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    Once-weekly Kyprolis with Dexamethasone Approved in US for Relapsed or Refractory Multiple Myeloma

    The U.S. Food and Drug Administration has approved a combination of once-weekly Kyprolis (carfilzomib), developed by Amgen, and dexamethasone for the treatment of multiple myeloma patients who failed prior therapies.

    “In the fight against multiple myeloma, we are committed to continued evidence generation and innovation to serve patients. Kyprolis now offers patients with relapsed or refractory multiple myeloma the option of a more convenient dosing regimen that provides better outcomes with a comparable safety profile,” David M. Reese, MD, executive vice president of research and development at Amgen, said in a press release.

    “We’re pleased that the FDA has recognized the importance of bringing more treatment options to cancer patients more quickly through its pilot programs and proud to participate with this Kyprolis data,” he said.

    The application, which was granted priority review, was approved in just over a month under the FDA’s Oncology Center of Excellence Real-Time Oncology Review and Assessment Aid pilot programs, focusing on the early submission of the most relevant data for assessing the safety and effectiveness of a given therapy in order to make new treatments available to patients as soon as possible.

    Kyprolis is a proteasome inhibitor. Proteasomes are barrel-shaped cellular structures that degrade misfolded, “used,” and nonfunctional proteins that have been molecularly tagged for destruction, acting as the cell’s protein garbage disposal.

    Proteasome inhibitors are particularly useful for treating multiple myeloma because they stop the protein clearance process, leading to “bad” protein buildup, which causes malignant cells to blow up and die.

    The FDA’s decision was based on data from Amgen’s Phase 3 ARROW trial (NCT02412878), aimed at comparing once-weekly and twice-weekly Kyprolis dosing, in combination with dexamethasone, in patients with multiple myeloma who had received between two and three prior lines of therapy, including Takeda‘s Velcade (bortezomib) and an immunomodulatory imide drug (IMiD).

    Velcade is another proteasome inhibitor, while IMiD modulates the molecular interaction between myeloma cells and its surroundings, leading to decreased myeloma cell growth and survival.

    A total of 478 subjects were randomized to receive a 30-minute infusion of Kyprolis (20 mg/m2 on day 1 and 70 mg/m2 thereafter) once a week plus dexamethasone (40 mg), or a 10-minute infusion twice weekly (20 mg/m2 on day 1 and 27 mg/m2 thereafter), also with dexamethasone.

    The study’s primary goals were to determine the overall response rate and progression-free survival, which refers to the time from randomization to disease worsening or death due to any cause.

    Results of the trial were published in The Lancet Oncology in the study, “Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study.”

    Findings were also presented by Amgen at the 54th Annual Meeting of the American Society of Clinical Oncology held in June in Chicago.

    Researchers reported that patients treated with Kyprolis once a week lived significantly longer without disease progression than those receiving the biweekly treatment (11.2 months vs. 7.6 months).

    Overall response rate was also higher in the once-weekly group than the biweekly one (62.9% vs. 40.8%).

    Additionally, 7.1% of the participants in the once-weekly regimen had no evidence of disease after treatment, in contrast with only 1.7% of patients in the twice-weekly protocol.

    In both groups, the most frequent side effects were anemia, diarrhea, fatigue, high blood pressure, insomnia, and fever.

    “While great progress has been made in the last decade, multiple myeloma remains an incurable disease characterized by a recurring pattern of remission and relapse, and it is important that patients have treatment options that meet their individual needs,” said David S. Siegel, MD, PhD, chief of the Division of Multiple Myeloma at John Theuer Cancer Center at Hackensack University Medical Center.

    “The availability of a more convenient once-weekly dosing regimen, with superior efficacy, comparable safety, and longer duration of therapy versus the twice-weekly regimen studied in the trial could allow patients to spend more time outside of the infusion center,” he said.

    Of note, Kyprolis is not approved for twice-weekly 27 mg/m2 administration in combination with dexamethasone alone.

    From Myeloma REsearch News

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    EMA Begins Review Process for Empliciti Triple Combo for Relapsed or Refractory Multiple Myeloma

    The European Medicines Agency has validated Bristol-Myers Squibb’s application for Empliciti (elotuzumab), in combination with Pomalyst (pomalidomide) and low-dose dexamethasone, for the treatment of adults with multiple myeloma.

    Validation confirms that the submission is complete and signals the beginning of the EMA’s review process.

    The company’s type-II variation application is intended for the treatment of patients who have received at least two previous therapies, including Revlimid (lenalidomide), by Celgene, and a type of therapy called a proteasome inhibitor — which cause the buildup of faulty proteins inside cells, triggering their death — and showed disease progression on the last therapy.

    “Given the need for new treatment options for patients with multiple myeloma, we look forward to working closely with the EMA as they review this application,” Fouad Namouni, MD, Bristol-Myers Squibb’s head of the oncology development, said in a press release. “It is our hope that this new Empliciti-based combination will soon become available for patients in the European Union with multiple myeloma.”

    Bristol-Myers Squibb’s application is based on results of the randomized Phase 2 ELOQUENT-3 clinical trial (NCT02654132), which assessed the triple combination versus Celgene’s Pomalyst (marketed as Imnovid in Europe) and dexamethasone alone in 117 patients with relapsed or refractory multiple myeloma.

