carfilzomib et panobinostat contre le myélome multiple

In patients with relapsed/refractory multiple myeloma, the combination of panobinostat (Farydak) and carfilzomib (Kyprolis) appears to be safe and effective, according to a phase I/II study by Berdeja et al in Haematologica. Further evaluation of this combination treatment is warranted to establish the optimal dose and schedule.

Although the therapeutic options, and survival rates, for patients with multiple myeloma have improved over the past 2 decades, multiple myeloma is generally considered to be an incurable malignancy. The majority of patients undergo multiple cycles of chemotherapy, which become less effective as patients relapse. Researchers continue to study new single and combination therapies that may address this problem.

Berdeja and colleagues conducted a study examining the efficacy and safety of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma. Carfilzomib is approved as a single agent for the treatment of multiple myeloma in patients who received at least two prior therapies, and panobinostat was the first histone deacetylase inhibitor approved for the treatment of multiple myeloma.

Study Details

Included in the study were 44 patients with relapsed/refractory myeloid leukemia. The study was divided into two phases. The first phase (n = 13) was to determine the maximum tolerated dose of the combination therapy. These patients were treated at four different dose levels.

The second phase (n = 31) was to assess the efficacy and safety of the combination therapy. These patients were treated at the highest dose level (30 mg of panobinostat and 20/45 mg/m2 of carfilzomib). The median number of prior therapies was five (range = 1–10); 89% of patients had received bortezomib (Velcade), 89% had received prior immune-modulating drugs, and 52% had had a prior stem cell transplantation.

The median age of patients was 66 years (range = 41–82), and 61% of patients were female. A total of 18 patients (41%) discontinued participation in the study due to disease progression, and 4 patients (9%) discontinued treatment due to treatment-related adverse events.

Overall Response Rate of 67%

The overall response rate in all patients was 67%. The overall response rate for all patients treated at the highest dose level was 72%.

Prior treatments did not appear to impact the overall response rates. The overall response rate for all patients who previously received bortezomib was 70%. Patients who were refractory to bortezomib, immune-modulating drugs, or both had an overall response rate of 67%, 75%, and 80%, respectively.

The overall survival rate at 24 months was 67%. At this time, the median overall survival has not been reached.

In regard to safety, grade 3/4 treatment-related adverse events included thrombocytopenia (38%), neutropenia (21%), fatigue (11%), anemia (9%), and hypertension (9%). Diarrhea, nausea and vomiting, and thrombocytopenia were the most commonly reported toxicities. Three patients discontinued treatment due to treatment-related toxicity. The toxicity associated with panobinostat often disappeared during the weeks off therapy; however, the toxicities returned with subsequent drug administration.

Closing Thoughts

The key finding of this study is that the combination of carfilzomib and the oral panobinostat appeared to be safe and effective at all dose levels. The researchers noted that further evaluation of this combination is warranted and will help establish the optimal dose and schedule.

The investigators concluded, “The combination of panobinostat and carfilzomib is feasible and effective in relapsed/refractory multiple myeloma patients.”

Jesus G. Berdeja, MD, of the Sarah Cannon Research Institute, Nashville, Tennessee,is the corresponding author of this article in Haematologica. The authors reported no potential conflicts of interest.

This study was supported in part by grants from Novartis and Onyx. For full disclosure of the study authors, visit www.haematologica.org.

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Chez les patients avec rechute du myélome multiple réfractaire, la combinaison de panobinostat (Farydak) et carfilzomib (Kyprolis) semble être sûr et efficace, selon une étude de phase I / II par Berdeja et al dans Haematologica. Une évaluation plus poussée de ce traitement d'association est justifiée pour établir la dose optimale et le calendrier.

Bien que les options thérapeutiques, et les taux de survie, pour les patients atteints de myélome multiple se sont améliorés au cours des deux dernières décennies, le myélome multiple est généralement considéré comme un cancer incurable. La majorité des patients subissent plusieurs cycles de chimiothérapie, qui deviennent moins efficaces alors que les patients rechutent. Les chercheurs continuent à étudier de nouvelles thérapies simples ou combinés qui peuvent résoudre ce problème.

Berdeja et ses collègues ont mené une étude sur l'efficacité et l'innocuité de la combinaison de panobinostat et carfilzomib chez les patients avec rechute du myélome multiple réfractaire. Le Carfilzomib est approuvé en monothérapie pour le traitement du myélome multiple chez les patients qui ont reçu au moins deux traitements antérieurs et panobinostat a été le premier inhibiteur d'histone déacétylase approuvé pour le traitement du myélome multiple.

