The final day of ASH gave us an important late-breaking abstract on Darzalex Faspro (daratumumab and hyaluronidase-fihj) in combination with the standard care regimen of Velcade (bortezomib), Revlimid (lenalidomide), and dexamethasone (VRd) in newly diagnosed patients with multiple myeloma (NDMM) who were eligible for an autologous stem cell transplant (ASCT).
Dr. Pieter Sonneveld and colleagues from the Netherlands presented findings from the phase 3 PERSEUS trial that showed the that subcutaneous Darzalex Faspro-based induction, consolidation and maintenance regimen reduced risk of progression or death by 58 percent compared to RVD (Abstract LBA-1).
Results of the trial, which included 709 patients with NDMM who were eligible for ASCT, were simultaneously published in the New England Journal of Medicine (Sonneveld P, NEJM 2023). The researchers reported that the 4-year PFS was 84% with D-VRd compared with 68% with VRd. Significantly more patients achieved higher minimum residual disease (MRD)-negative rates with the addition of Darzalex Faspro (75%) compared to VRd (48%). The overall safety profile of D-VRd was similar to previously reported (Voorhees PM, Lancet Haematol 2023) side effects with D-VRd. The most common (>10 percent) serious grade side effects with D-VRd vs VRd were low white blood cell counts (62% vs 51%), low platelet counts (29% vs 17%), diarrhea (11% vs 8%), and pneumonia (11% vs 6%).
The authors conclude that these results support Darzalex-based quadruplet induction and consolidation regimen and doublet maintenance regimen as a potential new standard of care for transplant-eligible patients with NDMM.
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!
Day 2 of ASH represented the calm before the storm, as only a couple of abstracts on myeloma were featured on Sunday compared to the more than a dozen presentations that will be highlighted on Day 3. Updates from Day 2 included a real-world comparison of quadruplet versus triplet regimens in standard- and high-risk newly diagnosed multiple myeloma and an assessment of the real-world utilization of autologous stem cell transplantation (ASCT) in newly diagnosed patients.
Preferred treatments for induction therapy (the first in a series of treatments used to treat multiple myeloma) typically consist of three-drug (triplets) or four-drug (quadruplets) regimens given over three to six cycles, each of which typically lasts 3 or 4 weeks. The combination of Revlimid (lenalidomide)-Velcade (bortezomib)-dexamethasone (RVd) is highly effective for patients with NDMM. However, the addition of Darzalex (daratumumab) to RVD (D-RVD) has shown improved depth of response and trend towards a benefit of 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.
In this presentation, Dr. Nisha Joseph and colleagues from Emory University (Abstract 647) analyzed the real-world response rates and long-term outcomes for both standard- and high-risk patients. High-risk disease was defined as having chromosomal alterations including del(17p), t(4;14), and t(4;16). The real-world analysis included 1000 NDMM patients treated with RVD and 326 NDMM patients treated with D-RVD induction therapy. The results showed:
Dr Joseph and colleagues concluded that D-RVD is a highly effective induction regimen that can improve upon outcomes in a historical NDMM population treated with RVD in terms of depth of response and PFS benefit. This analysis provides evidence of benefit with the addition of daratumumab to RVD in increasing depth of response and provides an early glimpse of the promising PFS and OS benefit not only in standard risk patients, but also in patients with high-risk cytogenetic and disease features.
High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains standard of care in multiple myeloma (MM) in eligible patients and is proven to improve progression free survival. However, some patients do not receive ASCT as part of their treatment. It is well documented that racial and socioeconomic disparities in the use of ASCT exist in myeloma treatment. Barriers to patients receiving ASCT as part of their treatment may include low income, insurance status, and poor access to care at an academic health center. In this presentation (Abstract 532), Dr. Chakra Chaulagain and colleagues at the Cleveland Clinic Florida evaluated data from the National Cancer Database and found that the ASCT opt out rate in real-world is low (approximately 2%) but still represents a missed opportunity to provide standard of care for myeloma patients. Older patients (aged over 60 years), females, African American patients with non-private health insurance (that is, those covered by Medicaid, Medicare, or another government insurance), higher comorbidities, and those with an income of less than $63,000 per year were found to be less likely to receive an ASCT.
