Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High-dose melphalan and autologous stem cell transplantation (HDM/SCT) have been used in patients with immunoglobulin light chain (AL) amyloidosis for over 2 decades now with durable responses, prolonged survival, and decreasing treatment-related mortality. Historically, patients with poorer baseline functional status, advanced age, renal compromise, and cardiac involvement have been treated with a risk-adapted modified conditioning dose of melphalan (mHDM) of 100 to 140 mg/m2 before SCT. In part because of these baseline characteristics, patients receiving mHDM/SCT have had poorer outcomes compared with patients receiving full-dose melphalan at 200 mg/m2. With the advent of novel therapeutic agents such as proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies for the treatment of AL amyloidosis, it is imperative to understand the long-term effects of mHDM/SCT. Here we report the long-term outcomes of 334 patients with AL amyloidosis treated with mHDM/SCT. Median overall survival was 6.1 years and median event-free survival 4.3 years, with median overall survival reaching 13.4 years for patients who had achieved a hematologic complete response (CR). Overall hematologic response rate was 69%, and treatment-related mortality was 3% after 2010. Thus, mHDM/SCT leads to prolonged survival and favorable outcomes, especially if a hematologic CR is achieved.
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PMID:Modified High-Dose Melphalan and Autologous Stem Cell Transplantation for Immunoglobulin Light Chain Amyloidosis. 2993 72

The significant advances made in the treatment of multiple myeloma (MM) have allowed for a paradigm shift away from the early use of high-dose melphalan with autologous stem cell transplant (HDM-ASCT). In 2015 alone, the US Food and Drug Administration (FDA) approved 4 novel drugs for MM. Novel drugs and regimens have shown unprecedented efficacy, which has increased the tempo of new drug development. Furthermore, the FDA recently approved a diagnostic test to detect minimal residual disease (MRD) that will allow community clinicians to conduct real-time testing of MRD. Most importantly, frontline regimens based on immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) have shown a large clinical benefit. The next era has begun, as several 4-drug combinations that include monoclonal antibodies are being evaluated in clinical trials in the attempt to replace HDM-ASCT in the treatment of MM. We and others have therefore questioned the need for early HDM-ASCT, especially in light of the possible complications. HDM-ASCT is associated not only with acute toxicities-cytopenia, infection, and even death-but also an increased risk of developing secondary cancers. This article discusses the historic context of HDM-ASCT, the modern role of HDM-ASCT given the availability of highly sensitive MRD testing, and the likely future of quadruplet treatment. In summary, patients who attain deep responses using IMiD- and PI-based regimens may not require early HDM-ASCT. A delayed approach to this treatment is acceptable, and might be preferred by patients.
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PMID:Delaying the use of high-dose melphalan with stem cell rescue in multiple myeloma is ready for prime time. 3173 May 82

State of the art treatment for myeloma involves using 3-drug combinations incorporating immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Clinical trials for 4-drug combinations incorporating monoclonal antibodies added to IMiD and PI based backbones are underway. Recent retrospective analyses show that patients who attain MRD negativity have similar long term outcomes regardless of early or delayed high dose melphalan with autologous stem cell support (HDM-ASCT). Given HDM-ASCT toxicity, not "overtreating" would be beneficial. Short of data from future prospective clinical trials addressing the question of the role of HDM-ASCT in MRD negative patients, varying expert opinions inherently arise. In this paper, we present the historical context of HDM-ASCT and data supporting 3-drug combinations. We then propose that a viable option for patients who reach MRD negativity is to transition to maintenance therapy directly without early HDM-ASCT, and reserving stem cell harvest to cases where HDM-ASCT is a possibility at relapse.
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PMID:The changing role of high dose melphalan with stem cell rescue in the treatment of newly diagnosed multiple myeloma in the era of modern therapies-back to the future! 3213 15