Détails de l'étude

44 patients en rechute d'une leucémie myéloïde réfractaire étaient Inclus dans l'étude. L'étude a été divisée en deux phases. La première phase (n = 13) était de déterminer la dose maximale tolérée de la combinaison thérapeutique. Ces patients ont été traités à quatre doses différentes.

La deuxième phase (n = 31) était d'évaluer l'efficacité et la sécurité de la thérapie de combinaison. Ces patients ont été traités au niveau de la dose la plus élevée (30 mg de panobinostat et 20/45 mg / m2 de carfilzomib). Le nombre médian de traitements antérieurs était de cinq (gamme = 1-10); 89% des patients avaient reçu bortezomib (Velcade), 89% avaient reçu des médicaments immunomodulateurs antérieurs, et 52% ont eu une transplantation de cellules souches.

L'âge médian des patients était de 66 ans (gamme = 41-82), et 61% des patients étaient des femmes. Un total de 18 patients (41%) de la participation ont abandonné dans l'étude en raison de la progression de la maladie, et quatre patients (9%) ont arrêté en raison d'effets indésirables liés au traitement.

Taux de réponse global de 67%

Le taux de réponse global chez tous les patients était de 67%. Le taux de réponse global pour tous les patients traités au niveau de la dose la plus élevée était de 72%.

Les traitements antérieurs ne semblent pas influer sur les taux de réponse globaux. Le taux de réponse global pour tous les patients qui ont déjà reçu le bortézomib était de 70%. Les patients qui étaient réfractaires au bortézomib, aux médicaments immunomodulateurs, ou les deux avaient un taux de réponse global de 67%, 75% et 80%, respectivement.

Le taux de survie globale à 24 mois était de 67%. A cette époque, la survie globale médiane n'a pas été atteinte.

La principale conclusion de cette étude est que la combinaison de carfilzomib et panobinostat orale semblaient être sûr et efficace à tous les niveaux de dose. Les chercheurs ont noté que la poursuite de l'évaluation de cette combinaison est justifiée et aidera à établir la dose optimale et le calendrier.

Les chercheurs ont conclu, «La combinaison de panobinostat et carfilzomib est faisable et efficace pour les patients en rechute ou réfractaires atteints de myélome."

Cette étude a été financée en partie par des subventions de Novartis et Onyx. Pour la divulgation complète des auteurs de l'étude, visitez www.haematologica.org.

Bonjour aranna,

Oui les médicaments sont parfois bien fatiguant, j'ai arrêté sous conseil de mon médecin de prendre les miens et je suis plus énergique ces temps-ci. Peut-être que ta mère redeviendra aussi plus en forme car à 61 ans, elle n'est pas veille et les progrès de la médecine sont réelles.

Par exemple pour ce duo de médicament, ça me donne l'occasion de mettre les connaissances du forum plus à jour car l'article date déja de plusieurs années et ils ont amélioré le Velcade l'ont mis sous forme de pilule, mais apparemment ça donne de bons résultats :

Citation :

MLN9708, “Son of Velcade,” Shows Promising Initial Results In Multiple Myeloma (ASH 2011)
No Comment By Virginia Li
Published: Dec 16, 2011 2:24 pm

MLN9708 dans la continuité de Velcade montre des résultats initiaux prometteurs contre le Myélome multiple

The initial results from three early-phase clinical trials suggest that the investigational drug MLN9708, either alone or in combination with Revlimid and dexamethasone, may be an effective treatment for both newly diagnosed multiple myeloma patients and patients with relapsed and/or treatment-resistant disease.

soit seul ou en combinaison avec Revlimid et dexamethasone

The findings from the three trials were presented earlier this week at the American Society of Hematology (ASH) annual meeting in San Diego.

MLN9708 belongs to the same class of drugs as Velcade (bortezomib), called proteasome inhibitors, and it is being developed by Millennium Pharmaceuticals, the same company that developed Velcade.

MLN9708 est de la même classe de médicaments que Velcade (inhibiteurs de proteasome) et fait par la même compagnie

However, unlike Velcade, which is given by infusion or injection, MLN9708 can be administered orally in capsule form.

mais administré en pilule

The results for MLN9708 that were presented at ASH are promising. For example, in the small trial with newly diagnosed myeloma patients, 100 percent of the patients had at least a partial response to treatment with a combination of MLN9708, Revlimid, and dexamethasone.