Among 43,653 patients evaluated in the study, those treated at non-academic medical centers were less likely to receive ASCT than patients treated at academic facilities. Patients living in the South Atlantic region of the United States were less likely to receive an ASCT compared to other regions of the country. The researchers conclude that their findings reveal significant racial, economic, and geographic variation regarding the use of ASCT across the US which should be further studied. Understanding the barriers to the use of ASCT is crucial for optimizing patient care and tailoring effective interventions.
Be sure to hear what myeloma experts Dr. Nisha Joseph and Dr. Alexander Lesokhin, had to say about the day’s presentations here.
Stay tuned for more updates from day 3 at ASH 2023!
Welcome to our 2023 recap of the latest findings on myeloma treatments reported at the American Society of Hematology (ASH) meeting that kicked off Saturday in San Diego. Highlights from today included real-world data on the use of the bispecific antibody Tecvayli, health-related quality of life findings with the CAR T-cell therapy Abecma, the use of minimum residual disease negativity, iberdomide maintenance therapy, and updates on the treatment of high-risk newly diagnosed disease and smoldering myeloma.
Tecvayli (Teclistamab) was the first “off-the shelf” BCMA-targeted bispecific antibody approved for patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM; that is patients who have received 4 or more lines of therapy), including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody. In this Abstract 91, Dr. Danai Dima and colleagues from the Cleveland Clinic reported that treatment with Tecvayli in a real-world setting showed similar responses to the previously reported data from the MajesTEC-1 clinical trial without any new side effects.
Of the 102 patients with RRMM included in Dr. Dima’s analysis, 25% were non-Hispanic Black, 44% had extramedullary disease (EMD; that is, myeloma cells that are growing outside of the bone marrow) and more than 80% (83/102) would not have met the MajesTEC-1 eligibility criteria. Their findings showed:
The authors note that results from the real-world study of the safety and efficacy of Tecvayli were like previously reported data from the MajesTEC-1 clinical trials; however, complete response (CR) rates were lower. The lower CR rates may be due to the fact that a majority of patients evaluated did not meet the eligibility criteria MajestTEC-1 trial population; due to stringent eligibility criteria, patients in clinical trials tend to be less sick and/or have fewer comorbidities than real-world patient population, so outcomes are typically better in clinical trials. Low blood cell counts and infections remain a challenge, thus, close monitoring, supportive care and other measures are important to help patients continue with therapy.
Dr. Michel Delforge and colleagues in Belgium reported findings from a preliminary analysis (Abstract 96) that showed the chimeric antigen receptor T cell (CAR T-cell) therapy Abecma (idecabtagene vicleucel) significantly improved health-related quality of life when compared to standard regimens [that is, Darzalex (dara, daratumumab), Pomalyst (pomalidomide), and dexamethasone; Darzalex, Velcade (bortezomib), and dexamethasone; Ninlaro (ixazomib), Revlimid, and dexamethasone; Kyprolis (carfilzomib) and dexamethasone; or Empliciti (elotuzuamb), Pomalyst, and dexamethasone].
Researchers evaluated data from patient-reported outcomes that were collected as part of the KarMMa-3 trial. In the phase 3 trial, Abecma significantly improved progression-free survival (PFS) and treatment response rates as compared with standard regimens, in patients with triple-class exposed (TCE) RRMM who had received 2–4 prior regimens (Rodriguez-Otero P, et al. N Engl J Med 2023).
Health-related quality of life captures information on the physical and mental health status of individuals, and on the impact of disease and treatment on a patient’s quality of life. The results from the patient-reported outcomes showed statistically significant and clinically meaningful improvements in health-related quality of life including cognitive functioning, fatigue, and pain reduction for patients with RRMM who received Abecma compared with standard treatment regimens. The authors noted that health-related quality of life improvements occurred earlier with Abecma therapy than with standard regimens, starting at approximately 2-3 months following infusion and were sustained for more than 2 years.
A couple of abstracts evaluated the role of minimal residual disease (MRD) as a tool to measure the success of therapy. MRD is an important topic in the field of multiple myeloma, in large part because we have very active treatment regimens that can bring deep and sustained responses to 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. For some patients, achieving MRD negativity (that is, no disease was detected after treatment) is associated with a significantly longer time before disease progression (progression-free survival [PFS]) and overall survival; however, to date, there has been limited information about its clinical meaning in patients treated with CAR T-cell therapy.
