Disease Overview
Multiple myeloma accounts for approximately 10% of hematologic malignancies.
Diagnosis
The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy‐proven plasmacytoma ...plus evidence of one or more multiple myeloma defining events (MDE): CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) attributable to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥ 100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging.
Risk Stratification
The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation is considered high‐risk multiple myeloma. The presence of any two high risk factors is considered double‐hit myeloma, and three or more high risk factors is triple‐hit myeloma.
Risk‐Adapted Initial Therapy
In patients who are candidates for autologous stem cell transplantation, induction therapy consists of bortezomib, lenalidomide, dexamethasone (VRd) given for approximately 3–4 cycles followed by autologous stem cell transplantation (ASCT). In high‐risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara‐VRd) is an alternative to VRd. Selected standard‐risk patients can collect stem cells, get additional cycles of induction therapy, and delay transplant until first relapse. Patients who are not candidates for transplant are treated with VRd for approximately 8–12 cycles followed by maintenance or alternatively with daratumumab, lenalidomide, dexamethasone (DRd) until progression.
Maintenance Therapy
Standard‐risk patients need lenalidomide maintenance, while bortezomib plus lenalidomide maintenance is needed for high‐risk myeloma.
Management of Relapsed Disease
A triplet regimen is usually needed at relapse, with the choice of regimen varying with each successive relapse.
Approach to treatment of newly diagnosed myeloma in transplant eligible patients.
Disease overview
Multiple myeloma accounts for approximately 10% of hematologic malignancies.
Diagnosis
The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma ...plus evidence of one or more multiple myeloma defining events (MDE) namely CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging (MRI).
Risk stratification
The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation is considered high‐risk multiple myeloma. Presence of any two high risk factors is considered double‐hit myeloma; three or more high risk factors is triple‐hit myeloma.
Risk‐adapted initial therapy
In transplant eligible patients, induction therapy consists of bortezomib, lenalidomide, dexamethasone (VRd) given for approximately 3‐4 cycles followed by autologous stem cell transplantation (ASCT). In high‐risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara‐VRd) is an alternative to VRd. Selected standard risk patients can get additional cycles of induction, and delay transplant until first relapse. Patients not candidates for transplant are typically treated with VRd for approximately 8‐12 cycles followed by lenalidomide; alternatively these patients can be treated with daratumumab, lenalidomide, dexamethasone (DRd).
Maintenance therapy
After ASCT, standard risk patients need lenalidomide maintenance, while bortezomib‐based maintenance is needed for patients with high‐risk myeloma.
Management of refractory disease
Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse.
The treatment of myeloma is rapidly evolving. This article reviews the current diagnostic criteria, risk stratification, and approach to treatment of multiple myeloma. Treatment approach for both ...newly diagnosed and relapsed disease are discussed.
Multiple myeloma accounts for approximately 10% of hematologic malignancies. The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more ...multiple myeloma defining events: CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging. Patients with del(17p), t(14;16), and t(14;20) have high‐risk multiple myeloma. Patients with t(4;14) translocation and gain(1q) have intermediate‐risk. All others are considered standard‐risk. Initial treatment consists of bortezomib, lenalidomide, dexamethasone (VRd). In high‐risk patients, carfilzomib, lenalidomide, dexamethasone (KRd) is an alternative to VRd. In eligible patients, initial therapy is given for approximately 3‐4 cycles followed by autologous stem cell transplantation (ASCT). Standard risk patients can opt for delayed ASCT at first relapse. Patients not candidates for transplant are treated with VRd for approximately 8‐12 cycles followed by lenalidomide or lenalidomide plus dexamethasone. After ASCT, lenalidomide maintenance is recommended for standard risk patients, while maintenance with a bortezomib‐based regimen is needed for patients with intermediate or high‐risk disease. Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse. Aggressive relapse with extramedullary plasmacytomas or plasma cell leukemia may require anthracycline containing combination chemotherapy regimens.
The diagnosis and treatment of multiple myeloma has changed dramatically in the past decade. The disease definition has been updated to include highly specific biomarkers in addition to established ...markers of end-organ damage. The staging system has been revised to combine both measures of tumor burden and disease biology. Advances in therapy have resulted in a marked improvement in overall survival. New drugs introduced in the past few years include carfilzomib, pomalidomide, panobinostat, ixazomib, elotuzumab, and daratumumab. In this review, we outline the current approach to the diagnosis, prognosis, and management of multiple myeloma.
The treatment of multiple myeloma (MM) continues to evolve rapidly with arrival of multiple new drugs, and emerging data from randomized trials to guide therapy. Along the disease course, the choice ...of specific therapy is affected by many variables including age, performance status, comorbidities, and eligibility for stem cell transplantation. In addition, another key variable that affects treatment strategy is risk stratification of patients into standard and high-risk MM. High-risk MM is defined by the presence of t(4;14), t(14;16), t(14;20), gain 1q, del(17p), or p53 mutation. In this paper, we provide algorithms for the treatment of newly diagnosed and relapsed MM based on the best available evidence. We have relied on data from randomized controlled trials whenever possible, and when appropriate trials to guide therapy are not available, our recommendations reflect best practices based on non-randomized data, and expert opinion. Each algorithm has been designed to facilitate easy decision-making for practicing clinicians. In all patients, clinical trials should be considered first, prior to resorting to the standard of care algorithms we outline.
Although motor learning is likely to involve multiple processes, phenomena observed in error-based motor learning paradigms tend to be conceptualized in terms of only a single process: adaptation, ...which occurs through updating an internal model. Here we argue that fundamental phenomena like movement direction biases, savings (faster relearning), and interference do not relate to adaptation but instead are attributable to two additional learning processes that can be characterized as model-free: use-dependent plasticity and operant reinforcement. Although usually “hidden” behind adaptation, we demonstrate, with modified visuomotor rotation paradigms, that these distinct model-based and model-free processes combine to learn an error-based motor task. (1) Adaptation of an internal model channels movements toward successful error reduction in visual space. (2) Repetition of the newly adapted movement induces directional biases toward the repeated movement. (3) Operant reinforcement through association of the adapted movement with successful error reduction is responsible for savings.
► Internal models are not sufficient to explain results in adaptation paradigms ► Repetition of adapted movements leads to use-dependent movement biases ► Operant association between adapted movements and success enables savings ► Motor tasks are learned by combining model-based and model-free processes
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