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23rd April 2024
A type II variation of ciltacabtagene autoleucel (cilta-cel; brand name Carvykti) has been approved by the European Commission (EC) for use in the treatment of eligible patients with multiple myeloma, its manufacturer Janssen has announced.
Cilta-cel has been recommended for adult patients with relapsed and refractory (R/R) multiple myeloma, who have received at least one prior therapy including an immunomodulatory agent and a proteasome inhibitor, have demonstrated disease progression on the last therapy, and are refractory to lenalidomide.
Cilta-cel is a chimeric antigen receptor (CAR) T-cell therapy directed against B-cell maturation antigen (BCMA) and is the first BCMA CAR-T therapy approved in Europe for the treatment of eligible patients as early as first relapse.
The approval follows a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use in March 2024.
Professor Jesús San Miguel, director of clinical & translational medicine at the University of Navarra in Pamplona, Spain, said: ‘Patients with lenalidomide-refractory multiple myeloma tend to experience early resistance to standard treatments and their disease worsens exponentially with each additional line of therapy.
‘A single infusion of cilta-cel has been shown to significantly lower the risk of progression or death compared to current treatment options, as early as after first relapse.’
The EC approval was based on the results of a phase 3 CARTITUDE-4 clinical trial evaluating the efficacy and safety of cilta-cel in patients with relapsed and lenalidomide-refractory multiple myeloma.
Data from the study were previously published in the New England Journal of Medicine.
The primary endpoint was progression-free survival (PFS), defined as the time from randomisation to the first documentation of disease progression or death.
In total, 419 patients with relapsed and lenalidomide-refractory multiple myeloma who had received one to three prior lines of therapy underwent randomisation.
Patients were randomised to receive either a sequence of apheresis, bridging therapy, lymphodepletion and cilta-cel (n=208) or standard of care, which included daratumumab, pomalidomide and dexamethasone (DPd) or pomalidomide, bortezomib and dexamethasone (PVd) (n=211).
At a median follow-up of 15.9 months, a single infusion of cilta-cel gave rise to a significantly lower risk of disease progression or death compared to standard care (hazard ratio, HR = 0.26, 95% CI 0.18 – 0.38, p < 0.001).
The median duration of PFS was not reached in the cilta-cel arm and was 11.8 months in the standard care arm (95% CI, 10-14).
After 12 months, PFS was 75.9% (95% CI 69.4 – 81.1) in the cilta-cel group and 48.6% (95% CI 41.5 – 55.3) in the standard care group. In addition, a higher proportion of patients in the cilta-cel group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs 21.8%) and an absence of minimal residual disease (60.6% vs. 15.6%).
In terms of safety, Grade 3 or 4 adverse events occurred in a similar proportion of participants in the two groups (96.6% vs 94.2%, cilta-cel vs standard care).
13th March 2024
A type II variation of ciltacabtagene autoleucel (cilta-cel; brand name Carvykti) has received a positive opinion from the European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) for use in the treatment of eligible patients with multiple myeloma, its manufacturer Janssen has announced.
Cilta-cel has been recommended for adult patients with relapsed and refractory (R/R) multiple myeloma, who have received at least one prior therapy including an immunomodulatory agent and a proteasome inhibitor, demonstrated disease progression on the last therapy, and are refractory to lenalidomide.
Cilta-cel is a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy and is the first CAR T-cell therapy to receive a positive CHMP opinion for this patient population as early as second line.
It is currently approved under conditional marketing authorisation in the EU for the treatment of adults with R/R multiple myeloma, after three prior lines of therapy.
Edmond Chan, EMEA lead for haematology at Janssen-Cilag, said: ‘Early resistance to standard treatments is becoming more common in patients with lenalidomide-refractory multiple myeloma, highlighting a need for new options earlier in the course of treatment.’
He added that the CHMP recommendation ‘recognises the potential of cilta-cel to significantly improve outcomes for eligible patients with relapsed and refractory multiple myeloma, as early as after first relapse.’