Les résultats présentés au congrès américain sont prometteurs. 100% des patients ont eu une réponse au moins partielle avec une combinaison de MLN9708 REvlimid et dexamethrone.

In addition, the rate of peripheral neuropathy among patients treated with MLN9708 appears to be 50 to 75 percent lower than seen among patients treated with Velcade. Peripheral neuropathy is a condition characterized by pain and tingling in the extremities.

En plus, le MLN9708 est moins dommage pour les douleurs dans les extrémités (sensation de froid dans le bout des doigts qui a été discuté sur ce fourm je suppose...)

MLN9708 In Combination With Revlimid And Dexamethasone

Dr. Jesus Berdeja from the Sarah Cannon Research Institute in Nashville, Tennessee, reported interim results from a Phase 1 study of MLN9708 in combination with Revlimid (lenalidomide) and dexamethasone (Decadron) in patients with previously untreated multiple myeloma.

Essais de phase I sur des patients non-traités auparavant avec le myélom multiple.

Preclinical studies showed that MLN9708 acted synergistically with Revlimid and dexamethasone.

The goal of the Phase 1 study was to determine the safety and maximum tolerated dose of this combination therapy.

Fifteen newly diagnosed patients have been enrolled in the study so far. They received 1.68 mg/m2 to 3.95 mg/m2 of MLN9708 orally on days 1, 8, and 15 of a 28-day treatment cycle. They also received 25 mg of Revlimid on days 1 to 21 of each treatment cycle and 40 mg of dexamethasone on days 1, 8, 15, and 22 for up to 12 cycles. Transplant-eligible patients could undergo stem cell transplantation after six cycles.

Thus far in the trial, participants have received a median of five treatment cycles. Seventy-three percent of patients are still receiving treatment.

A full 100 percent of the 15 patients enrolled so far in the trial had at least a partial response to the combination treatment after four cycles of treatment.

In addition, 33 percent of the patients achieved a very good partial response and 27 percent achieved a complete response.

Dr. Berdeja pointed out that response to treatment was rapid; 93 percent of patients experienced at least a 50 percent decrease in M-protein, the abnormal protein produced by myeloma cells, after one treatment cycle.

Eighty-seven percent of patients experienced drug-related side effects. The most common severe side effects included vomiting (13 percent), blood clots (13 percent), anemia (13 percent), and rash (13 percent).

Mild peripheral neuropathy was observed in 20 percent of patients.

Twenty-seven percent of patients required Revlimid dose reductions, and 13 percent required MLN9708 dose reductions due to side effects.

The maximum tolerated dose for MLN9708 was found to be 2.97 mg/m2. However, Dr. Bereja recom­mended a lower dose (2.23 mg/m2) for the Phase 2 trial because the lower dose was as active as the 2.97 mg/m2 dose but better tolerated. In addition, he pointed out that the lower dose did not compromise the dosing of the other two agents.

MLN9708 As A Single-Agent Treatment

Dr. Paul Richardson of the Dana-Farber Cancer Institute in Boston presented results from a Phase 1/2 clinical trial of single-agent MLN9708 in patients with relapsed and treatment-resistant multiple myeloma.

A total of 56 patients, with a median age of 65 years, were enrolled in the study. They had received a median of four prior therapies.

Almost all patients (88 percent) had previously received Velcade, 79 percent had received Revlimid, 59 percent thalidomide (Thalomid), and 4 percent carfilzomib. Fifty-two percent of patients demonstrated resistance to their last therapy, including 28 percent who were resistant to Velcade.

The purpose of the study was to determine the maximum tolerated dose of MLN9708.

Patients received 0.24 mg/m2 to 2.23 mg/m2 of MLN9708 on days 1, 4, 8, and 11 of a 21-day treatment cycle. They received a median of 3.5 treatment cycles.

Of the evaluable patients, 13 percent had at least a partial response to treatment, with 2 percent of patients achieving a complete response. Another 61 percent of patients have reached stable disease.

Overall, 91 percent of patients experienced drug-related side effects including fatigue (46 percent of patients), low platelet counts (39 percent), nausea (30 percent), diarrhea (23 percent), vomiting (23 percent), rash (21 percent), and peripheral neuropathy (11 percent).

