Nouvelle combinaison de traitement pour le myélome multiple.

Initial findings from a pivotal phase III trial showed that daratumumab (Darzalex) added to a standard two-drug regimen (bortezomib [Velcade] and dexamethasone) markedly improved outcomes for patients with recurrent or refractory multiple myeloma.

The daratumumab combination reduced the risk of cancer progression by 70% and doubled both very good partial response rates from 29% to 59% and complete response rates from 9% to 19%. Daratumumab, the first monoclonal antibody approved for multiple myeloma, targets a protein on the surface of cancer cells called CD-38.

These data were presented by Palumbo et al at the Plenary Session of the 2016 ASCO Annual Meeting (Abstract LBA4).

“We’ve suspected for a long time that CD-38 is the major treatment target for multiple myeloma, but these results are unprecedented in this cancer,” said lead study author Antonio Palumbo, MD, Chief of the Myeloma Unit at the Department of Oncology, University of Torino in Torino, Italy. “It’s clear now that we’ll be moving to a three-drug regimen with daratumumab as the standard of care.”

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Les premiers résultats d'un essai de phase III pivot a montré que daratumumab (Darzalex) ajouté à un régime standard de deux médicaments (bortezomib ]Velcade] et la dexaméthasone) a nettement amélioré les résultats pour les patients atteints de myélome multiple récidivant ou réfractaire.

La combinaison de daratumumab réduit le risque de progression du cancer de 70% et a doublé les deux très bons taux de réponse partielle de 29% à 59% et les taux de réponse complète de 9% à 19%. Daratumumab, le premier anticorps monoclonal approuvé pour le myélome multiple, cible une protéine à la surface des cellules cancéreuses appelé CD-38.

Ces données ont été présentées par Palumbo et al lors de la session plénière du congrès de l'ASCO 2016 (Résumé de LBA4).

«Nous avons soupçonné depuis longtemps que le CD-38 est la principale cible de traitement pour le myélome multiple, mais ces résultats sont sans précédent dans ce cancer», a déclaré Antonio Palumbo, MD, chef de l'Unité Myeloma au Département d'oncologie, Université de Turin à Turin, en Italie. «Il est clair maintenant que nous allons passons à un régime de trois médicaments avec daratumumab comme la norme de soins."

Several clinical trials have demonstrated that maintenance therapy with lenalidomide (Revlimid) after autologous hematopoietic stem cell transplant reduces the risk of disease progression in patients with multiple myeloma, but there have been no definitive results regarding overall survival. Philip McCarthy, MD, Director of Blood and Marrow Transplant at Roswell Park Cancer Institute (RPCI), presented the findings of an international meta-analysis at the 2016 ASCO Annual Meeting (Abstract 8001), which showed that continuous lenalidomide following autologous stem cell transplantation improved survival in these patients.

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Plusieurs essais cliniques ont démontré que la thérapie d'entretien avec lénalidomide (Revlimid) après des greffe de cellules souches autologues hématopoïétiques  réduit le risque de progression de la maladie chez les patients atteints de myélome multiple, mais il n'y a pas eu de résultats définitifs sur la survie globale. Philip McCarthy, MD, a présenté les résultats d'une méta-analyse internationale à la réunion annuelle de ASCO 2016 (Résumé 8001), qui a montré que le lénalidomide en continu suivant la greffe autologue de cellules souches amélioration de la survie chez ces patients.

Une équipe de chercheurs de l’Université de Montréal et de l’Hôpital Maisonneuve-Rosemont a mis au point un nouveau traitement du myélome multiple, un cancer de la moelle osseuse, qui a permis d’obtenir un taux de guérison inégalé jusqu’à présent.

Cette nouvelle approche thérapeutique consiste à utiliser l’autogreffe pour réduire la masse tumorale du cancer, suivie par une greffe venant d’un proche (allogreffe).

Une étude effectuée sur les résultats de ce traitement auprès de 92 patients atteints de ce cancer de 2001 à 2010 a permis d’enregistrer un taux de guérison total de 41 %, le plus élevé à ce jour.

De plus, le taux de survie sans rechute a été de 60 % chez les patients en rémission complète, six mois après les deux types de greffes.

«Dans plusieurs centres, les médecins ont abandonné l’utilisation de l’allogreffe pour le myélome multiple en raison des risques de toxicité et de rechute, a expliqué le Dr Jean Roy, hématologue à l’Hôpital Maisonneuve-Rosemont et professeur à l’Université de Montréal, auteur de l’étude. Ces résultats nous poussent plutôt à l’offrir à davantage de patients, notamment les plus jeunes et ceux qui ont une maladie à moins bon pronostic.»

Les résultats de ces recherches ont été publiés dans la revue Bone Marrow Transplantation.

Increased Progression-Free Survival With Addition of Carfilzomib to Lenalidomide/Dexamethasone in Relapsed Multiple Myeloma

In a planned interim analysis of the phase III ASPIRE trial reported in The New England Journal of Medicine, A. Keith Stewart, MB, ChB, of the Mayo Clinic, Scottsdale, Arizona, and colleagues found that the addition of the proteasome inhibitor carfilzomib (Kyprolis) to lenalidomide (Revlimid)/dexamethasone significantly increased progression-free survival.1 The interim analysis suggested a survival benefit with the three-drug regimen, which was also associated with a significantly higher response rate and improvement in health-related quality of life.