The CHMP recommendation was based on the results of a phase 3 CARTITUDE-4 clinical trial comparing the CAR T-cell therapy directed against b-cell maturation antigen versus the standard care treatment, which was the physician’s choice of pomalidomide, bortezomib and dexamethasone or daratumumab, pomalidomide and dexamethasone.
The primary endpoint was progression-free survival, defined as the time from randomisation to the first documentation of disease progression or death.
In total, 419 patients with relapsed and lenalidomide-refractory multiple myeloma who had received one to three prior lines of therapy underwent randomisation, with 208 (mean age 61.5 years, 55.8% male) receiving cilta-cel.
Cilta-cel treatment gave rise to a significantly lower risk of disease progression or death compared to standard care (hazard ratio, HR = 0.26, 95% CI 0.18 – 0.38, p < 0.001).
After 12 months, PFS was 75.9% (95% CI 69.4 – 81.1) in the cilta-cel group and 48.6% (95% CI 41.5 – 55.3) in the standard care group. In addition, a higher proportion of patients in the cilta-cel group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%) and an absence of minimal residual disease (60.6% vs. 15.6%).
In terms of safety, Grade 3 or 4 adverse events occurred in a similar proportion of participants in the two groups (96.6% vs 94.2%, cilta-cel vs standard care).
24th August 2023
Talquetamab has been granted a conditional marketing authorisation by the European Commission as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma.
Talquetamab (brand name Talvey) is approved as a weekly or biweekly subcutaneous injection after an initial step-up phase. It can be used as monotherapy for the treatment of patients relapsed and refractory multiple myeloma who have had an inadequate response to at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody. They must also have demonstrated disease progression on the last treatment.
The treatment is a bispecific engaging antibody that binds to CD3, on the surface of T-cells, and G protein-coupled receptor class C group 5 member D (GPRC5D), a novel target highly expressed on the surface of multiple myeloma cells and hard keratinised tissues.
Multiple myeloma is a malignancy of terminally differentiated plasma cells that typically presents with bone marrow infiltration of clonal plasma cells and monoclonal protein in the serum and/or urine.
Commenting on the EC decision, Edmond Chan, senior director EMEA therapeutic area lead haematology, Janssen-Cilag Limited, said: ‘[This] brings a new off-the-shelf option, with a novel cellular target and the immediate option of biweekly dosing, to an area of high unmet clinical need.
‘The high overall response rates in patients with heavily pretreated multiple myeloma, including those with prior T-cell redirection therapy, are encouraging, and we believe talquetamab has the potential to offer physicians flexibility and versatility when determining the optimal treatment regimen for their patients.‘
The EC approval follows a similar FDA approval in the US in August 2023.
The talquetamab approval was based on efficacy data from the phase 1 and phase 2 MonumenTAL-1 study. In the trial, patients had received a median of five prior lines of therapy and talquetamab was given at a weekly dose of 0.4 mg/kg or biweekly 0.8 mg/kg.
For both dosage regimens, patients showed meaningful overall response rates. After a median follow-up of 12.7 months, 71.7% of response-evaluable patients treated at the 0.8 mg/kg biweekly dose achieved a response. Some 60.8% achieved a very good partial response (VGPR) or better and 38.7% achieved a complete response (CR) or better.
After a median follow-up of 18.8 months, 74.1% of response-evaluable patients treated with the 0.4 mg/kg weekly dose of talquetamab achieved a response; 59.5% a VGPR or better and 33.6% achieved a CR or better.
An estimated 76.3% and 51.5% of patients maintained a response for at least nine months at the 0.8 mg/kg biweekly and 0.4 mg/kg weekly talquetamab doses, respectively.
Maria-Victoria Mateos, consultant physician in haematology at the University Hospital of Salamanca in Spain, said: ‘As multiple myeloma progresses and patients cycle through treatments, the disease becomes
more difficult to treat and remission periods shorten. Targeting GPRC5D has been shown to deliver deep responses, and unlike many other targets for multiple myeloma, its expression is limited on immune cells providing an important new approach to targeting this heterogenous disease.‘
15th June 2023
Selinexor triple therapy with bortezomib and dexamethasone, provides a clinically meaningful improvement in overall survival in lenalidomide-refractory patients with multiple myeloma, according to a study presented at the 2023 European Haematology Association (EHA) Congress.
