Proteasome inhibitor bortezomib inhibits T cell-dependent inflammatory responses - a new hope for autoimmune and inflammatory diseases?

In continuation of my update on Bortezomib, I found this info interesting to share with..

Japanese scientists lead by Dr. Koichi Yanaba, of Department of Dermatology at Nagasaki University Graduate School of Biomedical Sciences used mice to show that bortezomib, currently used to treat cancers that affect white blood cells, induces cell death only in harmful (active and proliferating) T cells, leaving the rest unharmed. If the results prove true in humans, it offers hope that this drugs or others similar to it might be used to treat inflammatory diseases without the side effects of current drugs that affect all T cells equally.

To make this discovery, scientists used two groups of mice the first treated with bortezomib and the second with saline. Researchers induced contact hypersensitivity reaction with oxazolone, a chemical allergen used for immunological experiments and found that bortezomib significantly inhibited the contact hypersensitivity responses. Results strongly suggest that bortezomib treatment enhanced T cell death by inhibiting NF-kappa B activation, which plays a key role in regulating the immune response to infection. This in turn led to the suppression of inflammatory responses in immune cells by reducing interferon-gamma production.

"We believe that this new-type remedy for autoimmune and inflammatory disease could successfully treat them in the near future", claims Dr. Koichi Yanaba...

As per the claim by the researchers, bortezomib potently inhibited CHS responses. The attenuation of CHS responses was associated with decreased inflammatory cell infiltration in the challenged skin. Specifically, bortezomib-treated mice showed significantly decreased numbers of CD4⁺ and CD8⁺ T cells in the challenged skin and draining lymph nodes. Cytoplasmic IFN- production by CD4⁺ and CD8⁺ T cells in the draining lymph nodes was decreased substantially by bortezomib treatment. Notably, bortezomib enhanced T cell apoptosis by inhibiting NF-B activation during CHS responses. Thus, bortezomib treatment is likely to induce T cell death, thereby suppressing CHS responses by reducing IFN- production. These findings suggest that bortezomib treatment could be a promising strategy for treating autoimmune and inflammatory disease.

Ref :http://www.jleukbio.org/cgi/content/abstract/88/1/117

Study shows three-drug combination delays recurrence and lengthens life for myeloma patients

In continuation of my update on lenalidomide, bortezomib and dexamethasone

The International Myeloma Foundation (IMF) today announced the publication in The Lancet of the results of a randomized, phase III trial, conducted by SWOG, a publicly funded international cancer clinical trials network, and led by IMF chairman of the board Brian G.M. Durie, MD. This important trial compared the effectiveness of two drug regimens in patients undergoing their first round of treatment for multiple myeloma. The trial shows that a three-drug combination - known as VRd - delays recurrence and lengthens life for myeloma patients, indicating a possible new standard of care.

One regimen used in the study was lenalidomide with dexamethasone, a standard first-line treatment for myeloma patients. The other drug regimen also included bortezomib, a second-line drug typically given to myeloma patients whose cancer progresses after initial therapy. SWOG researchers found that the addition of bortezomib earlier made a difference for myeloma patients, giving them about another year of remission and another year of life compared to the standard two-drug regimen.

"Our results are clear. Using bortezomib in combination with lenalidomide and dexamethasone in front-line treatment - hitting the disease early and hard - makes a meaningful difference for myeloma patients," said study principal investigator Dr. Durie, a physician at Cedars-Sinai Outpatient Cancer Center in Los Angeles. "Our results represent a potential new standard of care."

"This is a landmark study that lends clarity to frontline therapy of myeloma," said Dr. S. Vincent Rajkumar of Mayo Clinic and a co-author of the study. "Newer alternatives to VRd may be more expensive, cumbersome, or toxic. These regimens will therefore need to show superiority over VRd in randomized trials."

Also worth noting, Dr. Rajkumar said, is that the VRd regimen will become even more cost effective as the drugs in this combination become generic over time.

 bortezomib     lenalidomide

  dexamethasone

Patients in the trial receiving bortezomib, along with lenalidomide and dexamethasone, in their first six months of treatment had a median remission time of 43 months compared to a median remission of 30 months for patients who received lenalidomide and dexamethasone alone. Researchers also found that patients who received bortezomib lived a median of 75 months, or about six years, after their initial treatment. Patients who received the standard two-drug treatment lived a median of 64 months, or about five years, after initial treatment.

