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Source: Myeloma – Hematology Advisor

The Food and Drug Administration (FDA) has approved Abecma® (idecabtagene vicleucel; ide-cel) for the treatment of adult patients with relapsed or refractory multiple myeloma after 2 or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody (triple-class-refractory). This approval allows patients with relapsed/refractory multiple myeloma to receive the T-cell therapy earlier than previously indicated.

Abecma is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T-cell therapy. It is a customized treatment using the patient’s own T cells that have been genetically modified to include a new gene to target and destroy myeloma cells. Antigen-specific activation of Abecma results in CAR-positive T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

The expanded approval was based on data from the KarMMa-3 study (ClinicalTrials.gov Identifier: NCT03651128), which evaluated Abecma in patients with relapsed or refractory multiple myeloma who had received 2 to 4 lines of prior therapy. Study participants were randomly assigned to receive Abecma (n=254) or standard regimens (n=132). The primary endpoint was progression free survival (PFS); other measures included overall response rate and overall survival.

Results showed treatment with Abecma led to statistically significant improvement in PFS compared with standard regimens (hazard ratio, 0.49 [95% CI, 0.38-0.64]; P <.0001). Median PFS was 13.3 months (95% CI, 11.8-16.1) in the Abecma arm and 4.4 months (95% CI, 3.4-5.9) in the standard regimens arm. 

Overall response rate was 71% (95% CI, 66-77) with Abecma and 42% (95% CI, 33-50) with standard regimens (P <.0001). Median duration of response (DOR) was 14.8 months (95% CI, 12.0-18.6) in the Abecma group and 9.7 months (95% CI, 5.4-16.3) in the standard regimens group. In those patients with complete response or better, the median DOR was 20 months (95% CI, 15.8-24.3). At the time of data cutoff, overall survival data were immature.

“Abecma has demonstrated a progression free survival benefit 3 times that of standard regimens in relapsed or refractory multiple myeloma, and we are now bringing the promise of cell therapy to patients earlier in their treatment journey,” said Bryan Campbell, senior vice president, Head of Commercial, Cell Therapy, Bristol Myers Squibb.

As for safety, cytokine release syndrome occurred in 88% of patients who received Abecma; 5% of events were grade 3 or higher. Neurotoxic effects occurred in 15% of the Abecma-treated patients; 3% were grade 3 or higher.

The prescribing information for Abecma includes a Boxed Warning regarding the risk of cytokine release syndrome, neurologic toxicities, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged cytopenia, all of which can be fatal or life-threatening. It is available only through a restricted program called the Abecma REMS.

Abecma is administered as a single dose for infusion containing a suspension of CAR- positive T cells in 1 or more infusion bags. The new recommended dose range is 300 to 510 x 106 CAR-positive T cells.

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Source: Pharmacy Times articles

The approval expands the prior indication of idecabtagene vicleucel (Abecma; Bristol Myers Squibb), which will make the drug available to patients in earlier lines.
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Source: Pharmacy Times articles

FDA-approved BiTE therapies for relapsed/refractory multiple myeloma show promising response rates, offering off-the-shelf alternatives to CAR T therapy.
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Source: Myeloma – Hematology Advisor

Preventive photobiomodulation (PBM) appears to be more effective than a curative approach for mitigating the effects of oral mucositis (OM) among patients undergoing hematopoietic stem cell transplantation (HSCT) for multiple myeloma (MM), according to research published in Supportive Care in Cancer.

OM is associated with significant issues in this patient population, including systemic infection and consequent hospitalization. Moreover, this adverse event is associated with a significant amount of pain, and reduces patient quality of life.

PBM is increasingly becoming recognized as an effective strategy against OM, though protocols around PBM are not well established. For this retrospective study, researchers compared the safety and efficacy of curative vs preventive PBM against OM among patients with MM undergoing HSCT.

Overall, data from 24 patients were included, of whom 12 each received curative or preventive PBM. In the preventive and curative PBM groups, the mean ages were 59.3 and 55.9 years, respectively, 66.7% and 41.7% of patients were male gender, and transplantation engraftment rates were 100% and 100%. All patients developed OM.

Analysis showed that, after HSCT, preventive PBM was superior to curative PBM for reducing both OM severity and pain (both P <.0001). Patients in the preventive PBM group also reported lower rates of discomfort when swallowing, chewing, or speaking than did those in the curative PBM group. No adverse events deemed related to therapy were noted.

