Improvement in long-term outcomes with successive Total Therapy trials for multiple myeloma: Are patients now being cured?

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (Impact Factor: 10.43). 06/2012; 27(1). DOI: 10.1038/leu.2012.160
Source: PubMed


The concept of applying all active therapeutic agents in Total Therapy (TT) clinical trials for newly diagnosed multiple myeloma was pursued with the intent of developing curative treatment. The results of TT1 (n=231), TT2 (n=668) without or with thalidomide and TT3 with added bortezomib (n=303) have been reported. An update with median follow-up times of 17.1, 8.7 and 5.5 years, respectively, is provided. Conditional overall survival (OS) analysis from a 4-year landmark was applied to account for earlier protocol failure owing to disease aggressiveness and toxicities. Cumulative relative survival was computed in the context of age- and gender-matched US population, and interval-specific relative survival ratios were estimated to determine times to normal survival expectation. Based on Cox model-adjusted statistics, OS, progression-free survival and complete-response duration all improved with the transitions from TT1 to TT2 to TT3; improvement was also evident from time-to-progression estimates, 4-year conditional survival data and cumulative relative survival. Interval-specific relative survival normalized progressively sooner, reaching near-normal levels with TT3 in patients who attained complete response. Thus, a strategy using all myeloma-effective agents up-front seems effective at preventing, in progressively larger patient cohorts over time, the outgrowth of resistant tumor cells that account for ongoing relapses.Leukemia advance online publication, 13 July 2012; doi:10.1038/leu.2012.160.

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    • "Multiple myeloma is a malignant plasma cell dyscrasia characterized clinically in patients with symptomatic disease by anemia, hypercalcemia, renal insufficiency, or bony lesions [1], [2], and is the second most commonly diagnosed hematologic malignancy [3]. Novel drug classes such as proteasome inhibitors and immunomodulatory agents have had a significant impact upon the natural history of this disease, with some studies suggesting a doubling in the median overall survival [4], [5], [6], [7], [8], [9]. Bortezomib and carfilzomib are the currently approved proteasome inhibitors for multiple myeloma, and exert their effects by blocking the turnover of poly-ubiquitinated proteins through the proteasome, which is the final effector of the ubiquitin-proteasome pathway [10], [11], [12]. "
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    ABSTRACT: Intracellular proteolytic pathways have been validated as rational targets in multiple myeloma with the approval of two proteasome inhibitors in this disease, and with the finding that immunomodulatory agents work through an E3 ubiquitin ligase containing Cereblon. Another E3 ligase that could be a rational target is the murine double minute (MDM) 2 protein, which plays a role in p53 turnover. A novel inhibitor of this complex, MI-63, was found to induce apoptosis in p53 wild-type myeloma models in association with activation of a p53-mediated cell death program. MI-63 overcame adhesion-mediated drug resistance, showed anti-tumor activity in vivo, enhanced the activity of bortezomib and lenalidomide, and also overcame lenalidomide resistance. In mutant p53 models, inhibition of MDM2 with MI-63 also activated apoptosis, albeit at higher concentrations, and this was associated with activation of autophagy. When MI-63 was combined with the BH3 mimetic ABT-737, enhanced activity was seen in both wild-type and mutant p53 models. Finally, this regimen showed efficacy against primary plasma cells from patients with newly diagnosed and relapsed/refractory myeloma. These findings support the translation of novel MDM2 inhibitors both alone, and in combination with other novel agents, to the clinic for patients with multiple myeloma.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "MM accounts for about 15% of newly diagnosed hematologic cancers [2], [3] and the recent development of novel treatment options has led to considerably longer median survival [4]. While prolonged patient survival is being reported after the application of novel therapy regimens [5], [6], MM is generally still considered incurable with particularly unfavourable prognoses for certain genetically-defined patient subgroups [7], [8]. "
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    ABSTRACT: Cell lines represent the everyday workhorses for in vitro research on multiple myeloma (MM) and are regularly employed in all aspects of molecular and pharmacological investigations. Although loss-of-function studies using RNA interference in MM cell lines depend on successful knockdown, no well-established and widely applied protocol for efficient transient transfection has so far emerged. Here, we provide an appraisal of electroporation as a means to introduce either short-hairpin RNA expression vectors or synthesised siRNAs into MM cells. We found that electroporation using siRNAs was much more efficient than previously anticipated on the basis of transfection efficiencies deduced from EGFP-expression off protein expression vectors. Such knowledge can even confidently be exploited in "hard-to-transfect" MM cell lines to generate large numbers of transient knockdown phenotype MM cells. In addition, special attention was given to developing a protocol that provides easy implementation, good reproducibility and manageable experimental costs.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "Technological advancements have identified chromosomal and molecular abnormalities that underlie the pathogenesis of myeloma and are forming the basis for future targeted therapies. Multiple myeloma is a heterogeneous disease with some patients relapsing early after treatment, while about 50% of patients achieving a complete remission; enjoy remissions for more than 10 years [1,2]. Here we present a review of (1) known chromosomal and molecular abnormalities occurring in multiple myeloma and their effect on prognosis and treatment. "

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