Dans une analyse intermédiaire planifiée de l'essai de phase III ASPIRE rapportée dans le New England Journal of Medicine, A. Keith Stewart, MB, ChB, de la Clinique Mayo, Scottsdale, en Arizona, et ses collègues ont constaté que l'ajout de la carfilzomib inhibiteur de protéasome (Kyprolis) à la lénalidomide (Revlimid) / dexaméthasone a augmenté significativement la survie sans progression, l'analyse intermédiaire a suggéré un bénéfice de survie avec le régime de trois médicaments, qui a également été associée à un taux de réponse significativement plus élevée et l'amélioration de la qualité de vie liée à la santé .

Study Details

In this open-label trial, 792 patients from North America, Europe, and the Middle East with relapsed multiple myeloma and receipt of 1 to 3 prior treatments were randomized to receive carfilzomib plus lenalidomide/dexamethasone (n = 396) or lenalidomide/dexamethasone (n = 396) between July 2010 and March 2012. The primary endpoint was progression-free survival.

Dans cette étude ouverte, 792 patients d'Amérique du Nord, en Europe et au Moyen-Orient avec le myélome multiple en rechute et avec la réception de 1-3 traitements antérieurs ont été randomisés pour recevoir carfilzomib ainsi lénalidomide / dexaméthasone (n = 396) ou lénalidomide / dexaméthasone (n = 396) entre Juillet 2010 et Mars 2012. Le critère d'évaluation principal était la survie sans progression.

Treatment consisted of 28-day cycles, with carfilzomib given via 10-minute infusion on days 1, 2, 8, 9, 15, and 16 (starting dose = 20 mg/m2 on days 1 and 2 of cycle 1 and target dose = 27 mg/m2 for all subsequent treatment) during cycles 1 through 12 and on days 1, 2, 15, and 16 during cycles 13 through 18, after which carfilzomib was discontinued. Lenalidomide (25 mg) was given on days 1 through 21. Dexamethasone (40 mg) was given on days 1, 8, 15, and 22.

Patients previously treated with bortezomib (Velcade) were eligible if they had not progressed during bortezomib treatment. Patients previously treated with lenalidomide and dexamethasone were eligible if they did not discontinue treatment due to adverse effects, did not have disease progression during the first 3 months of treatment, and did not have disease progression at any time during treatment if lenalidomide/dexamethasone was the most recent treatment.

The carfilzomib and control groups were generally balanced for age (median 64 and 65 years, 47% and 53% ≥ 65 years), gender (54% and 59% male), Eastern Cooperative Oncology Group performance status (0 or 1 for 90% and 91%), cytogenetic risk (high in 12% and 13%, standard in 37% and 43%, unknown in 51% and 44%), creatinine clearance (≥ 50 mL/min, required at screening, in 93% and 90%), serum β2 microglobulin (≥ 2.5 mg/L in 81% in both), number of previous regimens (1 in 47% and 40%, 2 or 3 in 53% and 60%), and previous therapies (bortezomib in 66% in both, lenalidomide in 20% in both).

Les groupes de carfilzomib et de contrôle ont été généralement équilibrés pour l'âge (médiane 64 à 65 ans, 47% et 53% ≥ 65 ans), le sexe (54% et 59% d'hommes), le statut de performance Eastern Cooperative Oncology Group (0 ou 1 pour 90% et 91%), le risque cytogénétique (élevé dans 12% et 13%, la norme dans 37% et 43%, inconnue dans 51% et 44%), la clairance de la créatinine (≥ 50 ml / min, nécessaire au dépistage, à 93% et 90%), le sérum β2 microglobuline (≥ 2,5 mg / L dans 81% à la fois), nombre de traitements antérieurs (1 à 47% et 40%, 2 ou 3 dans 53% et 60%), et les thérapies précédentes (bortézomib dans 66% dans les deux, lénalidomide chez 20% dans les deux).

Progression-Free Survival

At the time of the interim analysis, the median progression-free survival was 26.3 months (95% confidence interval [CI] = 23.3–30.5 months) in the carfilzomib group vs 17.6 months (95% CI = 15.0–20.6); the hazard ratio

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was 0.69 (95% CI = 0.57–0.83, P = .0001), which crossed the prespecified stopping boundary. The benefit of carfilzomib was observed across all predefined subgroups.

survie sans progression

Au moment de l'analyse intermédiaire, la médiane de survie sans progression était de 26,3 mois (95% intervalle de confiance [IC] = 23,3 à 30,5 mois) dans le groupe de carfilzomib vs 17,6 mois (IC à 95% = 15,0 à 20,6); le rapport de risque

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était de 0,69 (IC à 95% = 0,57 à 0,83, P = 0,0001), qui a traversé la frontière d'arrêt prédéfinie. L'avantage de carfilzomib a été observée dans tous les sous-groupes prédéfinis.

Interim Analysis of Overall Survival

Since the primary study objective was met, an interim analysis of overall survival was also performed, after occurrence of 60% of the 510 events prespecified for final overall survival analysis. The median follow-up was 32.3 months in the carfilzomib group and 31.5 months in the control group.

Puisque l'objectif principal de l'étude a été atteint, une analyse intermédiaire de la survie globale a également été effectuée, après l'apparition de 60% des 510 événements prédéfinie pour analyse finale de la survie globale. Le suivi médian était de 32,3 mois dans le groupe de carfilzomib et 31,5 mois dans le groupe témoin.

Survival at 24 months was 73.3% (95% CI = 68.6%–77.5%) in the carfilzomib group vs 65.0% (95% CI = 59.9%–69.5%) in the control group. The median overall survival was not reached in either group, with a trend favoring the carfilzomib group (HR = 0.79, P = .04), but the difference did not cross the prespecified stopping boundary.

Responses and Quality of Life

Overall response rates were 87.1% vs 66.7% (P < .001), including complete response or better in 31.8% vs 9.3% (P < .001) and stringent complete response in 14.1% vs 4.3%. The mean time to response was 1.6 vs 2.3 months, and the median duration of response was 28.6 vs 21.2 months.

