Next-gen therapies expand options in multiple myeloma

Treatment landscape diversifies with ADCs, bispecific antibodies and CAR-T therapies

Limited options remain for lenalidomide-refractory patients…reimbursement decisions a key turning point

The treatment landscape for multiple myeloma is evolving rapidly.

With the introduction of therapies based on novel mechanisms of action, including antibody-drug conjugates (ADCs), bispecific antibodies and chimeric antigen receptor T-cell (CAR-T) therapies, treatment options have expanded significantly in Korea.

As competition shifts from regulatory approvals to National Health Insurance reimbursement, patient access to these next-generation therapies is emerging as a key factor shaping the future treatment landscape for multiple myeloma.

ADC oncology drug ‘Blenrep’

According to industry sources, GSK Korea is currently pursuing reimbursement for its BCMA-targeting ADC Blenrep (belantamab mafodotin).

In December last year, Blenrep was approved in Korea for use in combination with bortezomib and dexamethasone (BVd) in patients with relapsed or refractory multiple myeloma who had received at least one prior therapy.

It is also approved in combination with pomalidomide and dexamethasone (BPd) for patients who received at least one prior therapy including lenalidomide.

Under the Korean label, both combination regimens are indicated for patients who have received one or more prior therapies, and can be used beginning in the second-line setting. Accordingly, a key issue in reimbursement discussions is whether coverage will likewise begin from second-line treatment.

The approved indication differs from that in the United States. In October last year, the US Food and Drug Administration approved Blenrep in combination with BVd for patients with relapsed or refractory multiple myeloma who had previously received at least two therapies including a proteasome inhibitor and an immunomodulatory agent.

While the US indication effectively targets third-line or later treatment, as in Europe, Korea permits use beginning in the second line. Depending on the extent to which domestic reimbursement criteria are set, the actual therapeutic position of Blenrep may also vary.

Initial treatment strategies for multiple myeloma vary depending on whether a patient is eligible for hematopoietic stem cell transplantation.

Transplant-eligible patients typically receive induction therapy to reduce tumor burden, followed by autologous stem cell transplantation and maintenance therapy. Patients who are ineligible for transplantation, or who are not scheduled for transplant during initial treatment, generally continue drug therapy in consideration of each individual’s age, overall health, and comorbidities.

More recently, first-line treatment has increasingly incorporated combination regimens containing anti-CD38 monoclonal antibodies regardless of transplant status, reflecting a strategy aimed at achieving deeper responses from the outset.

In April, Johnson & Johnson's subcutaneous Darzalex (daratumumab) received an expanded indication allowing its use in the four-drug DVRd regimen (daratumumab, bortezomib, lenalidomide and dexamethasone) in both transplant-eligible and transplant-ineligible patients.

Lenalidomide remains a cornerstone therapy in both frontline combination regimens and maintenance treatment. Consequently, many patients have already become refractory to lenalidomide by the time they require second-line therapy following disease relapse.

Multiple myeloma is characterized by repeated cycles of relapse and treatment, and the duration of disease control generally becomes shorter with each successive line of therapy, increasing the need for therapies with novel mechanisms early in the relapsed setting.

This is one reason Blenrep is seeking reimbursement as a second-line treatment. In particular, the BPd regimen is indicated for patients previously treated with lenalidomide, closely reflecting current real-world treatment patterns in multiple myeloma.

Treatment sequence more important than mechanism…Reimbursement will reshape the market

CAR-T therapy ‘Carvykti’

Johnson & Johnson's CAR-T therapy Carvykti (ciltacabtagene autoleucel) is also reshaping treatment strategies by expanding into earlier stages of relapsed disease.

Carvykti is a personalized cell therapy in which a patient's own T cells are collected, genetically modified to recognize myeloma cells, and then reinfused. It is currently the first and only CAR-T therapy approved in Korea for multiple myeloma.

It is indicated for patients with relapsed or refractory multiple myeloma who are refractory to lenalidomide after receiving at least one prior regimen that included both a proteasome inhibitor and an immunomodulatory agent.

In the CARTITUDE-4 study, Carvykti reduced the risk of disease progression or death by 71% compared with standard therapy. At a median follow-up of 33.6 months, the median progression-free survival had not yet been reached in the Carvykti group, compared with 11.8 months in the standard-of-care group.

Carvykti also reduced the risk of death by 45% in the overall survival analysis. The overall response rate was 85% in the Carvykti arm versus 67% with standard therapy, while complete response or stringent complete response rates were 77% and 24%, respectively.

Experts believe CAR-T therapy is likely to become one of the major treatment pillars for relapsed or refractory multiple myeloma.

Because patients with multiple myeloma typically undergo long-term sequential treatment, repeated drug administration imposes not only a physical burden but also increasing demands associated with hospital visits and treatment costs.

CAR-T therapy has limitations in that it requires time for cell collection and manufacturing before treatment can begin. However, because durable responses may be achieved following a single administration, it has the potential to reduce the burden associated with prolonged, repeated treatment.

Although no specific reimbursement timetable has yet been confirmed for Carvykti, the need for discussions on reimbursement is being raised, given its high treatment cost and the limited number of centers capable of administering the therapy.

Meanwhile, bispecific antibodies are moving through the reimbursement process for patients in a more advanced setting.

Johnson & Johnson's Tecvayli (teclistamab) and Pfizer's Elrexfio (elranatamab) had reimbursement criteria established by the Health Insurance Review and Assessment Service's Cancer Disease Deliberation Committee in November last year.

(from the left) Bispecific antibodies ‘Tecvayli,’ ‘Elrexfio’

Both therapies simultaneously bind to BCMA expressed on myeloma cells and CD3 on T cells, directing the patient's immune system to attack cancer cells.

However, their approved populations are limited primarily to heavily pretreated patients with relapsed or refractory disease. Elrexfio is indicated for patients who have received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody. Tecvayli is similarly intended for later-line patients previously treated with a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody.

A key advantage of bispecific antibodies is that they are off-the-shelf therapies that can be administered immediately without the need to collect and manufacture a patient's own cells.

This enables rapid treatment for patients with rapidly progressing disease or those unable to wait for CAR-T cell manufacturing. Unlike CAR-T therapy, however, bispecific antibodies require repeated administration over time rather than relying on a single treatment.