Day 3 was a big day at ASH, with over a dozen abstracts that featured updates on CAR T-cell therapy, bispecific antibodies, the impact of age on transplant outcomes, and novel therapies in early phase clinical trials. Let us break down the key findings for you…
Induction therapy with proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs) followed by high-dose chemotherapy and autologous hematopoietic cell transplantation (ASCT) is considered a standard of care for front-line treatment of patients with newly diagnosed multiple myeloma (NDMM). Some individuals ages 65 and older may have a higher risk of complications and prolonged hospitalizations following ASCT. Therefore, healthcare professionals must carefully assess each patient when recommending ASCT.
Dr. Shohei Mizuno and colleagues from Japan analyzed global registry data that included over 60,000 patients to assess the impact of age on outcomes following ASCT (Abstract 785). Their results showed that patients aged 75 or older had a significantly lower progression free survival (PFS)—that is, the length of time during and after treatment in which a patient is living with a disease that does not get worse and overall survival. The researchers note that incidence of relapse was similar regardless of age and the incidence of death not related to disease progression or treatment failure was low (4%) compared to patients in other age groups (0%, 1%, 2%, and 2% for patients aged 18–39, 40–64, 65–69, and 70–74 ). While ASCT has been generally reserved for patients younger than 65, the authors note that age should not be considered a barrier to receiving this type of treatment.
Dr. Paula Rodríguez Otero and colleagues from Spain presented (Abstract 1028) the final PFS analysis of KarMMa-3 (Rodríguez-Otero et al. NEJM 2023), which showed that a single infusion of the CAR T-cell therapy, Abecma (idecabtagene vicleucel), significantly prolonged PFS and improved response rates in patients with relapsed and refractory multiple myeloma (RRMM) who had received two to four prior lines of therapy, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody, which makes them “triple-class exposed”. The researchers reported that patients treated with Abecma had a median PFS of 13.8 months compared with 4.4 months for standard regimens. Overall response rates (ORR) were higher with Abecma (71%) compared to standard regimens (42%). The authors noted that Abecma side effect profile was consistent with previous reports.
Dr. Jens Hillengass and colleagues from Roswell Park reported (Abstract 1021) follow-up results for patients in two of those groups: Cohort A, who had received between one and three prior lines of therapy (LOT) and whose disease progressed while receiving Revlimid and Cohort B, who had relapsed a year or less after either ASCT or from the beginning of initial treatment if they did not undergo ASCT. The results showed:
Talvey is the first approved bispecific antibody targeting G protein–coupled receptor family C group 5 member D (GPRC5D) for patients with RRMM who have received at least four prior lines of therapy, including a IMiD, a PI, and an anti-CD38 monoclonal antibody. The FDA granted an accelerated approval to Talvey based on initial findings from the MonumenTAL-1 study (Chari A NEJM 2022), which showed that patients who received the 0.8 mg/kg biweekly dose had an overall response rate (ORR) of 74%, similar to those who had received the 0.4 mg/kg biweekly dose. The most common side effects related to treatment with Talvey include cytokine release syndrome (CRS; which is a flu–like syndrome in which a patient experiences fevers, chills, and low blood pressure), immune effector cell-associated neurotoxicity syndrome (neurologic symptoms like confusion, but in some cases patients experience severe symptoms like delirium or seizures), infections, skin and nail disorders such as brittle or discolored nails, and oral toxicities such as dry mouth, difficulty swallowing, and altered taste.
In this presentation, Dr. Ajai Chari and colleagues at Mount Sinai School of Medicine (Abstract 1010) reported that dose modifications of Talvey improved side effects while maintaining responses for patients with RRMM. For this analysis, 9 patients received a starting dose of Talvey at 0.8 mg/kg every 2 weeks, which was reduced to 0.4 mg/kg every 2 weeks following a partial response (PR) or better. A separate group of 10 participants started at 0.8 mg/kg every 2 weeks, which was reduced to 0.8 mg/kg every 4 weeks following a PR or better. The results showed:
The researchers concluded that these data support flexibility to adjust the dosing of Talvey in patients who respond to potentially improve patient experience while maintaining efficacy.
