The role of complete response in multiple myeloma.
ABSTRACT In multiple myeloma (MM), the impact of complete response (CR) could be shown only after introduction of high-dose therapy plus autologous stem cell transplantation (ASCT). In the context of ASCT, achieving CR (negative immunofixation and normal bone marrow) or at least very good partial response is associated with longer progression-free survival and in most studies longer survival. With novel agents, high CR rates are achieved and this prognostic impact of CR is being shown as well, both in relapsed and in newly diagnosed MM. However the benefit of CR achievement depends on the type of treatment and is not identical for all patients. In elderly patients, treatments inducing more CR may be more toxic. Although CR achievement is necessary in patients with poor-risk disease, it might not be as critical for long survival in more indolent MM. CR achievement is not the only objective of treatment because it is possible to further improve the depth of response and the outcome by continuing treatment after CR achievement. Finally, there are several levels of CR and in the future it will be necessary to confirm the prognostic impact of immunophenotypic or molecular CR or of CR defined by imaging procedures.
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ABSTRACT: Multiparameter flow cytometry (MFC) and allele-specific oligonucleotide real-time quantitative PCR (ASO RQ-PCR) are the two most sensitive methods to detect minimal residual disease (MRD) in multiple myeloma (MM). We compared these methods in 129 paired post-therapy samples from 22 unselected, consecutive MM patients in complete/near complete remission. Appropriate immunophenotypic and ASO RQ-PCR-MRD targets could be detected and MRD analyses constructed for all patients. The high PCR coverage could be achieved by gradual widening of the primer sets used for clonality detection. In addition, for 13 (55%) of the patients, reverse orientation of the ASO primer and individual design of the TaqMan probe improved the sensitivity and specificity of ASO RQ-PCR analysis. A significant nonlinear correlation prevailed between MFC-MRD and PCR-MRD when both were positive. Discordance between the methods was found in 32 (35%) paired samples, which were negative by MFC-MRD, but positive by ASO RQ-PCR. The findings suggest that with the described technique, ASO RQ-PCR can be constructed for all patients with MM. ASO RQ-PCR is slightly more sensitive in MRD detection than 6-10-color flow cytometry. Owing to technical demands ASO RQ-PCR could be reserved for patients in immunophenotypic remission, especially in efficacy comparisons between different drugs and treatment modalities.Blood Cancer Journal 10/2014; 4:e250. · 2.88 Impact Factor
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ABSTRACT: We examine whether the historical dogma of multiple myeloma being incurable still holds true. The genomic chaos and resulting resistance to apoptosis of myeloma, long considered an obstacle to cure, formed the basis of the Arkansas Total Therapy (TT) program. The TT approach employs all myeloma-active drugs up-front to target drug-resistant sub-clones during initial treatment to prevent later relapse. Long-term follow up of altogether 1202 patients enrolled (TT1: n=231, median follow up: 21yr; TT2: 668, median follow up: 12yr; TT3a: n=303, median follow up: 9yr) permitted investigation of whether progression-free survival (PFS) and complete response (CR) duration were consistent with curability, i.e. observation of plateaus in Kaplan-Meier plots for PFS and CR duration. In the subset of 627 patients with plasma cell gene expression profiling data, cure plateaus were apparent at 5 years in the 14% with high-risk myeloma compared to 10 years in the remainder with low-risk disease. A parametric model based on PFS and CR duration supported an increase in curability with successive trials. Thus, 10-yr PFS and CR estimates increased from 8.8%/17.9% in TT1 to 15.5%/28.2% in TT2's control arm to 25.1%/35.6% in TT2's thalidomide arm and to 32.9/48.8% in TT3a. Toward developing novel therapies, we recommend a concerted focus on patients with high-risk myeloma whose outcome has not been advanced.Blood 10/2014; · 9.78 Impact Factor
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ABSTRACT: Multiple myeloma is an incurable hematological disease previously associated with poor prognosis and survival rates. However, following the advent of the so-called novel agents, the goal of therapy has now moved to long-term disease control and potential cure. However, despite these advances, myeloma displays considerable heterogeneity and, over time, control of disease can be lost. In order to counteract this, new strategies are incorporating risk stratification to provide more individualized therapy. Furthermore, there is now increasing focus on adapting therapy in elderly and frail patients to improve compliance and maximize treatment benefit.Blood and Lymphatic Cancer: Targets and Therapy. 11/2014; 4:121-134.