Health-related quality of life, assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life Core Module (QLQ-C30) questionnaire, was significantly improved in the carfilzomib group vs the control group during 18 cycles of treatment (P < .001). The minimal clinically important between-group difference on the QLQ-C30 Global Health Status and Quality-of-Life scale is 5.0 points, which was met at cycle 12 (difference = 5.6 points) and approached at cycle 18 (difference = 4.8 points).

Adverse Events

The median duration of treatment was 88.0 weeks in the carfilzomib group and 57.0 weeks in the control group. Adverse events of any grade that were at least 5% more frequent in the carfilzomib group included hypokalemia (28% vs 13%), cough (29% vs 17%), upper respiratory tract infection (29% vs 19%), diarrhea (42% vs 34%), pyrexia (29% vs 21%), hypertension (14% vs 7%), and muscle spasms (27% vs 21%), with rates of treatment discontinuation due to these events being less than 1% in both groups. Peripheral neuropathy occurred in 17% of both groups.

Adverse events of grade 3 or higher occurred in 84% vs 81%, and serious adverse events occurred in 60% vs 54%. Grade 3 or higher adverse events of specific interest included dyspnea (2.8% vs 1.8%), cardiac failure (3.8% vs 1.8%), ischemic heart disease (3.3% vs 2.1%), hypertension (4.3% vs 1.8%), and acute renal failure (3.3% vs 3.1%).

Adverse events led to carfilzomib dose reduction in 11.0% and lenalidomide dose reduction in 43% of the carfilzomib group, lenalidomide dose reduction in 39% of the control group, and discontinuation of treatment in 15.3% and 17.7% of patients. Adverse events led to death in 6.9% of patients in each group, with six deaths in the carfilzomib group and eight deaths in the control group considered related to treatment. The most common causes of toxicity-related death were myocardial infarction (three patients in the carfilzomib group and one in the control group), cardiac failure (one and three patients), and sepsis (three and two patients).

The investigators concluded: “Carfilzomib combined with lenalidomide and dexamethasone led to a significant improvement in progression-free survival, as compared with lenalidomide and dexamethasone alone, in patients with relapsed multiple myeloma. These findings were bolstered by higher response rates, more robust responses, a favorable risk-benefit profile, improved health-related quality of life, and a trend toward improved overall survival with the three-drug regimen.” ■

Each year, more than 25,000 Americans are diagnosed with multiple myeloma, a form of blood cancer that often develops resistance to therapies. However, researchers at Virginia Commonwealth University Massey Cancer Center are reporting promising results from laboratory experiments testing a new combination therapy that could potentially overcome the resistance hurdle.

While several drugs are effective against multiple myeloma, including the proteasome inhibitor bortezomib, multiple myeloma cells are often able to survive by increasing the production of a protein known as Mcl-1. Mcl-1 regulates a number of processes that promote cell survival and has been implicated in resistance to anti-myeloma drugs that were initially effective. However, a team of researchers led by Xin-Yan Pei, M.D., Ph.D., and Steven Grant, M.D., recently published the findings of a study in the journal PLoS ONE demonstrating that a novel drug combination both reduces Mcl-1 expression and disrupts its interactions with other proteins to effectively kill multiple myeloma cells. The therapy combines a type of drug known as a Chk1 inhibitor with another called a MEK inhibitor. Chk1 inhibitors prevent cells from arresting in stages of the cell cycle that facilitate the repair of DNA damage, while MEK inhibitors prevent cells from activating a variety of proteins that regulate DNA repair processes while promoting the accumulation of pro-death proteins.

"This research builds on our previous studies that showed exposing multiple myeloma and leukemia cells to Chk1 inhibitors activated a protective response through the Ras/MEK/ERK signaling pathway," says Pei, instructor in the Department of Internal Medicine at the VCU School of Medicine. "By combining a Chk1 inhibitor with a MEK inhibitor, we have developed one of only a limited number of strategies shown to circumvent therapeutic resistance caused by high expressions of Mcl-1."

In laboratory experiments, the scientists enforced overexpression of Mcl-1 in human multiple myeloma cells. They found that this caused the cells to become highly resistant to bortezomib, but it failed to protect them from the Chk1/MEK inhibitor regimen. Additionally, the combination therapy was able to completely overcome resistance due to microenvironmental factors associated with increased expression of Mcl-1. A cell's microenvironment consists of surrounding cells and the fluids in which they reside, and the communication between cancer cells and their surrounding cells can significantly impact resistance. Mcl-1 plays a key role in this communication by facilitating events that promote cancer cell survival.

"Not only was the combination therapy effective against multiple myeloma cells, it notably did not harm normal bone marrow cells, raising the possibility of therapeutic selectivity," says Grant, the study's lead investigator and Shirley Carter Olsson and Sture Gordon Olsson Chair in Cancer Research, associate director for translational research and program co-leader of Developmental Therapeutics at VCU Massey Cancer Center. "We are hopeful that this research will lead to better therapies for multiple myeloma, and help make current therapies more effective by overcoming resistance caused by Mcl-1."

The researchers have started initial discussions with clinical investigators and drug manufacturers with hopes of developing a clinical trial testing a combination of Chk1 and MEK inhibitors in patients with refractory multiple myeloma. It is too early to estimate when the trial will open.


Chaque année , plus de 25.000 Américains sont diagnostiqués avec le myélome multiple, une forme de cancer du sang qui développe souvent une résistance aux traitements. Cependant, les chercheurs de la Virginia Commonwealth University Massey Cancer Center rapportent des résultats prometteurs d'expériences de laboratoire d'essai d'un nouveau traitement en association qui pourrait surmonter l'obstacle de la résistance .