In this presentation, Dr. Jeffrey Matous and colleagues at the Colorado Blood Institute presented (Abstract 1014) initial efficacy and safety results of an early phase trial examined the combination of Talvey with Pomalyst. The results showed rapid, deep responses with the combination of Talvey and Pomalyst in patients with RRMM that had received 2 or more prior lines of therapy. Side effects of the combination were consistent with previous reports of the individual agents:
Dr. Chari and colleagues conclude that these findings support future investigation into the use of combination Talvey and Pomalyst in patients with RRMM.
CELMoDs are a new class of myeloma drugs that work like immunomodulators such as Revlimid and Pomalyst and are orally administered. They also stimulate the immune system and kill myeloma cells directly, even for patients whose myeloma has become resistant to certain treatment. Dr. Paul Richardson and colleagues presented their findings from an early phase trial evaluating mezigdomide (Abstract 1013), an oral CELMoD, in combination with Darzalex and dexamethasone (MeziDd) or Empliciti (elotuzumab) and dexamethasone (MeziEd) in RRMM. Data collected from 45 RRMM patients who received 2-4 prior lines of therapy showed:
Sonrotoclax is a next-generation BCL-2 inhibitor that has shown more potency than venetoclax in preclinical studies in patients who have a translocation of chromosomes 11 and 14 (t(11;14)). In this presentation (Abstract 1011), Dr. Hang Quach and colleagues in Australia reported preliminary findings from an early phase study of sonrotoclax in combination with dexamethasone in 10 RRMM patients with t(11;14). 70% of patients who received the highest dose of sonrotoclax (640mg) achieved a treatment response. 26% of patients experienced severe grade side effects such as increased liver enzymes, diarrhea, low potassium levels, cataracts, and retinal detachment.
Dr. Susan Bal and colleagues at the University of Alabama at Birmingham reported data from an early phase clinical trial with 70 patients that evaluated 5 different doses of BMS-986393, a novel GPRC5D-targeted CAR T-cell therapy for RRMM (Abstract 219). The results showed:
In the next presentation, Dr. Matthew Frigault and colleagues at Harvard Medical School reported data from an early phase trial of CART-ddBCMA, now known as anitocabtagene autoleucel (anito-cel) in 38 patients with RRMM who have received 3 or more lines of therapy (Abstract 1023). CART-ddBCMA has a unique protein, called a D-Domain, that is designed to bind more firmly to BCMA and reduce the risk of side effects such as CRS.
The results showed:
Dr. Aina Calde and colleagues in Spain shared an update on an early phase trial of ARI0002h (Cesnicabtagene Autoleucel), a novel CAR T-cell therapy for RRMM patients (Abstract 1026). Earlier this year, Dr. Calde reported (Oliver-Caldés, Lancet Onc. 2023) that ARI0002h produced durable responses in 30 patients with RRMM who had received at least 2 prior lines of therapy, including a PI, IMiD, and an anti-CD38 antibody, and were refractory to the last line of treatment. This update included 30 additional patients and a longer follow-up of the initial 30 patients treated with ARI0002h.
The results showed:
The final abstract features data from an early phase trial of a novel tri-specific antibody, HPN217, which binds to three targets: BCMA, CD3, and albumin. Researchers note that HPN217 was designed to bind to albumin to extend the length of time the tri-specific antibody can attack myeloma cells and reduce side effects. Dr. Sumit Madan and colleagues from the Banner MD Anderson Cancer Center shared their results of 97 patients with RRMM who had received at least three prior therapies (Abstract 1012). Their findings showed:
Ongoing studies will continue to explore the potential of these novel therapies for patients with RRMM.
Be sure to hear what myeloma experts Dr. Urvi Shah and Dr. Benjamin Diamond, had to say about the day’s presentations here.
Stay tuned for more updates from the final day of ASH 2023!