Dr. Richardson pointed out that all cases of peripheral neuropathy were mild to moderate; none of the patients experienced severe peripheral neuropathy.

In addition, 32 percent of patients required dose reductions due to side effects, and 9 percent discontinued treatment due to side effects.

The maximum tolerated dose was established at 2.0 mg/m2.

Weekly MLN9708 As A Single-Agent Treatment

Dr. Shaji Kumar from the Mayo Clinic in Rochester, Minnesota, presented results from another Phase 1 study of MLN9708 in patients with relapsed and refractory multiple myeloma.

The objective of this study was to determine the maximum tolerated dose and safety of MLN9708 administered once per week.

The study enrolled 32 patients, who had received a median of six prior therapies. The median patient age was 64 years old. Seventy-two percent of patients had previously received a stem cell transplant, and 56 percent were resistant to prior therapy (including 28 percent to Velcade and 41 percent to Revlimid or thalidomide).

Patients received 0.24 mg/m2 to 3.95 mg/m2 of MLN9708 on days 1, 8, and 15 of a 28-day treatment cycle.

Overall, patients received a median of two treatment cycles. Three patients are currently continuing treatment; all others have discontinued treatment, mainly due to disease progression (69 percent).

Of the 18 patients who have been evaluated thus far for their response to the drug, one reached a very good partial response and one reached a partial response, for an overall response rate of 11 percent.

Another 8 patients (44 percent) achieved stable disease.

The majority of patients (72 percent) experienced treatment-related side effects. The most common treatment-related side effects included fatigue (31 percent), low platelet counts (31 percent), nausea (28 percent), and diarrhea (25 percent).

Nine percent of patients reported peripheral neuropathy. Dr. Kumar pointed that all cases of peripheral neuropathy were mild to moderate in nature.

Nineteen percent of patients required a dose reduction due to side effects, and 11 percent discontinued treatment due to side effects.

The maximum tolerated dose for weekly administration has been determined to be 2.97 mg/m2.

For more information about these three trials, please see abstract 301, abstract 479, and abstract 816 on the American Society of Hematology Annual Meeting website.

Also, as a courtesy to The Beacon’s readers, Dr. Richardson has made the slides of his presentation available (pdf) for download and viewing.

Les progrès fait par ta mère sont impressionnnants et je lui souhaite de se rétablir encore plus. Tiens nous au courant...

Les peurs se transmettent , mais les joies aussi ! alors restez dans l'espoir et la joie le plus possible pour eux pour vous !

aranna a écrit:

En espérant que 2012 lui apportera et nous apportera un peu de moments un peu plus joyeux qu'en ce moment.

Gardez espoirs !!!!! pour eux, pour nous...

Bonsoir Aranna. Oui, garder espoir pour eux, malgré eux. Pas facile quand on les voit perdre pied. Pas d'espoir sans peur mais je crois que notre plus grande qualité d'être humain est de croire à l'impossible et au miracle, même dans la pire des situations.

BB

Ma maman de 61 ans est atteinte d'une LCP-P (forme rare du MM) et est actuellement sous ce protocole, elle est passée de 70% de cellule cancéreuses à 15% mais reste très très faible (transfusion sang/plaquette quasi journalière).
Même si nous connaissons à l'avance l'issue de la maladie nous mettons tous notre espoir dans ce type de traitement tout en voyant qu'il n'est pas facile pour elle (et pour nous) de la voir s'affaiblir de jour en jour.

En espérant que 2012 lui apportera et nous apportera un peu de moments un peu plus joyeux qu'en ce moment.

Gardez espoirs !!!!! pour eux, pour nous...

Les deux médicaments Velcade(bortezomib) et le Revlimid(lenalidomide) sont faits pour traiter le cancer de la moelle des os appelé myélome multiple. La phase I d'essais cliniques a montré que les médicaments peuvent être plus efficace ensemble qu'individuellement.

L'essai clinique mené à Boston a inclu 38 patients qui ont eu un cancer récurrent du myélome multiple. Les patients ont été divisé en groupes qui ont reçu successivement de plus grandes doses de Velcade et de Revlimid. Quelques patients ont reçu aussi de la dexaméthasome qui peut ajouter ses effets à ceux des autres médicament.


58% ont répondu à la médication et 6% ont eu une rémission complète.