Among newly diagnosed adults with multiple myeloma, first-line treatment options is lenalidomide. One potential treatment option if patients become lenalidomide-refractory is the use of selinexor. The drug is a potent, orally administered exportin 1 inhibitor, the action of which blocks nuclear export of tumour suppressor, growth regulatory and anti-inflammatory proteins. This leads to accumulation of these proteins in the nucleus, enhancing their anti-cancer activity in the cell.
The BOSTON trial in 2020 demonstrated how selinexor triple therapy (with bortezomib, and dexamethasone) was effective in patients with multiple myeloma who had received one to three previous lines of therapy.
For the study presented at the EHA Congress 2023, researchers undertook a subgroup analysis of data from the BOSTON trial. They focused on the impact being lenalidomide-refractory and how this affected the effectiveness and safety of either selinexor triple therapy (SVd) – comprising selinexor 100 mg, bortezomib and dexamethasone – or standard therapy (Vd) of bortezomib and dexamethasone only. The outcomes of interest were both progression-free survival (PFS) and overall survival (OS), but researchers also examined the objective response rate (ORR) and the very good partial response (VGPR).
Among a total of 402 patients, 106 were classified as lenalidomide-refractory and equally distributed between the two therapy arms, with 53 in each.
The median PFS was significantly longer for the SVd group (10.2 vs 7.1 months, hazard ratio, HR = 0.52, 95% CI 0.31 – 0.88, p = 0.012). In addition, the median OS was also statistically significant, representing clinically meaningful improvement for the SVd group (HR = 0.53, 95% CI 0.30 – 0.95, p = 0.03).
Patients assigned to selinexor also had a higher ORR (67.9% vs 47.2%) and a higher VGPR or better (35.8% vs 24.5%).
The most common treatment-emergent adverse events, defined as affecting more than a quarter of patients, with SVd and Vd, were thrombocytopenia (71.7% vs 40.4%), nausea (50.9% vs 11.5%), fatigue (45.3% vs 21.1%), diarrhoea (43.4% vs 19.2%), anaemia (39.6% vs 25.0%), and peripheral neuropathy (30.2% vs 38.5%).
Commenting on these findings at EHA, the presenting author, Professor Maria-Victoria Mateos said ‘The data presented emphasise the synergy between selinexor and bortezomib, highlighting the importance of a double mode of action switch. These results are particularly relevant considering the increased use of the daratumumab lenalidomide dexamethasone combination in clinical practice today,
‘These findings further support the use of selinexor in combination with bortezomib in proteasome inhibitor/bortezomib-naïve or lenalidomide-refractory relapsed refractory multiple myeloma patients, as well as for patients at first relapse.’
9th June 2023
A cilta-cel infusion lowers the risk of disease progression or death compared to standard care in lenalidomide-refractory patients with multiple myeloma, according to the findings of a recent randomised trial.
Multiple myeloma represents a malignant disease of plasma cells with a worldwide incidence of 6-7 cases per 100 000 persons per year. Lenalidomide is an immunomodulatory drug for maintenance treatment in newly diagnosed multiple myeloma which improves progression-free survival (PFS). But when patients fail to respond to lenalidomide, what is the most appropriate therapy?
This was the question addressed in a recent study published in the New England Journal of Medicine. Researchers undertook a randomised trial of cilta-cel – a B-cell maturation antigen-directed CAR-T cell therapy – in patients with lenalidomide-refractory disease.
All participants had received one to three prior therapies and were equally randomised to either cilta-cel or the physician’s choice of effective standard care. The physician’s standard care was pomalidomide, bortezomib and dexamethasone, or daratumumab, pomalidomide and dexamethasone. Researchers set the primary outcome as PFS, defined as the time from randomisation to the first documentation of disease progression or death.
In total, 419 patients underwent randomisation, with 208 (mean age 61.5 years, 55.8% male) receiving cilta-cel.
