glycoprotein that is highly expressed on myeloma cells. Daratumumab is a first in-class human IgG1 monoclonal antibody that targets CD38, and has antimyeloma effects through several mechanisms. Single-agent trials show surprising activity in heavily pretreated myeloma patients. Trials in the relapsed setting, where daratumumab is added to lenalidomide and dexamethasone or bortezomib and dexamethasone, have demonstrated significantly improved progression-free survival with acceptable toxicity. In this review, we discuss the mechanism of action, pharmacology and pharmacokinetics of daratumumab and review the available clinical data in detail. We examine how daratumumab interferes with transfusion testing due to the expression of CD38 on the red blood cells, leading to potential difficulties releasing blood products. Daratumumab also affects disease assessments in multiple myeloma, including serum protein electrophoresis, immunofixation and flow cytometry. Strategies to mitigate these effects are discussed. The optimal use of daratumumab has yet to be decided, and several trials are ongoing in the relapsed and upfront setting. We discuss the potential upfront role of this exciting therapy, which has significant potential for increased minimal residual disease negativity and improved progression-free survival even in high-risk groups.