Two major studies presented at the American Society of Clinical Oncology meeting in Chicago are pointing to a significant shift in the treatment of relapsed multiple myeloma, a blood cancer that develops in plasma cells in the bone marrow.
Multiple myeloma accounts for about 10% of blood cancers. Most patients eventually relapse after initial treatment, and those already exposed to the main classes of therapy, including anti-CD38 antibodies and immunomodulatory drugs, have often faced limited options.
The first study, SUCCESSOR-2, examined mezigdomide, an oral drug from a new class known as CELMoDs, in combination with carfilzomib and dexamethasone. The drug binds to the cereblon protein in myeloma cells, triggering the breakdown of growth factors needed by the tumor and helping activate the immune system against it.
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Mezigdomide is taken orally, unlike other treatments administered by infusion. Illustration
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The combined phase 2/3 trial (out of three stages required for approval of a new drug) included 479 patients with a median age of 68, about a quarter of them over 75. Most (92.1%) had already received the three main classes of myeloma treatment, and 85.8% were resistant to anti-CD38 antibodies. Another 37.2% had previously received pomalidomide and 7.3% had received anti-BCMA therapy, underscoring how difficult this patient population is to treat.
Patients who received mezigdomide had a median progression-free survival of 18 months, compared with 8.3 months in the control group, reducing the risk of disease progression or death by 52%.
The overall response rate was 80.2%, compared with 53.4% in the control group, while complete response was seen in 26.7% of patients, compared with 8.9%.
Overall survival data have not yet been fully assessed, but deaths were reported in 21.5% of patients receiving mezigdomide, compared with 26.7% in the control group, mostly due to disease progression. The benefit was seen across patient groups, including those over 75, high-risk patients with particularly aggressive disease features and patients with cancer outside the bone marrow.
Safety remains a key issue. Serious side effects, grade 3 or 4, were reported in 83.7% of patients receiving mezigdomide, compared with 56.5% in the control group. Severe neutropenia, a sharp drop in white blood cells, was the most common, seen in 61.1% of patients compared with 9.1%, though fatal infections were rare at 2.4% versus 1.1%.
Prof. Yael Cohen, head of the myeloma unit at Tel- Aviv Sourasky (Ichilov) Medical Center and chair of the Israeli Myeloma Study Group, said that “Mezigdomide works in patients who are very difficult to treat, those who have failed existing therapies and developed resistance. It offers a treatment option that can overcome resistance.”
Prof. Yael CohenPhoto: CourtesyCohen noted that a compassionate use program is already operating in Israel, giving several dozen patients access to the treatment, with promising results so far. Mezigdomide is currently undergoing the FDA approval process and is expected to be submitted for inclusion in Israel’s health basket next year.
The main advantage is convenience. Unlike many myeloma treatments that require hospital infusions, mezigdomide is taken orally at home and may also be prescribed in community clinics.
"What we hear from physicians is they're excited about oral regimens that are low burden and can provide a better overall experience for their patients," said, according to Reuters, Adam Lenkowsky, chief commercialization officer at Bristol Myers Squibb, which developed the drug.
No disease progression after 18 months
The second study, MajesTEC-9, examined Teclistamab, an immunotherapy that directs T cells toward BCMA, a protein found on myeloma cells. The trial included 593 patients from 24 countries whose disease had returned after one to three previous lines of treatment. About 85% were resistant to anti-CD38 antibodies and about 79% to lenalidomide, while more than 90% had not responded to their most recent line of treatment.
Patients were randomly assigned to two groups. One received teclistamab. The other group received standard treatment chosen by the physician: either carfilzomib and dexamethasone, or pomalidomide, bortezomib and dexamethasone.
The results were striking: about 70% of patients who received teclistamab, made by Johnson & Johnson’s Janssen unit, had no disease progression after 18 months, compared with about 27% in the standard-treatment group. The drug reduced the risk of disease progression by 71% and the risk of death by 40%.
Nearly two-thirds of patients (65.9%) receiving teclistamab achieved a complete response, compared with 16.8% in the control group. Many also reached levels of minimal residual disease so low that they could not be detected by the most sensitive tests.
The median treatment duration was 13.1 months, compared with 7.0 months in the control group.
“We now have chemotherapy-free immunotherapy options for patients whose myeloma has relapsed for the first time,” said Prof. C. Ola Landgren of the University of Miami’s Sylvester Comprehensive Cancer Center, who led the study, as reported in Medical Express. “This is part of a bigger transformation happening in myeloma care."
Teclistamab also carries risks. About 66% of patients experienced cytokine release syndrome, an immune overreaction that can cause fever, chills and low blood pressure. Most cases were mild to moderate, were controlled and did not lead to treatment discontinuation. Serious infections were more common with teclistamab, particularly during the first six months of treatment.
Fatal side effects (grade 5), were reported in 6.5% of patients compared with 3.5% in the control group, most of them due to infections.
Based on the findings, approval applications have been submitted to the FDA and the European Medicines Agency.
Together, the studies reflect a broader move in myeloma care: bringing advanced immunotherapy and targeted treatments earlier in the course of disease, while trying to reduce the treatment burden on patients.
"We are working toward treatments that can either eliminate the disease entirely or control it for very long periods while minimizing the burden on patients and preserving quality of life,” Landgren said.