In the first presentation, (Abstract 94), Dr. Aintzane Zabaleta and colleagues from Spain found that achieving sustained MRD negativity resulted in significantly prolonged survival of RRMM patients treated with newer immunotherapies such as CAR T-cell therapy and bispecific antibodies (also known as T-cell engagers). The researchers reported that MRD negativity was associated with 88% reduction in the risk of progression and/or death. MRD negative rates were significantly higher in patients treated with CAR T-cell therapy (78%) than bispecific antibody therapy (35%).
In the next abstract, Nizar Bahlis, MD and colleagues from Canada reported (Abstract 338) that Venetoclax (Ven) combined with daratumumab (D) and dexamethasone (d) [VenDd] showed higher rates of MRD-negativity and sustained MRD-negativity compared to bortezomib plus Dd (DVd) in patients with t(11;14)-positive RRMM.
Venetoclax is a potent and selective oral BCL-2 inhibitor with demonstrated anti-myeloma activity in patients with t(11;14)-positive RRMM. The combination of VenDd has shown a high overall response rate and tolerable safety profile in the early phase study. The results in 81 patients showed:
The authors concluded that VenDd treatment showed higher rates of MRD-negativity and sustained MRD-negativity compared to DVd in patients with t(11;14)-positive RRMM.
Maintenance therapy with Revlimid (lenalidomide) is the standard of care following induction therapy and ASCT; however, all patients are at risk of relapse following transplantation, and up to 30% stop Revlimid maintenance therapy due to intolerable side effects. Thus, new treatment options with improved activity and tolerability are needed for maintenance therapy.
Iberdomide is a novel, potent oral cereblon E3 ligase modulator (CELMoD™), which is similar to but more potent than Revlimid, with a dual function: activate the immune system and directly kill myeloma cells by inducing the destruction of proteins that drive cancer growth. Researchers from the Netherlands reported (Abstract 208) that iberdomide maintenance therapy following ASCT showed an improvement in response over time in patients who received IMiD/PI-based induction with or without anti-CD38 antibody therapy and ASCT. Researchers noted that:
The most common serious side effects observed with iberdomide were low blood cell counts, infections, and fatigue.
The researchers conclude that iberdomide represents a novel effective post-ASCT maintenance strategy with a favorable safety profile and superior response improvement at 6 months than what has been observed with Revlimid maintenance. Iberdomide is currently being studied (versus Revlimid) as maintenance therapy following ASCT in a phase 3 trial.
While observation is considered standard of care for smoldering multiple myeloma (SMM) patients who have been identified as having a high risk of progressing to active myeloma, therapeutic intervention at the SMM stage may help delay the progression to MM.
Dr. Ola Landgren, and colleagues from the University of Miami presented the final analysis of the phase 2 CENTAURUS study that showed Darzalex monotherapy demonstrated clinical activity in 123 patients with Intermediate-Risk or High-Risk SMM after a median follow-up of approximately 7 years (Abstract 210).
The researchers examined 3 different dosing schedules (that is, long intense; intermediate; short intense) to determine the optimal schedule of treatment administration for the phase 3 AQUILA study. At a median follow up of 85 months, the study found:
The researchers conclude that this final analysis of CENTAURUS continue to demonstrate the clinical activity of DARA monotherapy in patients with intermediate- or high-risk SMM after a median follow-up of about 7 years, which supports the ongoing phase 3 AQUILA study and future SMM trials.
The final day of ASH gave us some insights into treatment for high-risk patients: those who are newly diagnosed with active myeloma and those who have smoldering multiple myeloma (SMM). Additionally, new data were presented on the use of Sarclisa in patients who relapsed early vs. late as well as on the risk of developing second primary malignancies after treatment with Revlimid.
Patients who have high-risk SMM progress much more rapidly to active myeloma than other SMM patients; some SMM patients may never have active disease. The ASCENT study (ABSTRACT 757) is investigating a treatment strategy aimed at reducing the risk of progression in high-risk SMM patients. A four-drug regimen (Darzalex-Kyprolis-Revlimd-dex [Dara-KRd]) is used as induction and consolidation followed by maintenance with Dara-R. Of the 41 patients who completed the scheduled treatment, 38 remain on study with 90% of patients progression-free at three years.