    Of these patients, 60 were randomly assigned to the triple therapy and 57 to Pomalyst and dexamethasone alone, which was the control group.

    Empliciti was administered directly into the bloodstream at 10 mg/kg weekly over the first two cycles — lasting four weeks each — and 20 mg/kg monthly starting from cycle three. Revlimid was given at a daily 4 mg dose and dexamethasone at a weekly equivalent of 20 mg, for patients older than 75, or 40 mg, for patients 75 or younger.

    Results, presented at the 23rd Congress of the European Hematology Association in June, showed that adding Empliciti to Pomalyst and dexamethasone significantly delayed disease worsening or death. Patients on the triple therapy lived for a median of 10.3 months without their disease progressing versus 4.7 months for those in the control group, representing a 46% reduction in the risk of disease progression or death.

    Delayed disease progression was consistent across patients who failed to respond to two to three and four or more previous treatments with Revlimid and a proteasome inhibitor. Additionally, the overall response rate was superior in the triple combination — 53% versus 26%.

    The study, conducted by Bristol-Myers Squibb, in collaboration with Celgene and AbbVie — which co-develops Empliciti — also demonstrated that the triple therapy had an acceptable safety profile. Rates of adverse events (38% and 42%) and the percentage of patients stopping treatment (18 and 24%) were comparable between the two groups.

    In August, the triple combination was granted priority review by the U.S. Food and Drug Administration as a treatment for the same patient population.

    Empliciti is an antibody that specifically targets and binds to a molecule known as SLAMF7, which is found on the surface of both myeloma cells and a type of immune cell called natural killer cells, which help destroy tumors. The potential medication binds to natural killer cells to activate the immune system and to myeloma cells to tag them for natural killer cell-mediated destruction.
    From Myeloma Research News>>

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    Some with Smoldering Multiple Myeloma May Benefit from Immediate Treatment, Study Suggests

    Smoldering multiple myeloma (SMM) — an early, asymptomatic precursor of multiple myeloma — often exhibits similar genetic alterations as the full-blown disease, suggesting that patients could benefit from prompt treatment instead of waiting for symptoms to develop, research shows.

    The findings are paving the way for tests designed to identify patients with SMM who already have the genetic mutations characteristic of multiple myeloma and are at high risk of disease progression.

    The study, “Genomic patterns of progression in smoldering multiple myeloma,” was published in Nature Communications.

    Smoldering multiple myeloma, a condition that usually precedes myeloma, is characterized by the rapid growth of plasma cells — the same type of blood cells that cause myeloma — that are still in a “premalignant state” and lack some features of “true” cancer cells.

    SMM is puzzling to scientists because of its high degree of heterogeneity: while a percentage of patients diagnosed with SMM progress to symptomatic myeloma in a short period of time, there are others who experience practically no symptoms and whose disease comes to a halt or advances very slowly.

    Now investigators, led by Nikhil Munshi, MD, PhD at the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute in Boston, may have found the reason behind SMM variability and set the path for the development of tests to predict disease progression for individual patients.

    The study enrolled 11 patients with SMM who developed myeloma within three years of diagnosis.

    To analyze genetic alterations in plasma cells throughout disease progression, researchers collected different sets of samples: one when patients had been diagnosed with SMM and another after their myeloma diagnosis. Scientists then sequenced the genome of plasma cells to look for differences between the two stages of disease.

    With this approach, researchers first found that the genetic composition of premalignant plasma cells in SMM is almost identical to that of myeloma cells.

    They also described how SMM can progress in two ways: one in which the genetic composition of plasma cells practically does not change from SMM to myeloma and disease progression is rather fast (static progression model); and another in which the evolution of SMM to myeloma is accompanied by the appearance of new types of genetically different plasma cells and disease progression is usually slower.

    “Our study shows, however, when the disease follows the static progression model, SMM is, from a genomic standpoint, myeloma. The advance of the disease is solely a matter of an accumulation of diseased tissue. For such patients, it may make sense to begin treatment soon,” Munshi, the senior author of the study, said in a press release.

    “In the spontaneous evolution model, by contrast, SMM is genomically distinct from myeloma,” Munshi added. “It advances toward myeloma only when genetic mutations create new subsets of SMM cells that develop into myeloma. Treatment for such patients might involve agents that prevent such subsets from arising.”

    Although it is not yet possible to determine whether a particular patient diagnosed with SMM will follow the static progression or spontaneous evolution model, Munshi said his team and collaborators are focusing their efforts to drive research further.

    “These results suggest that multiple myeloma needs to be redefined to include some patients with smoldering myeloma, and points the way to new treatment approaches geared to the course of disease development in each patient,” Munshi said.
    From Myeloma Research News

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    This is a description of a clinical trial for smoldering myeloma. Has anyone been enrolled in this?

    It includes Daratumumab, Carfilzomib, Lenalidomide, Dexamethasone and it’s more aggressive than what they do for myeloma patients. The goal is never to get Myeloma and it lasts 2 years. First 2 months insane. First 6 months crazy includes stem cell collection just Incase. Then after 6 months, less drugs. After a year less and after 2 years Nothing.