Celebrating its 60th year, SWOG has conducted more than 1,300 cancer trials that have led to FDA approval of 14 new drugs and led to more than 100 changes to cancer standards of care. SWOG is part of the NCI's National Clinical Trials Network (NCTN), the nation's largest and oldest publicly funded cancer research network. SWOG members and other members in the NCTN enrolled 471 eligible and consented adult patients in the study, known as S0777, between February 2008 and February 2012, at 139 institutions across the US.

Patients ranged in age from 28 to 87, had active myeloma, and had not had a stem-cell transplant or any prior treatment for their disease. Patients were randomized into two groups. One group received the standard two-drug treatment for six cycles over six months. That includes lenalidomide, an immunomodulating therapy marketed as Revlimid by Celegene Corporation. The other group received a three-drug combination that included bortezomib, a proteasome inhibitor marketed as Velcade by Millennium Pharmaceuticals. These patients received the triple combination therapy for eight cycles over six months.

Phase I study of triple drug combination shows promise in multiple myeloma patients

In continuation of my updates on Dexamethasone,  Plitidepsin and  Bortezomib 

Dexamethasone    Plitidepsin

 Bortezomib 

PharmaMar (MSE:PHM) announces the positive results from a Phase I study of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma. Dr María Victoria Mateos, MD of the Hematological Department of the University Hospital of Salamanca, Spain, the principal investigator of the study, will present the results in an oral session on June 3rd, 2016 during the 52nd Congress of the American Society of the Clinical Oncology (ASCO), taking place in Chicago (USA), June 3 - 7.

The primary objective of this 20-patient study was to identify the recommended dose for the triple combination (dexamethasone / bortezomib / plitidepsin) administered every four weeks. Efficacy and the safety profile were also evaluated. The overall response rate (ORR) was 56%, including very good partial responses (VGPR) in 33% of the patients and a remarkable partial remission in one triple refractory patient. The median progression free survival (PFS) was 8.3 months. Additionally, 90% of the patients showed a DOR of 6 months or more and clinical benefit was observed in 72% of the patients.

Dose limiting toxicities were not seen in any of the evaluated patients; therefore, the full dose of plitidepsin and bortezomib when used alone were established as the recommended dose for the triple combination. The treatment was well tolerated. The hematological toxicity was manageable and the non-hematological toxicity was in general mild, with the exception of one case of creatinine increase.

Out of the 20 patients that participated in the study, 10 are still under the treatment. The median age was 65. All patients had relapsed after previously receiving, on average, 3.5 therapeutic regimens (range 1-10). Forty-five percent of these patients had been subject to a hematopoietic stem cell transplant (8 autologous, 1 allogeneic). Of the 18 patients evaluable for efficacy, 83% (15 patients) had previously received bortezomib and lenalidomide. One was refractory to bortezomib and seven to lenalidomide.

In abstract #8006, Dr María Victoria Mateos and her team explain that despite the recent progress in the treatment of multiple myeloma due to the introduction of proteasome inhibitors (PIs), the new immunomodulatory drugs (IMIDs), and monoclonal antibodies, the illness is still incurable. Therefore, active compounds with novel mechanisms of action and adequate safety profile are needed. Plitidepsin targets the eukaryotic Elongation Factor eEF1A2, an overexpressed protein in multiple myeloma that contributes to its pathogenesis. The positive results from this study will be added to the already extensive data package from Phase II and Phase III trials, where plitidepsin has shown activity and a favorable safety profile in combination with dexamethasone.

Role for carfilzomib in relapsed, refractory multiple myeloma treatment

In continuation of my update on carfilzomib

Carfilzomib significantly improves outcomes in previously treated patients with relapsed or refractory multiple myeloma, shows a head-to-head comparison with bortezomib.

In the ENDEAVOR phase III trial, published in The Lancet Oncology, median progression-free survival (PFS) was 18.7 months for the 464 patients randomly assigned to receive open-label carfilzomib plus dexamethasone. This was significantly longer than the 9.4 months for the 465 participants treated with bortezomib and dexamethasone, and equated to a 47% risk reduction in favour of carfilzomib.

Moreover, a significantly higher proportion of carfilzomib- than bortezomib-treated patients achieved an objective response, at 77% versus 63%, and the duration of response was also longer in the former group, at a respective 21.3 and 10.4 months.