Several trials have looked at different induction and maintenance strategies for multiple myeloma patients considered to have high-risk disease; that is, patients who have genetic abnormalities that result in a faster relapse than patients who don’t have these abnormalities. High-risk MM was defined as the presence of certain cytogenetic abnormalities; these abnormalities differed between studies but in general included 1q amplification, t(4;14), t(14;16), t(14;20), and/or deletion(17p).
The studies that were conducted included:
In these studies, the time until myeloma progressed in patients was lengthened and was observed with the use of KRd as induction (via retrospective analysis) or extended Dara-VR consolidation (via OPTIMUM) and high MRD negativity rates after consolidation with Isa-KRd (via CONCEPT).
The Myeloma XI study data (ABSTRACT 754) was conducted to assess the impact of Revlimid on the development of second primary malignancies (SPMs) in both patients who had received high-dose melphalan (chemotherapy) and those who did not. In both groups, some patients received Revlimid both at diagnosis and for maintenance therapy, while others only received Revlimid at diagnosis or for maintenance.
In patients who had a stem cell transplant:
For those patients who did not have a stem cell transplant:
Investigators conclude that double-exposure is associated with higher incidence of SPM and while deaths were lower in the groups treated with Revlimid, clinicians should assess each individual’s risk of an SPM before starting Revlimid and have a plan for rapid intervention if needed.
The IKEMA trial (Sarclisa-Kyprolis-dex [Isa-Kd] vs Kyprolis-dex [Kd]) showed that patients with RRMM (who had received 1-3 prior lines of therapy) benefit from the use of isa-Kd with respect to depth of response and prolonged PFS, regardless of whether the relapse was early or late (ABSTRACT 753).
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Day 2 of ASH myeloma presentations brought us some updates on the use of FDA-approved treatments, including a closer look on the length of Revlimid maintenance therapy, and the clinical potential of a few investigational therapies for heavily pre-treated patients with myeloma.
Darzalex
There were two presentations that reported findings on patients’ quality of life following Darzalex-containing treatment regimens. Dr. Aurore Perrot and colleagues analyzed quality of life data collected from older (median age: 77 years) patients in the phase 3 MAIA trial, which showed the combination Darzalex-Revlimid-dexamethasone (D-Rd) improved progression-free survival (PFS) in older patients with newly diagnosed multiple myeloma (NDMM) who were not planning to have high-dose chemotherapy and a stem cell transplant vs Rd alone (Abstract 472).
Dr. Perrot reported that older patients treated with D-Rd showed sustained improvements in global health (overall health-related quality of life) and physical functioning, with notable reduction in pain through the duration of therapy. Additionally, a higher percentage of older patients continued on D-Rd longer compared to Rd.
In the next presentation, Dr. Silbermann and colleagues reviewed quality of life data obtained from transplant-eligible NDMM patients in the phase 2 GRIFFIN study which compared Darzalex-Revlimid-Velcade-dexamethasone (D-RVd) with RVd (Abstract 473). The authors found that the addition of Darzalex to RVd resulted in greater improvements in health-related quality of life for patients who continued on Revlimid maintenance treatment following induction and consolidation therapy versus RVd alone, again with a notable reduction in pain symptoms. Overall, these findings further support the addition of Darzalex to RVd in transplant-eligible patients with NDMM without compromise of health-related quality of life.
Tocilizumab has proven to be an effective treatment to lessen the impact of cytokine release syndrome, a common side effect experienced by patients who receive either CAR-T or bispecific monoclonal antibody treatment. Preclinical trials suggest that tocilizumab could prevent the development of cytokine release syndrome without limiting the anti-myeloma activity of treatment. In this presentation, Dr. Suzanne Trudel and researchers shared their findings from a phase 1 study that examined whether a single dose of tocilizumab could reduce cytokine release syndrome in myeloma patients who receive the next-generation bispecific antibody, cevostamab (Abstract 567). The results showed that pretreatment with tocilizumab significantly lowered the percentage of patients who experienced cytokine release syndrome (39% with tocilizumab pretreatment versus 91% without pretreatment) without any impact on anti-myeloma activity. The researchers conclude that the data support additional investigation of the use of tocilizumab pretreatment with the goal of substantially reducing the severity of cytokine release syndrome and potentially enabling the outpatient administration of cevostamab and other bispecific antibodies, compared to current protocols, which call for administration in the hospital setting only.
