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- Kyle, R. A., et al.
(författare)
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Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management
- 2010
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 24:6, s. 1121-1127
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Forskningsöversikt (refereegranskat)abstract
- Monoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is approximately 1% per year. Low-risk MGUS is characterized by having an M protein < 15 g/l, IgG type and a normal free light chain (FLC) ratio. Patients should be followed with serum protein electrophoresis at six months and, if stable, can be followed every 2-3 years or when symptoms suggestive of a plasma cell malignancy arise. Patients with intermediate and high-risk MGUS should be followed in 6 months and then annually for life. The risk of smoldering (asymptomatic) multiple myeloma (SMM) progressing to multiple myeloma or a related disorder is 10% per year for the first 5 years, 3% per year for the next 5 years and 1-2% per year for the next 10 years. Testing should be done 2-3 months after the initial recognition of SMM. If the results are stable, the patient should be followed every 4-6 months for 1 year and, if stable, every 6-12 months. Leukemia (2010) 24, 1121-1127; doi:10.1038/leu.2010.60; published online 22 April 2010
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| 2. |
- Ocio, E. M., et al.
(författare)
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New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG)
- 2014
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 28:3, s. 525-542
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Forskningsöversikt (refereegranskat)abstract
- Treatment in medical oncology is gradually shifting from the use of nonspecific chemotherapeutic agents toward 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 third-generation proteasome inhibitors (PIs), immunomodulatory agents and alkylators). Next, we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAbs), 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. Moreover, 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, which has produced exciting results in the relapsed/refractory setting.
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| 5. |
- Cavo, M, et al.
(författare)
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International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 117:23, s. 6063-6073
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Tidskriftsartikel (refereegranskat)abstract
- The role of high-dose therapy followed by autologous stem cell transplantation (ASCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. The choice of induction therapy has moved from conventional chemotherapy to newer regimens incorporating the immunomodulatory derivatives thalidomide or lenalidomide and the proteasome inhibitor bortezomib. These drugs combine well with traditional therapies and with one another to form various doublet, triplet, and quadruplet regimens. Up-front use of these induction treatments, in particular 3-drug combinations, has affected unprecedented rates of complete response that rival those previously seen with conventional chemotherapy and subsequent ASCT. Autotransplantation applied after novel-agent-based induction regimens provides further improvement in the depth of response, a gain that translates into extended progression-free survival and, potentially, overall survival. High activity shown by immunomodulatory derivatives and bortezomib before ASCT has recently led to their use as consolidation and maintenance therapies after autotransplantation. Novel agents and ASCT are complementary treatment strategies for MM. This article reviews the current literature and provides important perspectives and guidance on the major issues surrounding the optimal current management of younger, transplantation-eligible MM patients.
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| 13. |
- Chubb, Daniel, et al.
(författare)
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Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:10, s. 366-1221
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Tidskriftsartikel (refereegranskat)abstract
- To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 individuals with multiple myeloma (cases) and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P = 8.70 x 10(-14)), 6p21.33 (rs2285803, PSORS1C2, P = 9.67 x 10(-11)), 17p11.2 (rs4273077, TNFRSF13B, P = 7.67 x 10(-9)) and 22q13.1 (rs877529, CBX7, P = 7.63 x 10(-16)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy, as well as insight into the biological basis of predisposition.
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| 18. |
- Kreutzman, A., et al.
(författare)
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Expansion of highly differentiated CD8(+) T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation
- 2011
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 25:10, s. 1587-1597
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Tidskriftsartikel (refereegranskat)abstract
- The tyrosine kinase inhibitor dasatinib exerts immunosuppressive effects on T-cells and NK-cells in vitro. However, in some dasatinib-treated leukemia patients, clonal lymphocytosis with large granular lymphocyte (LGL) morphology develops, and this is associated with enhanced therapeutic responses. To elucidate the mechanistic basis for this paradoxical observation, we conducted detailed phenotypic and functional analyses of T-cell and NK-cell populations from 25 dasatinib-treated leukemia patients. All tested patients with LGL expansions (15/16) were cytomegalovirus (CMV) immunoglobulin (IgG) seropositive with high frequencies of CMV-specific CD8(+) T-cells; 5/16 LGL patients also experienced symptomatic CMV reactivation during dasatinib therapy. Expanded T-cell and NK-cell populations exhibited late differentiated (CD27(_)(-) CD57(+)) phenotypes; this was associated with a predisposition to apoptosis within the T-cell compartment and impaired NK-cell cytotoxicity. Only 3/9 non-LGL patients were CMV IgG seropositive. Dasatinib inhibited in vitro lymphocyte functions, similarly in LGL patients and controls. Notably, distinct CD8(high) and CD8(low) T-cell subsets were observed in LGL patients; this phenotypic dichotomy was also apparent in CMV-specific CD8(+) T-cell populations, and exhibited features consistent with antigen-driven activation. In addition, plasma levels of IP-10, IL-6, monokine induced by interferon-c and interleukin-2R were significantly increased in LGL patients. These data provide evidence that dasatinib-associated LGL expansion is linked to CMV reactivation and suggest a potential mechanism for this phenomenon. Leukemia (2011) 25, 1587-1597; doi:10.1038/leu.2011.135; published online 7 June 2011
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| 21. |
- Ljungman, P., et al.
(författare)
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Long-term follow-up of HCV-infected hematopoietic SCT patients and effects of antiviral therapy
- 2012
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Ingår i: Bone Marrow Transplantation. - : Springer Science and Business Media LLC. - 1476-5365 .- 0268-3369. ; 47:9, s. 1217-1221
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Tidskriftsartikel (refereegranskat)abstract
- This prospective study was initiated in 1993 with the aim to study late effects and responses to antiviral therapy in a cohort of hepatitis C virus (HCV)-infected patients. A total of 195 patients were included from 12 centers. In all, 134 patients had undergone allogeneic and 61 autologous hematopoietic SCT (HSCT). The median follow-up from HSCT is currently 16.8 years and the maximum 27.2 years. Overall 33 of 195 patients have died of which 6 died from liver complications. The survival probability was 81.6% and the cumulative incidence for death in liver complications was 6.1% at 20 years after HSCT. The cumulative incidence of severe liver complications (death from liver failure, cirrhosis and liver transplantation) was 11.7% at 20 years after HSCT. In all, 85 patients have been treated with IFN; 42 in combination with ribavirin. The sustained response rate was 40%. The rates of severe side effects were comparable to other patient populations and no patient developed significant exacerbations of GVHD. Patients receiving antiviral therapy had a trend toward a decreased risk of severe liver complications (odds ratio=0.33; P=0.058). HCV infection is associated with morbidity and mortality in long-term survivors after HSCT. Antiviral therapy can be given safely and might reduce the risk for severe complications.
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