The most common side effects of grade 3 or worse that occurred more frequently in the carfilzomib than the bortezomib treatment arm were anaemia and hypertension, with rates of 14% versus 10% and 9% versus 3%, respectively.

However, peripheral neuropathy of grade 3 was observed in 2% of carfilzomib-treated patients and there were no grade 4 events, compared with 8% of patients in the bortezomib arm who experienced events of grade 3 or 4.

Serious adverse events occurred in 48% of patients in the carfilzomib group and in 36% of those given bortezomib, but Meletios Dimopoulos (National and Kapodistrian University of Athens, Greece) and team note that the number of discontinuations and deaths attributable to adverse events were comparable between the groups.

They conclude that carfilzomib plus dexamethasone could be considered for multiple myeloma patients for whom bortezomib is indicated.

Role for carfilzomib in relapsed, refractory multiple myeloma treatment

Bortezomib for bone cancer in children & teens..

We knew that Bortezomib marketed as Velcade by Millennium Pharmaceuticals is the first therapeutic proteasome inhibitor to be tested in humans. It is approved in the U.S. for treating relapsed multiple myeloma and mantle cell lymphoma (2008). In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease.

Recently researchers from University of Rochester have found more interesting fact that "bortezomib is effective against bone cancer in human cancer cell studies and in mice". In the current study, researchers sought to use Bortezomib (Velcade) against osteosarcoma, an aggressive cancer that starts in bone, spreads quickly and responds poorly to current chemotherapies. The drug, a proteasome inhibitor.

The researchers are excited because of the fact that "a drug already proven safe and effective in treating the most common cancers of the blood may be equally effective in suppressing bone cancer". Bortezomib caused osteosarcoma cells to self destruct, and prevented their spread. claims the researchers. While further studies are needed, these findings suggest that this drug may represent a new treatment option for a devastating disease and an effective complement to current chemotherapies. Congrats for this achievement.

More : http://www.urmc.rochester.edu/news/story/index.cfm?id=2676

Combination of bortezomib and panobinostat shows promise against advanced multiple myeloma

In co\continuation of  my update on Bortezomib...

A phase 2 clinical trial has shown that pairing bortezomib with an experimental drug, panobinostat: Panobinostat is a histone deacetylase (HDAC) inhibitor, a type of drug that blocks key processes involved in gene expression and protein degradation. Panobinostat clogs up a protein disposal mechanism in myeloma cells so that harmful byproducts accumulate and eventually cause programmed cell death.(see below structure), may be a promising new treatment for such patients, Dana-Farber Cancer Institute researchers say.

 The PANORAMA 2 trial included 53 patients with relapsed multiple myeloma who had undergone multiple rounds of prior treatment and, in more than half, also stem cell transplant. The researchers reported on 44 patients receiving the panobinostat-bortezomib-dexamethasone combination.

Results showed that in the first phase of the treatment, 9 of the patients had at least a partial response of their disease, and 2 of the 9 saw their myeloma almost disappear, a so-called near complete response. Another 7 patients experienced minimal response, which is also associated with clinical benefit. 

More : http://ash.confex.com/ash/2011/webprogram/Paper41145.html

Carfilzomib for multiple myeloma ?

The proteasome has emerged as an important target for cancer therapy with the approval of bortezomib, a first-in-class, reversible proteasome inhibitor, for relapsed/refractory multiple myeloma (MM). However, many patients have disease that does not respond to bortezomib, whereas others develop resistance, suggesting the need for other inhibitors with enhanced activity. Therefore the researchers evaluated a novel, irreversible, epoxomicin-related proteasome inhibitor - Carfilzomib.

The second-generation proteasome inhibitor carfilzomib is showing noteworthy response rates and low levels of adverse side effects among multiple myeloma patients in a phase II clinical trial.

The updated data from the 17-site study focuses on patients with relapsed or resistant multiple myeloma who have received one to three prior therapies, but not the drug bortezomib, the original proteasome inhibitor. The results are of grat importance because of the fact that multiple myeloma is an incurable, challenging disease with devastating consequences. While new agents are extending life expectancies, they often have adverse side effects, including severe neuropathy. Carfilzomib is showing good response rates, with an improved side effects, except for minor, included fatigue, nausea and anemia.