Cilta-cel treatment gave rise to a a significantly lower risk of disease progression or death compared to standard care (hazard ratio, HR = 0.26, 95% CI 0.18 – 0.38, p < 0.001).
After 12 months, PFS was 75.9% (95% CI 69.4 – 81.1) in the cilta-cel group and 48.6% (95% CI 41.5 – 55.3) in the standard care group. In addition, a higher proportion of patients in the cilta-cel group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%) and an absence of minimal residual disease (60.6% vs. 15.6%).
In terms of safety, Grade 3 or 4 adverse events occurred in a similar proportion of participants in the two groups (96.6% vs 94.2%, cilta-cel vs standard care).
17th February 2023
In a randomised controlled trial, an international group of researchers showed that the CAR T-cell therapy, Ide-cel (idecabtagene vicleucel) gave rise to greater progression-free survival than any of five other standard regimens in heavily pre-treated patients with relapsed or refractory multiple myeloma.
Although treatments for multiple myeloma have improved in recent years, evidence suggests that around 16% of patients relapse after 8 months of treatment. Nevertheless, while CD38-targeting monoclonal antibodies have made a significant impact to the treatment of patients with multiple myeloma (MM), those who a refractory to this regime have a poor prognosis. The use of CAR T-cell therapies directed against the B-cell maturation antigen (BCMA) expressed on myeloma cells, have proven to be effective in MM. In fact, one Phase II trial in which Ide-cel was given to relapsed or refractory MM patients, generated a response in over 70% of patients, with 33% experiencing a complete response. While CAR T-cell therapy clearly works in relapsed/refractory MM, there is an absence of comparative studies of the treatment compared to other regimes.
In the current study, researchers recruited MM patients who were refractory to between two and four prior regimes. Eligible participants were then randomised 2:1 to Ide-cel or one of five standard regimens and which included immunomodulatory agents, proteasome inhibitors and daratumumab. The primary endpoint was set as progression-free survival whereas secondary endpoints included the overall response and survival.
Ide-cel and progression-free survival
A total of 386 patients with a median age of 63 years (60.5% male) received either Ide-cel (254) or one of the standard regimes. Among the entire cohort, 66% had triple-class refractory disease and 95% daratumumab-refractory disease.
After a median of 18.6 months follow-up, the median progression-free survival in the Ide-cel group was 13.3 months compared to 4.4 months in the standard regime groups (hazard ratio for disease progression or death, HR = 0.49, 95% CI 0.38 – 0.65, p < 0.001). In fact, 12-month progression-free survival was 55% for Ide-cel but only 30% in the standard regimen. Furthermore, a complete response occurred in 39% of the intervention group and on 5% in the standard therapy group. Data on overall survival were immature. In addition, adverse effects of either grade 3 or 4 were more frequent in the Ide-cel group (93% vs 75).
Based on these results, the authors concluded that Ide-cel gave rise to an improved response compared to standard therapy in patients who failed to respond to two to four prior regimens.
Citation
Rodriguez-Otero P et al. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med 2023
21st December 2022
Data presented at the 64th American Society of Haematology (ASH) conference in New Orleans, showed that elranatamab is efficacious and has a manageable safety profile in patients with relapsed or refractory multiple myeloma (RRMM).
Multiple myeloma (MM) is a clonal plasma cell proliferative disorder characterised by the abnormal increase of monoclonal immunoglobulins and which if left unchecked, can ultimately lead to specific end-organ damage. It is an uncommon cancer, with the global, age-standardised rate incidence estimated to be 1·78 per 100 000 people but with a mortality rate of 1·14 (95% UI 1·07-1·21) per 100 000 people in 2020. Most patients present with symptoms related to organ involvement, including hypercalcaemia, renal insufficiency, anaemia, and bone lesions (known as calcium, renal failure, anaemia, and bone lesions [CRAB] symptoms). In contrast, a minority of patients are asymptomatic but are identified through abnormal blood and/or urine tests.