Optimal Duration of Revlimid Maintenance
Revlimid maintenance after stem cell transplant is standard of care for myeloma patients; however, the optimal length of time of maintenance therapy remains uncertain and may differ in subgroups of patients. Dr. Charlotte Pawlyn and colleagues presented their analysis of data from the Myeloma XI trial which included NDMM patients who were intending to receive high-dose chemotherapy and those who were not (Abstract 570). Their analysis reported clear evidence that continuing Revlimid maintenance beyond 3 years is associated with improved progression free survival, or the time before the disease came back, supporting recent findings from the DETERMINATION and STAMINA studies. There does, however, appear to be a time after stem cell transplant at which continuing maintenance may no longer have ongoing benefit over observation. The current analysis suggests that between 4 and 5 years, the benefit diminished in all patients, and this may occur earlier in the subgroup of patients who were minimal residual disease negative after stem cell transplant. Ongoing long term follow up of this and other studies is needed to define the optimal time point of stopping or continuing maintenance.
Modakafusp alfa
Dr. Dan Vogl and colleagues reported the final safety and efficacy findings from a phase 1 study of Modakafusp alfa, a first-in-class antibody–cytokine fusion protein (immunocytokine), allowing specific delivery of IFN to myeloma cells and immune cells involved in destruction of myeloma cells (Abstract 565). This trial was composed of heavily pre-treated myeloma patients, as participants had received at least 3 prior lines of treatment (including a proteasome inhibitor and one immunomodulatory drug), with 7 median lines of therapy. The results obtained from 30 myeloma patients showed:
The authors conclude that modakafusp alfa has a novel mechanism of action, a manageable safety profile, and encouraging efficacy at 1.5 mg/kg with once-a-week dosing. A phase 2 study to better define the best dosing with the optimal benefit/risk profile is currently enrolling.
Mezigdomide
CELMoDs are a new class of myeloma drugs that work like immunomodulators such as Revlimid and Pomalyst. They also stimulate the immune system and kill myeloma cells directly, even for myeloma that has become resistant to certain treatment. Dr. Paul Richardson and colleagues presented their findings from a phase 1/2 trial evaluating mezigdomide (Abstract 568), an oral CELMoD, alone or in combination with dexamethasone in myeloma patients who had previously received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. The median number of previous treatment regimens was 6. The results showed:
The researchers concluded that mezigdomide + dexamethasone had a manageable safety profile and demonstrated promising efficacy in patients with RRMM, including those with prior BCMA-targeted treatment. Mezigdomide is currently being evaluated in combination with standard treatment regimens in MM as part of a large, ongoing phase 1/2 trial and phase 3 trials in combination with proteasome inhibitors are planned.
BMS-986354
BMS-986354 is a next-generation CAR T-cell treatment that is made with a faster manufacturing process (about 5 or 6 days as opposed to several weeks with currently approved products). Dr. Luciano Costa and researchers reported their findings from the phase 1 CC-98633-MM-001 trial in patients who previously had received an autologous stem cell transplant, proteasome inhibitor, immunomodulatory drug, and an anti-CD38 monoclonal antibody – Darzalex or Sarclisa (Abstract 566). The results showed:
The study continues to enroll patients in the dose-expansion phase.
Stay tuned for more highlights from ASH!
Welcome to our 2022 recap of the latest updates on myeloma treatments reported at the American Society of Hematology (ASH) meeting that kicked off Saturday in New Orleans. Some of the studies presented provided updates to data previously presented at meetings earlier this year and late last year. Let’s dig into a big day of updates in myeloma treatment.
Tecvayli
Tecvayli is the first “off-the shelf” BCMA-targeted bispecific antibody approved for patients with heavily pretreated relapsed refractory multiple myeloma (RRMM). Dr Emma Searle and colleagues presented results from phase 1 MajesTEC-2 trial on 32 relapsed/refractory myeloma patients treated with Tecvayli-Darzalex-Revlimid, the first fully immune-based triplet treatment combination (ABSTRACT 160). The median prior lines of therapy were 2 (range of 1-3), and 31% had received a CD38 monoclonal antibody. Results showed that 93.5% of patients responded to treatment:
The authors conclude that Tecvayli-Darzalex-Revlimid was well tolerated, with a safety profile consistent with Tecvayli or Darzalex-Revlimid individually. Promising response rates rarely seen in this population supports the potential for this combination to have enhanced early disease control through the addition of Tecvayli. The randomized phase 3 MajesTEC-7 study will compare Tecvayli-Darzalex-Revlimid versus the combination of Darzalex-Revlimid-dexamethasone in newly diagnosed multiple myeloma patients not eligible for or not intending to pursue autologous stem cell transplant as initial treatment.