Ref : http://bloodjournal.hematologylibrary.org/cgi/content/full/110/9/3281/F1

Impressive Results of Velcade(R) (bortezomib) Based Therapy in Multiple Myeloma...

 In continuation of my update on Bortezomib [1, 2]

The Takeda Oncology Company today reported new correlative science data from the pivotal PINNACLE trial of VELCADE^® (bortezomib) in patients with relapsed/refractory mantle cell lymphoma (MCL). The data, derived from an analysis of archived tumor samples, tested pre-specified biomarkers for their association with time to progression and response to treatment with VELCADE in patients with relapsed MCL. The results add to the body of data supporting the potential usefulness of biomarkers in predicting outcome of MCL and predicting responsiveness to single agent VELCADE.

"This analysis of the PINNACLE study opens the door for additional research into targeted approaches to VELCADE treatment."..

The PINNACLE trial was a Phase II, open-label, single-arm, multicenter study of 155 patients with relapsed/refractory MCL and was the basis of the 2006 approval of VELCADE for the treatment of patients with relapsed/refractory MCL who had received one prior therapy. The overall response rate in the trial was 31 percent, with a median duration of response of 9.3 months; the CR rate was 8 percent, with a median duration of response of 15.4 months.

The Goy analysis used archived tumor samples from 73 patients who participated in the PINNACLE trial. The biopsies were examined for biomarkers associated with poor prognosis in MCL or those regulated by the proteasome. The biomarker levels were then compared to the effect of VELCADE on patients, according to response rates including overall survival and time to progression...

Ref : http://investor.millennium.com/phoenix.zhtml?c=80159&p=irol-newsArticle&ID=1434934&highlight=

Karyopharm Announces FDA Extension of Review Period for Selinexor New Drug Application

  

Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a clinical-stage pharmaceutical company,  announced that the U.S. Food and Drug Administration (FDA) has extended the Prescription Drug User Fee Act (PDUFA) action date for the New Drug Application (NDA) for selinexor. The NDA, which is currently under Priority Review by the FDA, is seeking accelerated approval for selinexor in combination with dexamethasone for the treatment of patients with relapsed refractory multiple myeloma who have received at least three prior therapies and whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent (IMiD), and one anti-CD38 monoclonal antibody. The previously disclosed April 6, 2019 PDUFA date has been extended by three months to July 6, 2019.

On February 26, 2019, the FDA'sOncologic Drugs Advisory Committee (ODAC) met to discuss the selinexor NDA and voted 8 to 5 recommending that the FDA wait for the results from Karyopharm's randomized, open-label, Phase 3 BOSTON study evaluating selinexor in patients with relapsed or refractory multiple myeloma, before making a final decision regarding approval.  Although the FDA considers the recommendation of this panel, the final decision regarding the approval of the product is made by the FDA solely, and the recommendations by the panel are non-binding.

Following the ODAC meeting, at the FDA's request,  Karyopharm submitted additional, existing clinical information as an amendment to the NDA, which allowed the FDA to extend the PDUFA action date by three months. "We look forward to the continued collaboration with FDA in trying to meet the needs of patients with relapsed refractory multiple myeloma," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm.

About Selinexor

Selinexor is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. In 2018, Karyopharm reported positive data from the Phase 2b STORM study evaluating selinexor in combination with low-dose dexamethasone in patients with triple class refractory multiple myeloma who have been previously exposed to all five of the most commonly prescribed anti-myeloma therapies currently available. Selinexor has been granted Orphan Drug Designation in multiple myeloma and Fast Track designation for the patient population evaluated in the STORM study. Karyopharm's New Drug Application (NDA) has been accepted for filing and granted Priority Review by the FDA, and oral selinexor is currently under review by the FDA as a possible new treatment for patients with triple class refractory multiple myeloma. The Company has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval and was granted accelerated assessment. Selinexor is also being studied in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In 2018, Karyopharm reported positive top-line results from the Phase 2b SADAL study evaluating selinexor in patients with relapsed or refractory DLBCL after at least two prior multi-agent therapies and who are ineligible for transplantation, including high dose chemotherapy with stem cell rescue. Selinexor has received Fast Track designation from the FDA for the patient population evaluated in the SADAL study.  Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade® (bortezomib) and low-dose dexamethasone (BOSTON), as a potential backbone therapy in combination with approved therapies (STOMP), in liposarcoma (SEAL), and an investigator-sponsored study in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm's clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

https://pubchem.ncbi.nlm.nih.gov/compound/Selinexor#section=2D-Structure

Karyopharm Announces FDA Extension of Review Period for Selinexor New Drug Application