Bien que plusieurs médicaments soient efficaces contre le myélome multiple, y compris le bortézomib, un inhibiteur de protéasome, les cellules de myélome multiple sont souvent capables de survivre en augmentant la production d'une protéine connue en tant que Mcl- 1.

Mcl- 1 régule un certain nombre de procédés qui favorisent la survie des cellules et a été impliqué dans la résistance aux médicaments anti-myélome qui étaient initialement efficace. Cependant, une équipe de chercheurs dirigée par Xin - Yan Pei , MD, Ph.D., et Steven Grant, MD, a récemment publié les résultats d'une étude dans la revue PLoS ONE pour démontrer qu'une nouvelle combinaison de médicaments à la fois réduit l'expression de Mcl- 1 et perturbe ses interactions avec d'autres protéines pour tuer efficacement les cellules du myélome multiple.

Le traitement associe un type de médicament connu comme un inhibiteur de Chk1 avec un autre appelé inhibiteur de MEK. Des inhibiteurs de Chk1 empêchent d'arrêter les cellules dans les phases du cycle cellulaire qui facilitent la réparation des lésions de l'ADN, tandis que les inhibiteurs de MEK empêchent les cellules à partir de l'activation d'une variété de protéines qui régulent les processus de réparation d'ADN , tout en favorisant l'accumulation de protéines pro-mort.

«Cette recherche s'appuie sur nos études antérieures qui ont montré qu'exposer les cellules de myélome multiple et la leucémie aux inhibiteurs de Chk1 active une réponse protectrice par la voie de signalisation Ras / MEK / ERK », dit Pei , instructeur au département de médecine interne à la Faculté de Médecine de VCU . "En combinant un inhibiteur de Chk1 avec un inhibiteur de MEK, nous avons développé une bonne thérapie parmi un nombre limité de stratégies indiquées pour contourner la résistance causée par les expressions thérapeutique élevé de Mcl- 1. "

Dans des expériences de laboratoire, les scientifiques ont renforcé la surexpression de Mcl -1 dans les cellules du myélome multiple humain. Ils ont constaté que cela a provoqué les cellules à devenir hautement résistantes au bortézomib, mais n'ont pas réussi à les protéger de la posologie de l'inhibiteur de Chk1/MEK. En outre, la thérapie de combinaison a été capable de surmonter complètement la résistance due à des facteurs liés à micro-environnementales augmentation de l'expression de Mcl- 1. Le microenvironnement Une cellule est constituée de cellules environnantes et les fluides dans lequel elles résident, et la communication entre les cellules cancéreuses et leurs cellules environnantes peuvent avoir une incidence importante résistance. Mcl- 1 joue un rôle clé dans cette communication en facilitant les événements qui favorisent la survie des cellules de cancer .

"Non seulement la thérapie de combinaison est efficace contre les cellules du myélome multiple, elle n'a notamment pas nui aux cellules normales de moelle osseuse, ce qui soulève la possibilité de thérapeutique sélective», disent les chercheurs. "Nous espérons que cette recherche mènera à de meilleurs traitements pour le myélome multiple, et aidera à rendre les traitements actuels plus efficaces par vaincre la résistance causée par Mcl- 1 . "

Les chercheurs ont entamé des discussions préliminaires avec les investigateurs cliniques et les fabricants de médicaments avec l'espoir de développer un essai clinique testant une combinaison d'inhibiteurs de Chk1 et MEK chez les patients atteints de myélome multiple réfractaire. Il est trop tôt pour estimer quand le test s'ouvrira.

Patients were administered four mg/day of pomalidomide plus 40 mg/week of dexamethasone, a steroid used in standard treatment, for 21 days of a 28-day cycle. Progression-free survival was 4.6 months and overall survival was 16.5 months.

The scientists also conducted a subanalysis of this group based on age, as treating older people with multiple myeloma is especially difficult. Progression-free survival was 4.7 months in people under 65 and 3.7 months in people over 65, and overall survival was 19.7 months in people under 65 and 11.8 months in people over 65.

"We have made great strides in prolonging the lives of people with multiple myeloma, increasing overall survival from three years to as high as seven years in less than a decade," said Dr. Jagannath. "These results show that pomalidomide in combination with dexamethasone is a promising new option to extend survival even longer, including in older patients."

Nous avons augmenté la survie de 3 à 7 ans en moins d'une décennie.

(Aug. 14, 2012) — Researchers at Virginia Commonwealth University Massey Cancer Center are reporting promising results from laboratory and animal experiments involving a new combination therapy for multiple myeloma, the second most common form of blood cancer.

Des chercheurs rapportent des résultats prometteurs pour des expériences de laboratoire et sur des animaux pour une combinaison de médicaments contre le myélome multiple.

The study published online in the journal Cancer Research details a dramatic increase in multiple myeloma cell death caused by a combination of the drugs obatoclax and flavopiridol. The researchers, led by Steven Grant, M.D., Shirley Carter Olsson and Sture Gordon Olsson Chair in Oncology Research, associate director for translational research, program co-leader and member of Developmental Therapeutics and member of the Cancer Cell Signaling program at VCU Massey Cancer Center, found that the two drugs worked together through different mechanisms to promote a form of cell suicide known as apoptosis.

L'obatoclax et le flavopiridol.

"There is an urgent need for curative therapies for multiple myeloma," says Grant. "Our hope is that this research will lay the foundation for new and more effective treatments for patients with multiple myeloma and potentially other blood cancers for which adequate therapies are lacking."