Talquetamab
Talquetamab is a first-in-class, T-cell redirecting bispecific antibody targeting GPRC5D on myeloma cells and CD3 receptors on T cells. Last week Janssen submitted a Biologics License Application to the U.S. Food and Drug Administration for talquetamab for the treatment of patients with RRMM. Dr. Ajai Chari and researchers presented results from a phase 2 study of talquetamab as administered as an injection as opposed to an infusion which is how most other bispecifics are given at 2 different doses (0.405 mg/kg weekly and 0.8 mg/kg every other week) in relapsed/refractory patients (ABSTRACT 157). Eligible patients had RRMM or were intolerant to standard therapies. Patients had received at least 3 or more lines of prior therapy or were double refractory to a proteasome inhibitor such as Velcade and/or Kyprolis and an immunomodulatory drug such as Revlimid and/or Pomalyst. Prior treatment with a CD38 monoclonal antibody was allowed with a 90-day washout; prior BCMA-directed therapies were permitted. The results showed:
The authors conclude that talquetamab shows highly promising efficacy in a heavily pretreated RRMM patient population. An ongoing phase 3 study is comparing talquetamab with approved therapies.
Elranatamab
Updated results were presented on the MagnetisMM-1 trial, a phase 1 trial investigating the safety and efficacy of the BCMA-targeted bispecific antibody elranatamab as a single agent. Fifty-five patients who had been exposed to a median of 6 prior treatments (91% no longer responded to three classes of standard therapies; 24% had received prior BCMA-targeted therapy) received elranatamab subcutaneously (via injection) (ABSTRACT 158). Dr Noopur Raje and investigators reported:
Dr Nizar Bahlis presented results from the MagnetisMM-3 trial (ABSTRACT 159), a phase 2 study of elranatamab in patients with RRMM (exposed to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody). One hundred and twenty-three patients with relapsed/refractory myeloma (exposed to at least 6 prior lines of therapy) were treated with Darzalex (subcutaneously) and differing doses of talquetamab. Results showed:
The researchers suggest that subcutaneous elranatamab is efficacious and has a manageable safety profile in patients with triple-class- and penta-drug refractory MM and no prior BCMA-targeted treatment. These results support continued development of elranatamab for pts with MM.
Alnuctamab
Alnuctamab is a bispecific antibody that targets BCMA on myeloma cells and CD3 receptors on T cells that is being evaluated in a phase 1 study for patients who have been exposed to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody (ABSTRACT 162). Results collected from 55 patients treated with alnuctamab found:
Cytokine release syndrome and low red and white blood counts were the most common side effects, which is consistent with other similar therapies.
RG6234
Dr Carmelo Carlo-Stella reported findings from a phase 1 study of RG6234, a bispecific antibody targeting GPRC5D, an orphan receptor expressed on MM cells with limited expression in other tissues, and CD3 receptors on T cells (ABSTRACT 161). One hundred and five patients with relapsed/refractory myeloma (exposed to at least a proteasome inhibitor and an immunomodulatory drug) were treated with differing doses of RG6234 (subcutaneously or intravenously). Results showed:
Dr. Paul Richardson from the Dana-Farber Cancer Institute presented updated data from the ICARIA-MM phase 3 trial which compared Sarclisa-Pomalyst-dexamethasone with Pomalyst- dexamethasone in 307 patients with relapsed or refractory myeloma (Abstract 247). Sarclisa is an antibody in the same class as Darzalex. The initial results from this trial were the basis for the approval of Sarclisa in combination with Pomalyst-dexamethasone.
In the follow-up analysis presented by Dr. Richardson, the findings showed how patients fared on subsequent therapies after no longer being on Pomalyst-dexamethasone with or without Sarclisa:
The researchers conclude that immediate use of an anti-CD38 monoclonal antibody such as Darzalex with currently available combinations appears to be less effective following treatment with Sarclisa-Pomalyst-dexamethasone. These findings will help guide the best sequencing of treatment for patients.