“With the limitation of the sample size, our results show how the timing for the beginning of PBM therapy in patients undergoing HSCT is crucial: when started on the first day of conditioning, it significantly reduces both pain and OM severity, providing an important benefit also in subjective oral functions such as speaking, swallowing, and chewing and increasing overall tolerance of the procedure,” the authors wrote in their report.

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Source: Pharmacy Times articles

Unlike conventional monoclonal antibodies, BsAbs possess dual binding domains that target 2 distinct antigens simultaneously.
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Source: Myeloma – Hematology Advisor

BCMA-directed chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies can produce transient responses in patients with multiple myeloma (MM) whose disease relapsed on prior BCMA-directed CAR T-cell therapy, according to research published in Blood Advances.

Researchers performed a retrospective analysis of 68 MM patients whose disease had relapsed after BCMA-directed CAR T-cell therapy. The patients had received CAR-T cell therapy on a clinical trial (n=48), commercial idecabtagene vicleucel (n=17), or commercial ciltacabtagene autoleucel (n=3). Overall, the patients had received a median of 7 prior lines of therapy (range, 1-14).

There were 58 patients who started another line of therapy after relapse on CAR-T therapy. They received a median of 2 salvage lines of therapy (range, 1-8).

The overall response rate (ORR) after first salvage therapy was 41%. The most common first salvage therapies were alkylator-containing therapy (n=13), CD38-based combination therapy (n=11), BCMA-directed bispecific antibodies (n=6), belantamab mafadotin (n=4), and CAR-T therapy (n=1). The median time spent on first-line salvage treatment was 2.2 months.

There were 34 patients who received at least 1 line of salvage BCMA-directed therapy after CAR-T relapse. The ORR was 55% in this group overall, 89% in patients who received another BCMA-directed CAR-T therapy, 60% in patients who received BCMA-directed bispecific antibodies, and 11% in patients who received belantamab mafadotin.

The median duration of response was 8 months with subsequent BCMA-directed CAR-T therapy, 4.4 months with bispecific antibodies, and 2.8 months with belantamab mafadotin. The median progression-free survival was 8.3 months, 3.6 months, and 1 month, respectively.

There was a trend toward improved overall survival (OS) in patients who received BCMA-directed CAR-T therapy or bispecific antibodies within 6 months of relapse. The median OS was not reached in these patients and was 16.5 months in patients who did not receive BCMA-directed CAR-T therapy or bispecific antibodies (P =.06).

“Our study shows that a variety of treatment regimens can be effective in eliciting hematologic responses after CAR-T therapies, including for classes of agents that patients were previously deemed refractory to,” the researchers wrote. “However, response durations continue to be limited. Novel therapies targeting new antigens continue to be needed for this patient population, and further studies are needed to determine the optimal sequencing and combinations to use in conjunction with BCMA-directed CAR T-cell therapy and after BCMA-directed CAR-T relapse.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

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Source: Myeloma – Hematology Advisor

In a meeting of the Oncologic Drugs Advisory Committee (ODAC), the committee of 11 members unanimously voted that the potential benefits of ciltacabtagene autoleucel (cilta-cel) outweigh its risks for its proposed indication.1 

The US Food and Drug Administration (FDA) convened the meeting on March 15, 2024, to obtain committee input on the results of the CARTITUDE-4 trial (ClinicalTrials.gov Identifier: NCT04181827). 

The trial data served as the primary evidence for a supplemental Biologics Licensing Application submitted by Janssen Biotech, Inc. for CARVYKTI (cilta-cel) for the treatment of relapsed or refractory multiple myeloma (MM) in adults who have received at least 1 line of therapy and are refractory to lenalidomide. 2 Participants who had received 1 to 3 prior lines of therapy for MM were randomly assigned to receive cilta-cel or standard care.

Unmet Need

Based on data from the phase 1b/2 study CARTITUDE-1 (ClinicalTrials.gov Identifier: NCT03548207), cilta-cel is currently approved in the United States for the treatment of relapsed or refractory MM in adults who have received 4 or more prior lines of therapy.3

In the presentation from Janssen Biotech, Inc., Irene Ghobrial, MD, professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School, outlined the current unmet need for the use of CAR-T therapy as early treatment in MM.

Dr Ghobrial cited data showing that 85% of multiple myeloma patients were unable to receive treatments beyond the third line of therapy. This underscores the need for administering effective treatments earlier in the disease course. “Initial treatment is the best chance for deep and durable remissions,” she said.  