Obatoclax is an experimental agent currently being investigated in various forms of blood cancers. It works by disabling proteins that prevent cancer cells from undergoing apoptosis. Flavopiridol is a member of a class of agents known as a cyclin-dependant kinase (CDK) inhibitors, and blocks the growth of cancer cells in addition to reducing levels of anti-apoptotic proteins.

Obatoclax est un agent experimental couramment étudié dans diverses formes de cancer du Il fonctionne en désactivant des protéines qui empêchent la cellule cancéreuse d'aller vers l'apoptose. Le Flavopiridol est de la famille des CDK (inhibiteurs de kinases dépendantes de la cyclin), elle bloque la croissance des cellules cancéreuses en plus de réduire les niveaux de protéines anti-apoptiques.

In laboratory experiments, the novel drug combination dramatically increased multiple myeloma cell death. These results were confirmed in animal models where the drugs significantly improved the survival of immune-compromised mice with human multiple myeloma. An unexpected effect was also observed -- flavopiridol, in addition to reducing levels of anti-apoptotic proteins, significantly increased the expression of apoptosis-inducing proteins such as Bim, a protein shown in previous studies to trigger cell death.

Dans les expériences de laboratoire, la nouvelle combinaison de médicaments a augmenté grandement la mort des cellules du myélome multiple. Ces résultats ont été confirmés dans les modèles d'animaux ou les médicaments ont significativement augmenté la survie d'animaux dont la vie était compromise par le myélom multiple. Un effet inattendu a aussi été observé, le flavopiridol, en plus de réduire les niveaux de protéines anti-apoptiques, accroit l'expressions de protéines induisant l'apoptose comme Bim, une protéine reconnue pour initier la mort cellulaire.

"This research builds on nearly a decade of work carried out by our laboratory that focuses on manipulating mechanisms that lead to apoptosis in hematological malignancies," says Grant. "Our findings could have immediate implications for the design of clinical trials using combinations of these types of drugs. In fact, plans to develop such a trial at Massey are currently underway."

"Cette recherche s'est construite sur presque dix ans de travail et a été prise en charge par nos laboratoires sur la manipulation des mécanismes qui conduisent à l'apoptose dans les cancers du " a dit GRant "nos découvertes pourraient avoir des imlications immédiates pour des essais cliniques utilisant des combinaisons de ces types de médicaments. En fait, des plans pour développer de tels essais sont déjà sur pied.

Because the findings showed synergism between these two classes of drugs, the researchers plan to test other clinically-relevant CDK inhibitors in combination with obatoclax for multiple myeloma.

Parce que les découvertes montrent du synergisme entre ces deux classes de médicaments, les chercheurs veulent tester d'autres inhibiteurs de CDK en combinaison avec obatoclax pour le myélome multiple.

Carfilzomib is a novel, highly selective proteasome inhibitor, a type of medication that blocks the actions of certain proteins (proteasomes) that cancer cells need to survive and multiply. Carfilzomib is also known by its branded name Kyprolis™.

Le Carfilzomib est un nouvel inhibiteur de proteasome , une sorte de médicaments qui bloque les actions de protéines (les protéasomes) dont les cellules cancéreuses ont besoin pour survivre et se multiplier. Le Carfilzomib est aussi connu sous le nom de marque Kyprolis.

On July 20th the U.S. Food and Drug Administration (FDA) approved Kyprolis (carfilzomib) as a new treatment for advanced multiple myeloma. The treatment was fast-tracked due to the unmet need in multiple myeloma.

LA FDA a approuvé le kyprolis (Carfilzomib) nouveau traitement pour pour le myélome multiple. Le médicament a bénéficié du fast track dû aux manques de besoins non remplis.

The most recent Blood study, published online July 25, includes results from the open-label, single arm phase IIb 003-A1 study of single-agent carfilzomib for patients with relapsed and refractory multiple myeloma. Carfilzomib's New Drug Application (NDA) is based primarily on this study. This research, along with the two other Blood studies, may change the way multiple myeloma is managed for newly diagnosed and relapsed/refractory patients

Le numéro récent de "Blood", présente les résultats d'un essai clinique de phase II sur le Carfilzomib.

(June 21, 2012) — Weill Cornell Medical College researchers have devised an innovative boxer-like strategy, based on the serial use of two anti-cancer drugs, to deliver a one-two punch to first weaken the defenses of multiple myeloma and then deliver the final knock-out punch to win the fight.

Les chercheurs ont inventé une nouvelle stratégie qui ressemble à stratégie de boxeurs car c'est basé sur l'utilisation de deux médicaments anti-cancer pour délivrer un punch "une-deux", le premier pour affaiblir les défenses du myélomes multiples et le deuxième pour pour le terasser et gagner le combat.

The study, published online by the journal Blood, is the first to show that precise timing of therapies that target a cancer cell's cycle -- the life phases leading to its division and replication -- disables key survival genes, resulting in cell death. The drug that delivers the weakening jab at the cell cycle is the experimental agent PD 0332991, which allows bortezomib, a proteasome inhibitor already approved for use in myeloma and lymphoma, to land the final defeating blow at lower than normal doses.

L'étude est la première de se servir d'un timing précis pour cibler une partie du cycle des cellules : la première phase qui conduit à sa division et réplication ce qui désengagent des gènes clé pour la survie résultant en mort pour la cellule. Le médicament qui livre le jab affaiblissant au cycle cellulaire est l'agent expérimental PD0332991, ce qui permet au bortezomib, un inhibiteur de proteasome déja approuvé pour utiliser contre le myélome et le lymphome qui amène finalement la mort de la cellule avec une dose plus petite que normalement.