FDA Approves Xpovio (selinexor) for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma

In continuation of my update on Selinexor

Karyopharm Therapeutics Inc. an oncology-focused pharmaceutical company, announced that the U.S. Food and Drug Administration (FDA) has approved oral Xpovio (selinexor), a nuclear export inhibitor, in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. The ongoing, randomized Phase 3 BOSTON study evaluating selinexor in combination with Velcade® (bortezomib) and low-dose dexamethasone will serve as the confirmatory trial. The FDA’s Accelerated Approval Program was developed to allow for expedited approval of drugs that treat serious conditions and that fill an unmet medical need.  

Karyopharm expects Xpovio to become commercially available in the U.S. on or before July 10, 2019.  A Marketing Authorization Application for selinexor is also currently under review by the European Medicines Agency.

“With today’s accelerated approval of Xpovio by the FDA, patients with heavily pretreated multiple myeloma will now have a new therapeutic option to treat their disease,” said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm. “Discovering, developing and securing FDA approval for XPOVIO with its novel mechanism of action over the past decade required the dedication of many people, including the patients, caregivers and physicians involved in our clinical trials, along with the many employees at Karyopharm.  We are tremendously grateful for everyone’s contributions to this important milestone, and we look forward to the next stage in our pursuit of improving the lives of patients with cancer.”

“The 25.3% response rate seen in the subgroup of 83 patients in the pivotal Phase 2b STORM study that served as the basis for Xpovio's accelerated approval is clinically meaningful and a validated surrogate marker for clinical benefit in our patients with advanced refractory disease,” said Sundar Jagannath, MD, Director of the Multiple Myeloma Program, Professor of Medicine (Hematology and Medical Oncology) at Tisch Cancer Institute at Mount Sinai School of Medicine, and principal investigator of the STORM study.

“Despite recent advances in the treatment of multiple myeloma, almost all our patients will develop disease that is resistant to the five most commonly used anti-myeloma drugs we currently have available, and the prognosis for this patient population is particularly poor.  The accelerated approval of oral Xpovio marks an important advance in the treatment paradigm for patients with relapsed refractory multiple myeloma, and in my view, is an important addition to our therapeutic armamentarium,” said Dr. Paul Richardson, MD, Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute.

Michael G. Kauffman, MD, PhD, Chief Executive Officer of Karyopharm, commented, “Having worked on novel drugs in myeloma beginning with Velcade in the year 2000, I have been thrilled to see such exciting progress overall in the field where there are substantial increases in patients’ duration and quality of life.  The accelerated approval of oral Xpovio targeting XPO1 represents the first approval against a new target in myeloma since 2015, and we look forward to advancing the further clinical development of Xpovio.”

https://pubchem.ncbi.nlm.nih.gov/compound/Selinexor

Onyx receives FDA approval for Kyprolis to treat multiple myeloma

 In continuation of my update on  Kyprolis.......

Onyx receives FDA approval for Kyprolis to treat multiple myeloma: The Multiple Myeloma Research Foundation (MMRF) today announced that its partner, Onyx Pharmaceuticals, Inc., received U.S. Food and Drug Administration (FDA) approval for Kyprolis (carfilzomib) for the treatment of patients with multiple myeloma who have received at least two prior therapies, including Velcade (bortezomib) for Injection and an immunomodulatory agent, such as Thalomid (thalidomide) or Revlimid (lenalidomide), and have demonstrated disease progression on or within 60 days of completion of the last therapy.....

ASCO 2015: AMGEN presents new data evaluating less-frequent dosing of kyprolis for multiple myeloma patients

Amgen announced the initiation of the ARROW trial, a global Phase 3 study evaluating the benefit of Kyprolis®(carfilzomib) for Injection administered once-weekly with dexamethasone versus the current U.S. Food and Drug Administration (FDA) approved twice-weekly administration schedule in patients with relapsed and refractory multiple myeloma who have received prior treatment with bortezomib and an immunomodulatory agent (IMiD). The trial was initiated based on results from the Phase 1/2 CHAMPION study, which were presented (abstract no. 8527) at the 51stAnnual Meeting of the American Society of Clinical Oncology (ASCO) on Sunday, May 31 at 8:00 a.m. CT.

