Blood cancers

Myeloma – three research highlights from ASCO 2022

Genomic studies promising future targeted therapy for multiple myeloma along with clinical trials of stem cell transplantation in newly diagnosed disease and bispecific antibodies in relapsed or refractory disease were just some of the research highlights presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

ASCT benefit

In the phase 3 DETERMINATION study, concurrently published in the NEJM, researchers confirmed the superiority of ASCT-based first-line therapy with respect to progression-free survival (PFS) among eligible patients with newly diagnosed myeloma.

Their study comprised 722 newly diagnosed patients (median age 56 yrs) who had received an initial induction cycle of lenalidomide, bortezomib, and dexamethasone (RVD) and were then randomised to either RVD alone (8 cycles in total) or RVD plus ASCT (2 additional cycles of RVD then melphalen and ASCT followed by two more cycles of RVD). Maintenance therapy in both groups consisted of daily lenalidomide.

The study found the risk of disease progression or death was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% CI, 1.23 to 1.91; P<0.001) at a median follow-up of 76 months.

“The median duration of progression-free survival was 46.2 months (95% CI, 38.1 to 53.7) in the RVD-alone group and 67.5 months (95% CI, 58.6 to not reached) in the transplantation group,” the NEJM article said.

The median PFS among patients with a high-risk cytogenetic profile was 17.1 months in the RVD-alone group and 55.5 months in the transplantation group.

However there was no difference between the RVD-alone and RVD plus ACSCT groups in the estimated 5-year survival rates (79.2% v 80.7%, HR for death, 1.10; 95% CI, 0.73 to 1.65; P>0.99).

The US researchers said their results confirm those of the IFM 2009 trial and give a better understanding of the timing of stem cell treatment and its evolving role in an era of novel therapies.

“We found a significant 21.3-month benefit in median progression-free survival and a 35% lower risk of disease progression or death with RVD plus ASCT than with RVD alone.”

“The lack of an overall survival benefit of RVD plus ASCT is probably associated with the multiple, highly efficacious options available after first-line therapy that have emerged over the past 10 years.”

Teclistamab promising

Also presented at ASCO and published in the NEJM was the phase 1/2 MajesTEC-1 trial of the T-cell–redirecting bispecific antibody teclistamab in relapsed or refractory multiple myeloma after at least three lines of therapy.

In 165 patients receiving a weekly subcutaneous injection of teclistamab (1.5mg per kilogram), 39.4% achieved a complete response or better and 58.8% achieved a very good partial response or better after a median follow-up of 14.1 months.

Response rates were consistent across most clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities and those who were the most heavily pretreated.

No minimal residual disease was detected in 26.7% of patients overall and in 46% of those who had a complete response or better.

The researchers said the high rate of deep and durable responses, low rate of adverse events and few discontinuations indicated the potential for teclistamab to provide substantial clinical benefit to a broad population of patients.

Towards targeted therapy

Australian research presented at ASCO suggested an opportunity to design targeted salvage treatment in high-risk myeloma patients.

The study, presented by Monash University’s Dr Sridurga Mithraprabhu, identified somatic variants in bone marrow and ctDNA samples from the phase 2 Australasian Leukaemia and Lymphoma Group (ALLG) MM17 trial.

It found a significantly higher proportion of mutations in RAS/RAF (25% v 3%) and DNA damage repair genes ATM/ATR/TP53 (41% v 17%; p < 0.0001) in patients who relapsed on carfilzomib-thalidomide-dexamethasone (CarTD) than those who did not.

The mutations were also more common in primary refractory patients than those with a suboptimal response to therapy (p = 0.0002).

Senior investigator Professor Andrew Spencer told the limbic the findings of potentially prognostic biomarkers of response to therapy pointed at a future for more personalised therapy in myeloma.

“Nearly all the treatment in myeloma is with drugs which target plasma cells whether they are malignant or not. And that’s one of the reasons that there are issues, for example with daratumumab. It’s a great drug but it’s very immunosuppressive because it kills all the normal plasma cells.”

“Now this work has demonstrated …a pathway which is druggable…and there are drugs out there, and some fantastic new drugs in development, which would work against that pathway.”

“If the normal therapies are failing… isn’t it time to consider some targeted therapy?” he said.

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