While this is potentially good news for patients with multiple myeloma, a cancer of blood plasma cells that is currently incurable, the study suggests that using this therapeutic strategy could also work for other tumor types, says the study's senior investigator, Dr. Selina Chen-Kiang, professor of Pathology and Laboratory Medicine and of Microbiology and Immunology at Weill Cornell Medical College.

C'est une bonne nouvelle potentielle pour ceux qui ont le myélome multiple, un cancer des cellules plasmatique du mais l'étude suggère que cette stratégie pourrait aussi marcher pour d'autres formes de cancers.

"Because robust functioning of the cell cycle is crucial to cancer growth and survival, this mechanism-based strategy could theoretically be used against many kinds of cancers," she says.

Parce que le bon fonctionnement du cycle cellulaire est crucial pour la croissance du cancer et sa survie, ce mécanisme pourrait théoriquement être utilisé contre plusieurs sortes de cancers.

"Based on the genetics of a patient's tumor, we could pair PD 0332991 with the right cytotoxic partner drug to both inhibit cancer cell division and sensitize the cells for that knock-out punch," says Dr. Chen-Kiang. "We are very excited about the promise of this approach."

Basé sur la génétique des tumeurs de patient, nous pourrions mettre ensemble le PD 0332991 avec le bon médicament cytotoxique pour inhiber la division cellulaire et sensibiliser les cellules pour le coup final. Nous sommes très excité à propos de cette approche

In fact, physicians at Weill Cornell have opened two new human clinical trials, one in multiple myeloma and one in mantle cell lymphoma, based on the findings of this study in a mouse model as well as on a previous phase I clinical trial led by Weill Cornell investigators that tested PD 0332991 in patients with mantle cell lymphoma.

Playing Havoc with the Cancer Cell Cycle Dr. Chen-Kiang and her laboratory colleagues have long studied genes and proteins that control the cell cycle and cell suicide (apoptosis) in cancer. Cancer is fundamentally a disease of uncontrolled cell proliferation, where cells are able to continuously divide. In contrast, cell division in a healthy individual is regulated by the cell cycle, an orderly sequence of programmed gene expression in which the cell is driven through various checkpoints by a highly regulated network of proteins.

Cyclin-dependent kinases (CDKs) are molecules that power the progression of the cell cycle through its four phases. For example, CDK4 and CDK6 help move cells through the first G1 "gap" phase to later phases where the cell splits in two. In many cancers, these two enzymes are over-expressed, ensuring continual growth. Therefore, targeting CDK4 and CDK6 to shut them down has long been a goal of cancer drug discovery, but clinical success, so far, has been disappointing because of lack of effectiveness as well as drug toxicity, says Dr. Chen-Kiang.

PD 0332991, a small molecule synthesized by Pfizer, is different because it is exceptionally selective for CDK4 and CDK6, she says. The drug initially did not receive much attention because it is also reversible, meaning that it needs to be used continuously to inhibit CDK4 and CDK6; withdrawing it would reactivate these enzymes, stimulating growth.

But Dr. Chen-Kiang had been searching for a drug that she could use for her selective cell cycle-based therapy -- the idea being that playing havoc with a cancer cell's cycle would fatally weaken it when more traditional anti-cancer drugs are used sequentially. "Given that the gene expression program is coupled to the cell cycle, we hypothesize that inhibition of CDK4/CDK6 maintains gene expression programmed for early G1, while preventing the expression of genes scheduled for other cell cycle phases," she explains. "And because metabolic needs in tumor cells differ from normal cells, this prolonged arrest in G1 would create an imbalance in gene expression that preferentially sensitizes tumor cells to cytotoxic drugs, allowing for low-dosage treatments."

hypothesize that release from G1 by removal of the inhibitor would synchronize the cell cycles, but may not synchronize gene expression schedules," Dr. Chen-Kiang adds. "This tension between cell cycle synchronization and differential gene expression synchronization further weakens the tumor cells during their progression, as does the heightened metabolic load and demand for energy to replicate DNA."

Loss of Survival Protein This is exactly what the researchers found. By using PD 0332991 several times to induce a prolonged arrest of G1, and then a release from that arrest, the cells were sensitized to killing by bortezomib. They found this to be the case in laboratory studies of primary myeloma tumor cells and in mice, which were left with healthy bone marrow cells. "We found bortezomib, even when used in a low dose, was significantly more effective when the cancer cells were sensitized by our strategy," says the study's first author, Dr. Xiangao Huang, assistant research professor of Pathology and Laboratory Medicine at Weill Cornell Medical College.

In exploring the underpinning mechanism, the researchers discovered that prolonged arrest in G1 markedly enhances cell suicide, induced by bortezomib. They discovered that during this phase, the cell loses a protein called IRF4, an essential survival factor for myeloma cells, and gains several pro-apoptotic proteins.

"These findings demonstrate for the first time that key survival and apoptotic genes are regulated by the cell cycle in cancer cells, and suggest new molecular targets for intervention," Dr. Chen-Kiang says.

"This work represents the seamless integration of basic biological research on the cell cycle and direct medical application in clinical trials," she adds. "Both the tools available to us, and our unique location at NewYork-Presbyterian/Weill Cornell Medical Center, allow us to move biological research forward while rapidly translating our findings to therapy."

(Feb. 11, 2011) — Scientists at Virginia Commonwealth University Massey Cancer Center have developed a novel treatment strategy for multiple myeloma that pairs two targeted agents to kill cancer cells. The study's findings, published in the journal Blood, are the first to demonstrate the synergistic, anti-myeloma effects of this combination regimen both in vitro and in vivo.

Des scientifiques ont développé un nouveau traitement pour le myélome multiple qui met ensemble deux agents ciblants pour tuer les cellules cancéreuses. Leurs études sont les premières à démontrer des effets combinés anti-myélomes in vivo et in vitro.

