Welcome to our final day of coverage from the latest advances presented at the 20th International Myeloma Society (IMS) Annual Meeting. Highlights from today include recent findings on standard and emerging treatments including bispecific antibodies, and CAR T-cell therapy in patients with relapsed/refractory multiple myeloma (RRMM). Here’s a quick recap!
Sarclisa (isatuximab) is an anti-CD38 monoclonal antibody approved in combination with Kyprolis (carfilzomib) and dexamethasone (Isa-Kd) for patients with relapsed/refractory multiple myeloma (RRMM) after one or more prior therapy. The IKEMA trial, which compared the combination of Sarclisa, Kyprolis, dexamethasone (Isa-Kd) with Kyprolis and dexamethasone, showed that patients with RRMM (who had received 1-3 prior lines of therapy) benefit from the use of Isa-Kd, with a longer time before their disease returns (progression-free survival [PFS]) of 36 months compared to 19 months with Kd. In this final analysis of the IKEMA trial, French researchers reported a meaningful benefit in overall survival with Isa-Kd compared to Kd. Side effects associated with Isa-Kd, such as infusion reactions, diarrhea, and high blood pressure, were consistent with previous analyses, supporting it as a standard-of-care therapy for RRMM.
Yesterday we learned about the activity of venetoclax when combined with Kyprolis and dexamethasone in patients with a translocation of chromosomes 11 and 14 (t[11;14]). Today, researchers from Spain shared their findings from the Phase 3 CANOVA study that evaluated venetoclax and dexamethasone (VenDex) against pomalidomide and dexamethasone (PomDex) in patients with t(11;14)-positive RRMM who have received two or more prior treatments.
Their findings revealed that patients receiving VenDex showed a small improvement in progression free survival (the time before their disease came back) compared to PomDex (10 months vs 6 months) as well as an 8-month improvement in overall survival (32 months for VenDex compared to 24 months with PomDex. The most common side effects experienced by patients treated with VenDex included any infection, diarrhea, low white blood cell counts, and nausea (22%).
Forimtamig, a GPRC5DxCD3 T-cell-engaging bispecific antibody (BsAb), is currently being evaluated in patients with RRMM who have received one or more prior line(s) of therapy, and were refractory to a proteasome inhibitor (such as Velcade, Kyprolis or Ninlaro) and an immunomodulatory drug (such as Revlimid or Pomalyst). Forimtamig is in the same class as Talvey (talquetamab), which received FDA approval several weeks ago. Findings from an early phase study showed forimtamig induced deep and durable responses in heavily pre-treated pts and had a safety profile consistent with other investigational GPRC5D-directed therapies. (Carlo-Stella et al. ASH 2022).
In this abstract, researchers from the United Kingdom presented their analysis of clinical responses in high-risk patients. For this study, high-risk patients were defined as: age ≥65 years, >4 prior LOT, triple-class and penta-drug refractory disease, prior BCMA-targeted therapy (such as CAR-T or a bispecific antibody like Tecvayli aka teclistimab), high-risk cytogenetics (del(17p), t(4;14), t(14;16)), 1q21 gain (irrespective of other high-risk aberrations), International Staging System Stage III at baseline, and presence of soft tissue plasmacytoma (bone-based and extramedullary).
ORR across all dose levels of forimtamig was 67% and high ORRs were observed across all risk groups. Future studies will seek to identify the best dose and schedule of forimtamig for patients with RRMM.
Tecvayli (Teclistamab) was the first “off-the shelf” BCMA-targeted bispecific antibody approved for patients with heavily pretreated RRMM (patients who have received 4 or more lines of therapy). In this abstract, Dr Shonali Midha and colleagues from the Dana-Farber Cancer Institute in Boston shared their preliminary experience with the real-world use of Tecvayli. Their findings revealed that treatment with Tecvayli in a real-world setting showed similar responses to the previously reported clinical trials without any new side effects. The authors conclude that additional real-world follow up on the use Tecvayli in the real-world is needed to confirm these findings.
Carvykti (ciltacabtagene autoleucel) is approved for RRMM patients after at least four previous treatments. Given the success of CAR T-cell therapy in patients with RRMM who have failed many different treatments there is an interest in testing CAR T-cell therapy for patients who have received fewer prior therapies. Findings from the CARTITUDE-4 trial showed Carvykti significantly improved PFS compared to the standard of care (that is physician’s choice of either Pomalyst, Velcade and dexamethasone or Darzalex, Pomalyst, and dexamethasone. In this abstract, researchers from France reported findings from a prespecified subgroup of patients, including those aged < 65 yrs, patients who received 1 prior line of therapy (that is first relapse), ISS stage III, triple-class refractory, etc.