Additionally, T-cells become exhausted with disease progression. Administering CAR-T therapy earlier in the disease course, when T-cells are less exhausted, is associated with better long-term outcomes, Dr Ghobrial noted.

The current standard care for MM patients is continuous treatment, which contributes to “added toxicity and added burden for the patient,” said Dr Ghobrial. A one-and-done treatment such as cilta-cel early in the disease course creates the opportunity for patients to achieve remission without having to undergo continuous, burdensome treatments. 

Trial Data

Jordan Schechter, MD, vice president of research and development for the Janssen Pharmaceutical Companies of Johnson & Johnson, presented data from CARTITUDE-4 at the meeting.1

Cilta-cel was associated with significant and meaningful PFS improvement compared to the standard care arm, and this finding was consistent across subgroups. Median PFS was not reached in the cilta-arm, while it was 11.8 months for the standard care arm.

Additionally, 85% of patients in the cilta-cel arm obtained a response, compared with 67% patients in the standard care arm. 

Dr Schecter addressed an increased risk for early death in the cilta-cel arm. “The only period in which we see more deaths in the experimental arm versus standard of care arm is between 0 and 3 months,” he stated. Before 3 months, there were 7 deaths in the cilta-arm and 1 death in the standard care arm. 

Dr Schechter noted that a cause for the disparity in early deaths prior to receiving treatment was disease progression in the cilta-cel arm, and not cilta-cel toxicity. For example, 6 out of the 7 deaths prior to 3 months were in patients randomized to cilta-cel, but who progressed prior to infusion with cilta-cel. Additionally, he noted that between 3 and 6 months, the OS curves began to balance and then trended towards fewer deaths in the cilta-cel arm. 

“The depth and durability of response observed with cilta-cel is something not observed with any other modality and is important for long-term outcomes such as progression-free survival and of course, overall survival,” said Dr Schecter.

FDA Concerns

The FDA raised concerns over the lower overall survival (OS) in the first 10 months of treatment in the cilta-cel arm compared to the standard care arm. In the first 10 months of treatment, 14% of patients died in the cilta-cel arm, whereas 12% died in the standard care arm. 

Additionally, 4.8% of patients in the cilta-cel arm died prior to receiving CAR-T therapy and 0.5% of patients in the standard care arm died before treatment.

“One might consider that since the subject did not receive cilta-cel, there is no treatment causality,” said Helkha Peredo-Pinto, MD, a clinical reviewer for the FDA, during the meeting. “However, it is [a] consequence of proceeding to receive treatment in the investigation arm. In this case, [the] CAR-T product, therefore, is relevant to the subject outcome.”

The FDA noted that it is the responsibility of Janssen Biotech, Inc. to demonstrate or prove that a more adequate bridging therapy regimen has the capacity to prevent death or early progression of disease. Additionally, the FDA stated that data is too immature to draw a conclusion about the OS benefit of cilta-cel.

“It represents a challenge for the agency to make a conclusive regulatory decision based solely on a speculative assessment of the benefit-risk profile rather than robust scientific evidence,” Dr Peredo-Pinto said.

Discussion

Based on the trial data, the FDA proposed 2 questions for the committee to discuss. These included: 

Whether the results of the CARTITUDE-4 trial are sufficient to support a positive risk-benefit assessment of cilta-cel for the proposed indication; and

Whether the risk of early death associated with cilta-cel treatment is acceptable in the context of the PFS benefit.

Some committee members mentioned that the imbalance in early OS seemed to be a case of front-loaded risk, and that providers should be encouraged to inform patients of this before treatment. 

“The curves really remind me of transplant related toxicities that are high early on,” said Mary Kwok, MD, clinical associate professor at the University of Washington School of Medicine.”

Additionally, some members mentioned that cilta-cel is an important consideration for early treatment because it would allow patients periods of nontreatment and a higher quality of life.

“We can’t understate the ability of individuals to have this period of nontreatment that allows them higher quality of life — that the data did support — and moving into a disease-free state,” Susan Lattimore, RN, a nonvoting member of the committee and consumer representative, stated during the meeting.

“The sense of the panel’s discussion here has been that there are issues upfront, but they are small, and perhaps balanced by the long-term benefits,” said Ravi Madan, MD, chair of ODAC, during the meeting. Dr Madan also noted that bridging therapy and protecting patients against infection are areas for further research and development to optimize cilta-cel treatment. 

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Source: Pharmacy Times articles

The study authors are hopeful that this finding can help in the development of new drugs or treatments for patients with multiple myeloma.
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