Multiple myeloma is a cancer involving antibody-producing cells in the bone marrow, and, in most cases, is incurable. Targeted therapies work by interfering with biological and biochemical functions critical for cancer cell survival and proliferation. The new treatment strategy from VCU Massey combines Src inhibitors, which block the activity of an important group of proteins that regulate cancer cell behavior, with Chk1 inhibitors, which interfere with cancer cells' ability to undergo cell cycle arrest and repair DNA damage.

La thérapie ciblée travaille en interférant avec des fonctions biologiques et biochimiques critiques pour la survie des cellules cancéreuses. Le nouveau traitement combine les inhibiteurs de Src, qui bloquent l'activité d'un groupe important de protéines qui régulent le comportement du cancer, avec les inhibiteurs de Chk1 qui interfèrent avec la capacité des cellules de arrêter leur cycle pour réparer les dommages à leurs ADN.

"Chk1 inhibitors are currently used primarily in conjunction with conventional DNA-damaging chemotherapeutic agents," says the study's lead investigator Steven Grant, M.D., associate director for translational research, Shirley Carter and Sture Gordon Olsson Chair in Oncology Research and professor of internal medicine at VCU Massey Cancer Center. "By combining Chk1 inhibitors with another targeted agent, such as Src inhibitors, we were able to induce cell death in multiple myeloma cells while sparing healthy, normal cells."

When multiple myeloma cells are subjected to DNA-damaging agents, or even when they are undergoing normal DNA replication, their DNA is subject to breakage. To survive, they must slow down their progression through the cell cycle in order to repair the DNA, or, if the damage is too severe, undergo a form of cell suicide.

Chk1 is an enzyme that allows cells to undergo cell cycle arrest, a process required to repair the DNA damage. When cancer cells are exposed to Chk1 inhibitors, they experience DNA damage and, as a consequence, launch another defense mechanism by activating a protein known as ERK1/2.

"The activation of ERK1/2 explains why multiple myeloma cells are able to survive the lethal effects of Chk1 inhibitors," says Grant. "Therefore, we used Src inhibitors to block the activation of ERK1/2." The results were more promising than even the researchers had hoped.

Chk1 est un enzyme qui permet aux cellules d'arrêtr leur cycle pour réaprer les dommages à leurs ADN mais quand les cellules cancéreuses arrêtent leur cycles, elles lancent un autre mécanisme de défense une protéine qui s'appelle ERK1/2.

Cette activation explique pourquoi les cellules du myélome multiple sont capables de survivre aux CHk1 mais lorsqu'on utilise l'inhivbiteur de Src cela bloque l'activation de ERK1/2 et le résultat est que plus prometteurs qu'espérés.

Grant's team discovered that Src inhibitors not only blocked ERK1/2 activation, but also synergized with Chk1 inhibitors to trigger a dramatic increase in cell death. In addition, the combined treatment greatly reduced blood vessel formation, which plays an important role in the maintenance of many tumors, including multiple myeloma. Significantly, the treatment exerted virtually no effects on healthy, normal cells.

"We found tumors treated with the combined regimen were noticeably smaller and showed signs of a lack of blood supply when compared to tumors from the control group or those treated only with Chk1 inhibitors," says Grant. "This study is not only the first to demonstrate that Src inhibitors can dramatically increase the effects of Chk1 inhibitors, but it is also the first to show that preventing blood vessel formation may contribute to the effectiveness of this combination strategy."

Nous avons trouvé qu'avec le régime associé de ces deux inhibiteurs, les tumeurs étaient plus petites et montraient des signent de manque de fournitire en sang. L'étude ne montre pas seulement que les inhibiteurs Src peuvent accroitrent de beaucoup les effets de l'inhibiteurs de Chk1 mais aussi que prévenir la formation des vaisseaux sanguins peut contribuer à l'efficacité de la thérapie.

This study builds upon more than seven years of research by Grant's team investigating cell signaling in relation to DNA damage repair and survival pathways involving Src and ERK1/2 proteins. The researchers are now developing more complex experiments as a prelude to clinical trials in multiple myeloma patients. "We're hopeful the approach of combining targeted agents will open up the possibility of developing entirely new therapies for patients with multiple myeloma and potentially other blood cancers," says Grant.

(Dec. 11, 2010) — A new three-drug combination used to treat the blood cancer multiple myeloma may be effective as a front-line therapy for newly diagnosed patients, according to a study led by the University of Michigan Comprehensive Cancer Center.

Une nouvelle tri-thérapie utilisée pour traiter le myélome multiple pourrait être efficace en thérapie de première intention.

The drug combination includes a novel proteasome inhibitor called carfilzomib, combined with lenalidomide and low-dose dexamethasone. This is the first study to look at carfilzomib as a front-line treatment of patients with myeloma, a type of cancer that arises in the plasma cells.

La combinaison incult un nouveau inhibiteur de protéasome appelé carfilzomib, combiné avec le lenalidomide et de petites doses de dexamethasone.

Initial results of the phase I study were presented Dec. 6 at the American Society of Hematology Annual Meeting and Exposition.

"This combination treatment appears to deliver everything we expected and more. We have seen no neurotoxicity and fantastic efficacy, the best reported to date," says study author Andrzej Jakubowiak, M.D., Ph.D., director of the multiple myeloma program at the University of Michigan Comprehensive Cancer Center.

The study, which still is accruing participants, has enrolled 31 people to date. All patients responded to this combination, measured by at least a 50 percent reduction of the disease, and the disease was completely or nearly eliminated in a significant portion of patients.