The results showed that Carvykti improved progression free survival in all subgroups, including by age, in those with high-risk features, and after first relapse. The authors conclude that these findings offer further support for the use of Carvykti in earlier lines of therapy.
Please be sure to listen to hear what myeloma experts had to say as they recap each day’s clinical research and discuss what these findings mean for myeloma patients here.
We look forward to more clinical updates in the months ahead!
Day 2 of IMS brought us some recent findings covered a mix of different drug combinations for both newly diagnosed and relapsed/refractory myeloma. Let’s dig into a big day of updates in myeloma treatment.
Revlimid is a key drug in the treatment of newly diagnosed patients with multiple myeloma. Unfortunately, due to the extensive use of Revlimid (lenalidomide)-containing regimens in the frontline setting and Revlimid-maintenance therapy, patients may develop resistance to treatment early in the disease course. Refractoriness is defined as no response to primary therapy (lenalidomide in our case) or progression within 60 days of the last dose.
Pomalyst (Pomalidomide) is approved for the use in patients who have previously received at least 2 drugs to treat multiple myeloma, including a proteasome inhibitor and Revlimid and have demonstrated disease progression on or within 60 days of completion of the last therapy. The combination of Pomalyst-Velcade (bortezomib), and dexamethasone (PVd) is a preferred option in patients who have received one ore more prior therapies, including those who have received Revlimid and Velcade.
In the first abstract, researchers from Turkey reported updates from the phase 3 OPTIMISMM, which has previously shown that PVd significantly prolonged progression-free survival (that is the length of time during and after treatment in which a patient is living with a disease that does not get worse) compared to Vd (11 vs 7 months). Participants enrolled in OPTIMISMM had a diagnosis of RRMM and had received 1-3 prior lines of therapy, including at least one round of Revlimid.
Their findings showed that patients who received PVd achieved a median overall survival (that is the length of time a patient survives) of 36 months compared with 32 months among patients treated with Vd. The most common side effects with PVd were low white blood cell counts (54%), burning/tingling in the hands and feet, also known as peripheral neuropathy (48%), and low platelet counts (40%). The researchers conclude that PVd is effective in patients for whom Revlimid is no longer a treatment option, including Revlimid-refractory patients after 1 prior line of therapy.
Venetoclax is a selective small‐molecule inhibitor of BCL‐2 that is FDA-approved for the treatment of chronic lymphocytic leukemia and has shown to be effective in treating myeloma patients with a translocation of chromosomes 11 and 14 (t[11;14]). An early phase clinical study showed that combination of venetoclax with plus Kyprolis (carfilzomib) and dexamethasone (VenKd) in RRMM showed an overall response rate (ORR) of 92% in patients who had a t(11;14).
In this abstract, Dr Jonathan Kaufman reported initial safety and efficacy data in patients with t(11;14) RRMM treated with one of 2 doses of Ven (400 or 800 mg) combined with Kyprolis and dexamethasone (Ven400Kd or Ven800Kd) compared to Kd alone. Their findings showed that patients treated with VenKd 400mg or VenKd 800mg achieved an ORR of 89% and 95%, respectively. Most common side effects observed were diarrhea, nausea, vomiting and fatigue. The incidence of side effects was higher with the higher dose of venetoclax.
This trial is ongoing and additional results will shed light on the clinical potential of venetoclax for the treatment of patients with t(11;14).
Iberdomide, Velcade, and Dexamethasone (IberVd) in Patients with Transplant-Ineligible Newly Diagnosed Multiple Myeloma (NDMM)
Iberdomide is a novel, potent oral cereblon E3 ligase modulator (CELMoD™) with a dual function: activate the immune system and directly kill myeloma cells by inducing the destruction of tumor-promoting proteins known as ikaros and aiolos.
In this abstract, researchers from Canada presented results from an early phase clinical trial that evaluated iberdomide in combination with Velcade and dexamethasone (IberVd). This combination has shown promising preliminary efficacy and safety in patients with RRMM in an early phase clinical trial.
Patients in the trial had untreated symptomatic NDMM, no autologous stem cell transplant planned, nor ineligibility due to age or comorbidities. Their findings showed:
The researchers concluded that IberVd showed high efficacy with deep responses in transplant ineligible patients with NDMM. The safety profile was manageable with no new safety signals, and no pts discontinued due to AEs. These findings support further assessment of iberdomide combinations in the frontline setting.
Be sure to hear what myeloma experts Dr. Sagar Lonial and Dr. Keith Stewart, had to say about the day’s presentations here.
Stay tuned for more updates from the final day at IMS 2023!
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!