At the ASH conference, data were presented for elranatamab, which is a bispecific antibody that targets expression of B-cell maturation antigen (BCMA) and CD3 on T-cells, activates and redirects the T-cell mediated immune response against MM. The findings come from the MagnetisMM-1 trial designed to assess the safety and tolerability at increasing dose levels of elranatamab in patients with relapse/ refractory multiple myeloma in order to determine the maximum tolerated dose and select the recommended Phase 2 dose. Within the trial, elranatamab was administered subcutaneously at doses from 80 to 1000µg/kg either weekly or every 2 weeks.
Elranatamab clinical response
A total of 55 patients with a median age of 64 years and of whom, 27% were Black/African American or Asian, received elranatamab at a dose ≥215μg/kg. The median number of prior regimens was 5 (range 2-14) with 91% being triple-class refractory, 69% of whom had prior stem cell transplantation, 29% had a high cytogenetic risk and 24% received prior BCMA-targeted therapy.
After a median follow-up of 12.0 months and including only those with an International Myeloma Working Group (IMWC) confirmed responses, the objective response rate (ORR) was 64% (95% CI 50 – 75%) and with 56% of participants achieving very good partial response (VGPR) or better and 38% achieving complete response (CR) or better.
Among 35 responders, the probability of being event-free at 12 months was 59% (95% CI 39-74%) and the Kaplan-Meier estimate for the median duration of response was 17.1 months (95% CI 10.6 – not estimable). Elranatamab induced durable clinical and molecular responses and 100% (12/12) of evaluable patients with confirmed CR or better achieved minimal residual disease (MRD) negativity at a sensitivity of 1×10-5 including 2 participants with MRD negativity and ongoing stringent complete response beyond 2 years.
The most common treatment-emergent adverse effects included the cytokine release syndrome in 67% of participants but this was limited to grade 1 (33%) or grade 2 (33%) severity with no grade 3 or higher responses.
The authors concluded that elranatamab induced durable clinical and molecular responses for patients with relapsed or refractory MM, with an ORR of 64% and more than half of these patients (38%) achieving CR or better, and 100% of evaluable patients able to achieve MRD negativity. They added that these results support further development of elranatamab for patients with MM.
Citation
Raje N et al. Elranatamab, a BCMA Targeted T-Cell Engaging Bispecific Antibody, Induces Durable Clinical and Molecular Responses for Patients with Relapsed or Refractory Multiple Myeloma. Abstract No 158, ASH 2022
16th December 2021
The screening of older black patients or those with a first-degree relative who has a haematological cancer led to the detection of monoclonal gammopathy of undetermined significance (MGUS), which is a precursor to multiple myeloma (MM). This was the conclusion of a study by a researchers from the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, US, presented at ASH 2021.
MGUS a benign condition which is usually diagnosed incidentally when tests are performed to investigate other problems although MGUS is a precursor to multiple myeloma in around 1% of cases. However, the prevalence of MGUS has not been described in a population at high risk of developing MM, in particular, Black/African American (AA) individuals or first-degree relatives of patients with haematologic malignancies (HM).
In 2019, the US researchers launched the first nationwide US (PROMISE) screening older black patients study for individuals at high risk of MM to help better identify what population would benefit most from screening and early intervention for precursor MM stages. The overarching aim of the study is to assess the prevalence of MGUS in a high risk population and to characterise the clinical variables of individuals who screen positive. For the present study, the researchers reported on screening data available for the first 2960 participants.
The researcher team recruited individuals aged 40 or older with an additional MM risk factor which included Black/AAs and those with a first-degree relative diagnosed with a haematologic malignancy or a precursor condition to MM. Blood from all participants was analysed to measure the serum free light chains (sFLC), IgG, IgA and IgM. In addition and for comparative purposes, the team also identified and screened additional individuals from the Mass General Brigham (MGB) Biobank who met the PROMISE enrolment criteria. The researchers measured Heavy-Chain MGUS (HC-MGUS) as a marker for MGUS.
Findings
Screening older black patients occurred with 2960 individuals participants (1092 from PROMISE). The overall prevalence of HC-MGUS was 9.6% (95% CI 8.6 – 11%) and 10% (95% CI 8.3-12%) in PROMISE and 9.4% (95% CI 8.1 – 11%) in the MGB cohort.
