Renowned myeloma doctors and researchers from all over the world gathered in Athens, Greece at the 20th International Myeloma Society (IMS) Annual Meeting to present and discuss the latest advances in multiple myeloma research. Highlights from today included the use of risk factors to better predict minimal residual disease negativity, new findings on sustained MRD negativity with Sarclisa, Kyprolis, Revlimid, and dexamethasone in patients with high-risk myeloma, the latest results on mezigdomide, a novel cereblon E3 ligase modulator (CELMoD™) for the treatment of relapsed/refractory multiple myeloma, and the long-term benefits of using Zometa (zoledronic acid) for protection of bone disease in myeloma.
Minimal residual disease (MRD) is an important topic in the field of multiple myeloma, in large part because we have very active treatment regimens that can induce deep and sustained responses in most patients, something that was not possible just several years ago. Measuring MRD refers to counting the number of multiple myeloma cells that remain in a patient after a course of therapy is completed. Achieving MRD negativity (that is, no disease detected after treatment) in clinical trials is associated with a significantly longer time before disease progression (progression-free survival [PFS]) and overall survival; however, to date, there has been limited data on the role of sustained MRD negativity to inform whether to stop treatment. It is important to identify risk-factors of MRD resurgence and/or progressive disease (PD) among patients achieving undetectable MRD to avoid undertreatment and to test these hypotheses in clinical trials prior to adopting in clinical care.
Researchers from Spain reported their findings from an analysis of transplant-eligible MM patients enrolled in the GEM2012MENOS65/GEM2014MAIN clinical trials who achieved MRD negativity.
The only prognostic factors at diagnosis that predicted MRD resurgence and/or PD were an International Staging System (ISS) score of 3 and ≥0.01% of detectable circulating myeloma cells. Patients who achieved MRD negativity after induction (less than 6 months after starting treatment) had significantly lower risk of MRD resurgence and/or PD than those who achieved MRD negativity after 6 months from starting treatment.
The researchers conclude this model could be used in clinical trials to predict the risk of MRD resurgence and/or PD among patients achieving undetectable MRD to avoid undertreatment of transplant-eligible MM patients.
Specific cytogenetic abnormalities can be predictive of high risk of poor prognosis in patients with multiple myeloma; these include the presence of gain or amplification of chromosome arm 1q21 (gain/amp[1q21]), deletion of chromosome 1p (del[1p]), deletion of chromosome 17p (del[17p]), translocation of chromosomes 4 and 14 (t[4;14]), translocation of chromosomes 14 and 16 (t[14;16]), and translocation of chromosomes 14 and 20 (t[14;20]). MRD negativity has recently emerged as a potential surrogate for longer survival, regardless of a patient’s cytogenetic risk. Information from recent clinical trials suggests that extended intensified treatment can help achieve MRD negativity in patients who may have one or more of these high-risk features, which may lead to improved outcomes.
In the next abstract, researchers from Germany presented their findings from the phase 2 GMMG-CONCEPT trial that evaluated Sarclisa, Kyprolis, Revlimid, and dexamethasone (Isa-KRd) as induction therapy in high-risk multiple myeloma. Patients with high-risk multiple myeloma were defined by ISS stage 2 or 3 and any of del17p, t(4;14), t(14;16), or >3 copies 1q21 (amp1q21). Findings from this study were recently published in the Journal of Clinical Oncology (link). The authors showed that the combination of Isa-KRd resulted in high MRD negativity rates in patients with newly diagnosed, high-risk multiple myeloma, regardless of their transplant status.
The authors conclude that Isa-KRd effectively induces high rates of sustainable MRD negativity in the difficult-to-treat HRNDMM population, regardless of transplant status.
Mezigdomide is a novel cereblon E3 ligase modulator (CELMoD™) designed to activate the immune system and directly kill myeloma cells by inducing the destruction of tumor-promoting proteins known as ikaros and aiolos. CELMoDs are oral (taken by mouth) medications that have many similarities to immunomodulatory agents or IMiDs, but CELMoDs can be used even in patients who have relapsed after treatment with immunomodulatory agents.
In this abstract, researchers from Spain presented their findings from an early phase clinical trial that evaluated mezigdomide, a novel cereblon E3 ligase modulator (CELMoD™), in combination either Velcade and dexamethasone (MeziVd) or Kyprolis and dexamethasone (MeziVd) in relapsed/refractory multiple myeloma (RRMM) who had previously received the standard of care – a combination of three classes of drugs — and in some cases had been treated with BCMA targeting treatment, including CAR T-cell therapy. Results of the early phase trial were published online by the New England Journal of Medicine (link). Data reported from participants who received MeziVd was divided into two groups: MeziVd at varying doses (0.3, 0.6, 1.0mg) or 1.0mg of mezigdomide (MeziVd-1.0mg).
Researchers reported overall response rates (ORR) of 75% with MeziVd (either 0.3, 0.6, or 1.0mg of mezigdomide), 84% with MeziVd-1.0mg, and 85% with MeziKd.
The most frequent treatment-related side effects were low white blood cell counts (36%) and low platelet counts (21%) with MeziVd; low white blood cell counts (58%) and all infections (34%) with MeziVd-1.0mg; and low white blood cell counts (41%) and all infections (30%) with MeziKd.
With longer follow-up, MeziVd and MeziKd continued to show promising efficacy at all dose levels tested with a manageable safety profile in patients with RRMM. Future clinical trials will continue to examine the potential of this novel CELMoD in combination with other treatments.
Up to 85% of people with multiple myeloma experience bone disease. In some people, myeloma may cause thinning and weakening of the bones to the point where holes are formed in the bone, which can lead to pain or fractures. Even more patients will experience bone complications at some time point in their course of disease.
Progression of bone disease can be inhibited by treatment with Zometa. Zometa has been shown to increase quality of life and overall survival in myeloma patients, however Zometa is also associated to osteonecrosis of the jaw. The best length of treatment with Zometa is yet uncertain, as previous studies followed myeloma patients for up to 2 years.
In the final abstract, researchers from Denmark examined if treatment of myeloma bone disease up to 4 years with Zometa was safe and effective. Their findings showed that four years of monthly Zometa are superior to two years treatment in protection against progressive bone disease in multiple myeloma. The incidence of osteonecrosis of the jaw after 4 years was 4% and not significantly different between the two treatment groups. These results shed light on the clinical potential of long-term use of Zometa in protection of bone disease in myeloma.
Be sure to hear what myeloma expert, Dr. Saad Usmani, had to say about the day’s presentations here.
Stay tuned for more updates from IMS 2023!