Responses were rapid, and the depth of response continued to improve with additional treatment. Of patients who completed eight cycles of therapy, more than two-thirds achieved a complete response, meaning they showed little or no signs of cancer. These response rates appear to be higher than those achieved by the best current regimens in newly diagnosed multiple myeloma.

Les réponses ont été rapides et la profondeur de la réponse continue de s'Améliorer avec les traitements additionnels. Des patients qui ont complétés 8 cycles de thérapie. Plus des deux tiers ont eu une réponse complète, ce qui veut dire qu'ils ont montré trè speu ou pas de signe de cancers. Ces réponses sont supérieures à celles obtenues avec d'autres thérapies pour les gens avec le myélome multiple nouvellment diagnostiqués.

After a median follow-up of six months, all patients were alive with no progression of their cancer.

Après 6 mois de suivi, les patients sont encore en vie et sans progression de leur maladie.

Researchers found that the three-drug combination, called CRd, was well-tolerated, with few serious side effects. Most notably, peripheral neuropathy -- which is marked by numbness or tingling of the fingers and toes and can cause significant pain, depending on the severity -- was infrequent and mild with this treatment. This side effect typically limits extended use of currently available multiple myeloma treatments and is often the reason patients discontinue a therapy.

The study also included patients who were eligible for a stem cell transplant. The researchers found that these patients were able to remain on CRd treatment and achieved responses similar to or better than those observed after a stem cell transplant. This outcome delayed the need for a stem cell transplant in these patients.

"Newly diagnosed myeloma is most sensitive to treatment. A great response in the initial phase of treatment is critical because it projects how long patients will remain in remission, as well as their overall survival. Patients have a better chance of living longer if their response to initial treatment is better," says Jakubowiak, associate professor of internal medicine at the U-M Medical School.

Carfilzomib has recently emerged as an important drug in treatment of multiple myeloma. It has previously been tested as a single-agent in patients who have exhausted all available treatment options and in relapsed disease. Currently, a Phase III trial is ongoing looking at CRd compared with lenalidomide and low dose dexamethasone alone for patients with relapsed multiple myeloma.

Dec. 7, 2009 — A new three-drug combination has shown in a phase 1/2 clinical trial that it is a "highly effective regimen" in the treatment of patients newly diagnosed with multiple myeloma, a cancer of white blood cells in bone marrow, say researchers from Dana-Farber Cancer Institute.

Une nouvelle combinaison de 3 médicaments a démontré en phase clinique 1 et 2 qu'elle est hautement efficace dans le traitement des patients diagnostiqués avec le myélome multiple.

Partial responses or better were seen in all of the 66 patients treated with the drug combination in the multi-center study, with 74 percent having a "very good partial response rate" in the phase 2 population, reports Paul G. Richardson, MD, of Dana-Farber, who led the study. The rate of complete or "near complete" responses to the therapy was also encouraging at 54 percent.

Des réponses partielles ou mieux encore ont été observés dans l'ensemble des 66 patients traités par l'association des médicaments. 74 % ont eu un "très bon taux de réponse partielle». Une érponse complète ou «presque complète» était de 54%.

Richardson will describe the results in an oral presentation at the American Society of Hematology's 51st annual meeting on Saturday, Dec. 5.

The regimen, known as RVD, combined the drugs Revlimid (lenalidomide), Velcade (bortezomib) and dexamethasone, which previously were found to be highly effective in multiple myeloma patients who had relapsed or no longer responded to first-line therapies.
Fifteen of the 35 newly diagnosed patients in the open-label phase 2 portion of the study subsequently underwent autologous (using their own blood-forming stem cells) transplants, a standard treatment for multiple myeloma "and did very well," says Richardson.
For the entire group, after a median 19.3 months of follow up, the median time-to-progression (TTP) of the disease, progression-free survival (PFS), and overall survival (OS) had not yet been reached, according to the presentation. The estimated TTP and PFS at one year are 76 percent, and the estimated one-year overall survival is 100 percent, the results showed.
An estimated 20,580 new cases of multiple myeloma will be diagnosed in 2009, according to the American Cancer Society, and 10,580 patients will die from the disease.
Richardson says it was "particularly exciting" to observe that the high response rate was not affected by the specific genetic characteristics of the patients' disease. Patients with so-called "adverse cytogenetics" are at higher risk for treatment failure and death, but in the current study the drug combination worked as well for them as it did in patients with more favorable cytogenetic features.
The toxic side effects of the treatment were "manageable," Richard says. The main adverse effect was peripheral neuropathy (numbness or pain in the extremities), which typically cleared up after dosages were lowered and the treatment was completed.
"Our conclusion is that this is a highly effective regimen for newly diagnosed multiple myeloma patients," says Richardson. "The combination has now gone into large phase 3 clinical trials, and we think it has the potential to be a new standard of treatment in multiple myeloma."

La combinaison de traitement de Revlimid (lenalidomide), oncovine (vincristine), Doxil (pegylated doxorubicine) et le dexamethasone apparaissent comme hautement efficace pour le traitement du myélome multiple qui a récidivé suite à des traitements antérieurs.



Des chercheurs de Cleveland ont conduit des essais cliniques pour évlauer cette combinaison de médicaments. L'étude comportait 62 patients, 75% de ceux-ci ont eu une réponse anti-cancer et 29% de ces patients ont eu rémission complète ou très près d'être complète de leurs cancers.

Citation :

Le myélome multiple (plus connu sous le nom de maladie de Kahler) est un cancer hématologique (signifiant qu'il se développe dans le sang) de la moelle osseuse. C'est un cancer des cellules plasmatiques : les plasmocytes (qui sont des lymphocytes B activés), une fraction majeure du système immunitaire qui produit des anticorps (immunoglobulines) pour combattre les infections et maladies.