Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed, refractory, or ineligible, to an IMiD (Immunomodulatory Drug), with measurable disease and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T0). The median age at diagnosis was 58 years and time from diagnosis to T0 was 3.3 years. Following T0, 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T0 in 94 patients (51%) including >=partial response in 69 (38%). The median overall survival and event free survival from T0 were 9 and 5 months respectively. This study confirms the poor outcome once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.
Bortezomib-associated peripheral neuropathy seemed reversible in the majority of patients after dose reduction or discontinuation. Although severe neuropathy was more frequent in the presence of baseline neuropathy, the overall occurrence was independent of baseline neuropathy or type of prior therapy.
IntroductionThe plasma cell proliferative disorders are characterized by the proliferation of a single clone of plasma cells in the bone marrow and by the production of monoclonal immunoglobulins. These disorders may range from a phenotypically benign entity, monoclonal gammopathy of undetermined significance, to symptomatic myeloma with bone destruction, suppression of bone marrow function, and renal damage. The International Myeloma Working Group has established criteria for the diagnosis of plasma cell proliferative disorders. These test criteria have been adopted and/or slightly modified by other groups and are shown in Table 1.  In everyday practice, there is still some confusion regarding the use of standard laboratory tests that evaluate serum and urine monoclonal proteins. Furthermore, a new test, serum-free light measurement, has emerged. Over the last decade, newer imaging techniques, such as magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT), are increasingly used in the assessment of patients with multiple myeloma. In this paper, we report International Myeloma Working Group Consensus Panel recommendations for the minimal diagnostic and prognostic tests, the follow-up investigation after therapy, and the tests to be performed at relapse for patients with multiple myeloma. The Consensus Panel consisted of several physicians with a research interest in plasma cell dyscrasias who held several teleconferences, and their recommendations were presented during the 2009 International Myeloma Workshop.
Minimal diagnostic and prognostic testsInitial investigation of a patient with suspected multiple myeloma should include the tests shown in Table 2. Family history should focus on first-degree relatives with the diagnosis of hematologic malignancies, especially lymphoma, chronic lymphocytic leukemia, and plasma cell dyscrasias. Past medical history should focus on comorbid conditions that may affect treatment decisions, such as coronary artery disease, congestive heart failure, hypertension, renal disorders, liver disorders, and lung diseases. A complete blood count with differential should be ordered, and a peripheral blood smear should be evaluated in search of specific findings, such as rouleaux formation and circulating plasma cells. A complete biochemistry screen should be ordered, which includes liver function tests, renal function tests, electrolytes, calcium, and albumin.Both serum and urine should be assessed for monoclonal protein. Agarose gel electrophoresis or capillary zone electrophoresis of serum and urine is preferred to screen for the presence of monoclonal protein. However, quantitation of serum immunoglobulins by nephelometry should also be performed. Measurement of monoclonal protein both by densitometer tracing and by nephelometric quantitation is recommended. These 2 tests are complementary, and nephelometric quantitation may be particularly useful for low levels of uninvolved immunoglobulins. 4 However, it should be
This multicenter, first-in-human study evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of the anti-CS1 monoclonal antibody elotuzumab. A standard 3 ؉ 3 design was used to determine maximum tolerated dose; dose-limiting toxicities were assessed during cycle 1. Thirty-five patients with relapsed/refractory multiple myeloma were treated with intravenous elotuzumab at doses ranging from 0.5 to 20 mg/kg every 2 weeks. Patients who achieved at least stable disease after 4 treatments could receive another 4 treatments. No maximum tolerated dose was identified up to the maximum planned dose of 20 mg/kg. The most common adverse events, regardless of attribution, were cough, headache, back pain, fever, and chills. Adverse events were generally mild to moderate in severity, and adverse events attributed to study medication were primarily infusion-related. Plasma elotuzumab levels and terminal half-life increased with dose whereas clearance decreased, suggesting target-mediated clearance. CS1 on bone marrow-derived plasma cells was reliably saturated (> 95%) at the 10-mg/kg and 20-mg/kg dose levels. Using the European Group for Bone and Marrow Transplantation myeloma response criteria, 9 patients (26.5%) had stable disease. In summary, elotuzumab was generally well tolerated in this population, justifying further exploration of this agent in combination regimens. (Blood. 2012;120(3):552-559)
IntroductionMultiple myeloma (MM) is an incurable malignancy arising from postgerminal mature B cells, characterized by an excess of monotypic plasma cells in the bone marrow and elevated levels of monoclonal immunoglobulins in the serum and/or urine. 1 Common clinical sequelae include lytic bone lesions, fractures, myelosuppression, and renal failure. In the United States, the estimated annual diagnosed incidence is 20 000, with a prevalence of approximately 62 000 as of 2007. 2,3 MM accounts for 15% of all hematologic malignancies and 2% of all malignancies. 4 Advances in high-dose chemotherapy and stem cell transplantation have improved overall survival (OS) and event-free disease periods in MM, 5-7 although relapses are inevitable. Newer therapeutic agents, such as bortezomib, thalidomide, and lenalidomide, have demonstrated clinical benefit in patients with newly diagnosed  and relapsed or refractory disease. 5,14,15 Despite these therapeutic advances, longterm control of relapsed/refractory MM remains elusive for most patients. Progressive disease that is resistant to both immunomodulatory drugs and bortezomib is associated with a particularly poor prognosis. 16 As such, there remains an important need for additional novel therapies to augment existing first-generation agents and continue to improve patient outcome.Elotuzumab is a humanized monoclonal IgG1 antibody directed against human CS1 (also known as CD2 subset-1, SLAMF7, CRACC, and CD319), a cell surface antigen glycoprotein that is highly expressed on MM cells and normal plasma cells. CS1 is expressed at a lower ...
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