Results from the Phase 1 and 2 portions of CHAMPION were presented for 104 patients (Phase 1, n=15; Phase 2, n=89) with relapsed or refractory multiple myeloma who had received one to three prior treatment regimens at the determined maximum tolerated dose (MTD) of 20/70 mg/m2. In the Phase 2 portion of the study, the overall response rate (ORR; defined as the percentage of patients achieving a partial response or better) was 77 percent. The clinical benefit rate (CBR; defined as the percentage of patients with minimal response or better) was 84 percent; the median time to response for patients who achieved a partial response or better was 1.6 months (range, 0.7-7.2); Kaplan-Meier median duration of response (DOR) was 15 months (95 percent CI 9-not estimable); and the Kaplan-Meier median progression-free survival (PFS) was 10.6 months (95 percent CI 9.0-16.1).

ASCO 2015: AMGEN presents new data evaluating less-frequent dosing of kyprolis for multiple myeloma patients

New three-drug combination for multiple myeloma ! ...

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.

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.

The more interesting part of the study is 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.

Except for the main adverse effect, peripheral neuropathy (numbness or pain in the extremities), which typically cleared up after dosages were lowered and the treatment was completed.

The combination has now gone into large phase 3 clinical trials, and the researchers think that this regimen has the potential to be a new standard of treatment in multiple myeloma....

http://www.dana-farber.org/abo/news/press/2009/multiple-myeloma-patients-experience-high-response-rate-with-new-three-drug-combination.html

Carfilzomib therapy shows promise for pre-kidney transplant patients

In continuation of my update on carfilzomib,

Early findings by researchers at the University of Cincinnati (UC) College of Medicine suggest that the use of a second generation cancer drug, carfilzomib, may provide an improved approach for the reduction of antibodies in potential kidney transplant candidates. The research team includes members from UC Transplant Clinical Research, UC's Division of Hematology Oncology and the Cincinnati Children's Hospital Medical Center's Biomedical Informatics division.

 carfilzomib

This pre-transplant drug therapy approach is aimed at reducing antibodies in kidney transplant candidates with greater success than with traditional methods and with reduced side effects.

Antibodies are Y-shaped proteins that in most instances are good because they help fight infection, but people can also make antibodies that work against other humans, which is often a major barrier to transplantation.

"Carfilzomib has been well tolerated by the first group of six study patients who experienced antibody reductions between 31 to 100 percent," says the study's lead author Simon Tremblay, PharmD, research associate in the UC College of Medicine's transplant research programs.

The study's preliminary findings will be presented at the annual American Transplant Congress on June 13, in Boston, Mass., where Tremblay will be awarded the American Transplant Society's Young Investigator award.

Since 2008, the UC research team has been developing therapies that target plasma cells—the cells that make antibodies. The first generation of drug therapy studied was the cancer drug bortezomib, a proteasome inhibitor that, like carfilzomib, is already approved by the Food and Drug Administration for treatment of multiple myeloma. In that 50 person study, which was published in 2015, a significant decrease in antibodies was observed. Furthermore, transplanted patients had low rejection rates and the chances of developing a new antibody against their kidney was also low. In addition, in some patients, antibodies remained suppressed for several months—something that has not previously been described with other approaches.

In the same scientific session, James Driscoll, MD, PhD, assistant professor in the UC College of Medicine's Division of Hematology Oncology, will present the results of translational research studies in the carfilzomib-treated patients. Driscoll will present new genomic data on plasma cells isolated from patients prior to and after receiving carfilzomib therapy.

"Our gene expression profiling studies in normal human plasma cells are giving us a detailed, comprehensive view of how plasma cells survive and avoid the death inducing effects of carfilzomib," says Driscoll. These studies, he says, were performed in collaboration with Bruce Aronow, PhD, at Cincinnati Children's.

Carfilzomib is one of four new regimens—described as "second-generation plasma cell targeted therapies that are being evaluated by the UC transplant Clinical Research Team, " says the principal investigator on both studies, E. Steve Woodle, MD, UC Health transplant surgeon and director of the division of transplantation at the UC College of Medicine.