The prevalence of HC-MGUS increased with age in high-risk individuals from 4.9% (CI 3.3 – 6.9%) for participants aged 40-49 to 13% (95% CI 10 – 17%) in the 70-79 range (P < 0.005 ). Among monoclonal HC-MGUS, they detected 65% IgG, 18% IgM, and 18% IgA. M-spike was quantified in 97% of samples.
The authors concluded that screening older black patients or those who have a first-degree relative with an HM have a high prevalence MGUS and may therefore benefit from precision screening approaches to allow for early detection and clinical intervention.
Citation
El-Khoury H et al. High Prevalence of Monoclonal Gammopathy in a Population at Risk: The First Results of the Promise Study. ASH Conference 2021
13th December 2021
Addition of isatuximab to standard induction chemotherapy in patients with multiple myeloma (MM) produces superior minimal residual disease negativity in patients with multiple myeloma. This was the finding of a study by a team from the University Hospital Heidelberg and National Center of Tumour Diseases, Heidelberg, Germany, and presented at ASH 2021.
In newly-diagnosed MM patients, lenalidomide / bortezomib/ dexamethasone (RVd) has become one of the most widely used combination induction regimens. CD38 antigen is highly and uniformly expressed on plasma cells and has therefore become an ideal target for the treatment of MM with anti-CD38 monoclonal antibodies-CD38 such as isatuximab.
The German researchers have now presented the first primary endpoint data of the randomised, open-label, multicentre, Phase III GMMG-HD7 trial, designed to compare RVd without or with the isatuximab (isa) with respect to the rate of minimal residual disease (MRD) negativity (i.e., no evidence of cancer in the bone marrow) induction therapy in patients with transplant-eligible MM. The primary endpoint of the trial was MRD negativity assessed by next-generation flow after induction and the secondary endpoint was the rate of complete response (CR) after induction as well as safety data.
Findings
A total of 658 patients were started induction (RVd: 329/328 and Isatuximab-RVd: 331/330) with a median age of 58 years and baseline characteristics were well balanced between treatment arms. On induction, 35 (10.6%) and 18 (5.4%) patients discontinued treatment in the RVd vs. Isa-RVd arms (p = 0.02). Among these, 8 (2.4%, RVd) vs. 7 (2.1%, Isa-RVd) patients discontinued induction due to adverse events (AE). 293 (89.1%) vs. 312 (94.3%) patients in the RVd vs. Isa-RVd arms continued further study treatment after induction.
MRD negativity rates after induction were 35.6% vs. 50.1% (RVd vs. Isa-RVd), giving an odds ratio, OR = 1.83 (95% CI 1.34-2.51, p<0.001). While the rates of CR after induction did not yet differ between the RVd vs. Isa-RVd arms (21.6% vs. 24.2%, p = 0.46), the rate of very good partial response or better was significantly higher in the Isatuximab-RVd arm (60.5% vs. 77.3%, p < 0.001). The rates of progressive disease were 4.0% (RVd) vs. 1.5% (Isa-RVd).
With respect to safety there was no significant difference with at least one adverse event (grade ≥3) on induction which occurred in 61.3% (RVd) and 63.6% (Isa-RVd) of patients (p = 0.57). Rates of serious adverse events on induction were also between the two groups (36.3% vs. 34.8%, RVd vs. Isa-RVd p = 0.75).
The authors concluded that the GMMG-HD7 trial demonstrated superiority of MRD negativity rates after induction by adding isatuximab to RVd. They added that the trial is ongoing, including analyses post autologous transplantation, which is followed by a second randomisation to compare the efficacy of the addition of Isa to lenalidomide maintenance.
Citation
Goldschmidt H et al. Addition of Isatuximab to Lenalidomide, Bortezomib and Dexamethasone As Induction Therapy for Newly-Diagnosed, Transplant-Eligible Multiple Myeloma Patients: The Phase III GMMG-HD7 Trial. ASH conference 2021
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