Abecma
Patients with MM who relapse early after frontline therapy with autologous stem cell transplant (ASCT) have a poor prognosis. In the pivotal phase 2 KarMMa study, treatment with the BCMA-directed chimeric antigen receptor (CAR) T cell therapy Abecma resulted in frequent, deep, and durable responses in patients who were triple-class exposed and refractory to last treatment. In this presentation, Dr Krina Patel presented data collected from 37 patients who were treated with Abecma after early relapse within 18 months of frontline therapy with ASCT and Revlimid maintenance (Abstract 361). The results showed:
The researchers conclude that these results support a favorable clinical benefit-risk profile of Abecma and its potential use in earlier lines of treatment.
BMS-986393
CAR T cell therapies targeting B‑cell maturation antigen (BCMA) have resulted in unprecedented responses in RRMM; however, relapses are frequent, and the development of new approaches is needed. Dr Susan Bal and colleagues presented interim results from a phase 1 dose-finding study of BMS-986393, a GPRC5D-targeted CAR T cell therapy, in patients with RRMM (Abstract 364). Patients enrolled in the trial had at least 3 prior lines of therapy containing a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 therapy, and, unless ineligible, a stem cell transplant. The results showed:
These results appear promising, especially for patients who relapse following BCMA-targeted treatment. The dose-finding trial is ongoing and additional updates will be presented at future meetings.
GC012F
GC012F is a new, dual-targeting CAR-T cell therapy that binds to BCMA and CD19 on myeloma cells and is manufactured within 24 hours of removal of plasma from a patient. Dr Juan Du and colleagues reported their findings from a phase 1 trial of GC012F in high-risk, transplant-eligible patients with NDMM (Abstract 366). Patients were considered high-risk if they had one or more of the following features: R-ISS-2 or-3; del17p, t (4;14), t (14;16), or 1q21amp ≥ 4 copies; extramedullary disease; IgD or IgE subtype; LDH > the upper limit of normal; or any of the high-risk definition of mSMART3.0. The results showed:
The authors conclude that these promising preliminary results require further assessment of GC012F for transplant-eligible NDMM with more patients and longer follow-up.
Racial disparities exist in incidence and survival from myeloma and other blood cancers, and these differences are driven by multiple factors the most influential likely being access to clinical trials. Black patients only make up 5-7% of participants in cancer clinical trials, despite accounting for 14% of the population in the United States and more than 20% of multiple myeloma patients. Dr Shakira Grant presented two abstracts (Abstract 360 and Abstract 363) in Patient Representation and Equity in Hematologic Malignancies. Dr Grant and researchers conducted focus groups with Black patients with MM and interviewed hematologists to identify factors that influence Black participant enrollment in hematology-focused clinical trials).
Dr Grant and colleagues reported that the relationship between the patient and their hematologist is one of the most influential drivers of whether Black patients are given an opportunity to participate in clinical trials. Additional factors include 1) race and socioeconomic status-based bias and stereotyping on the part of hematologists, 2) the legacy of medical mistrust among Black persons, 3) geographic barriers, and 4) the use of stigmatizing languages such as the word “trial.”
Researchers reported that addressing disparities in clinical trial enrollment among Black participants requires numerous interventions such as
Increasing equitable access to clinical trials and ensuring our own research efforts are representative of the broader multiple myeloma population in the US are priorities for the MMRF, reflected in our most recent strategic plan.
Dr Shaji Kumar presented findings from the MMRF’s MyDRUG platform trial (Abstract 1931). Unlike traditional clinical trials, which test one drug or a single combination of drugs, the MyDRUG platform trial is a phase 1/2 study of patients with RRMM, who have received at least one prior but no more than 3 prior therapies and were exposed to both a proteasome inhibitor and an immunomodulatory drug and had early relapse after initial treatment or were primary refractory to initial treatment. Through different subprotocols, patients received targeted agents, immunotherapy, or novel agents in combination with a backbone regimen of Ninlaro/Pomalyst/dexamethasone, also known as IPD.
In this abstract, Dr Kumar and colleagues reported data collected from thirty-eight patients who were treated with Darzalex plus IPD. Results showed:
Stay tuned for more updates from ASH 2022!
