On April 12, the FDA Oncologic Drugs Advisory Committee, or ODAC, met with leading multiple myeloma key opinion leaders (KOLs) and other stakeholders to discuss the topic of minimal residual disease, or MRD, as a clinical endpoint. Two groups, the Sylvester Comprehensive Cancer Center of Miami FL, led by Dr. Ola Landgren, and the i2TEAMM, led by Drs. Brian Durie (IMF) and Nikhil Munshi (DFCI), presented data from separate meta-analyses (meaning data from numerous previous studies that are combined to produce a summary study that is more likely to have statistically significant results) of previous clinical trials where MRD was measured at specific timepoints and then correlated to progression free survival (PFS) and overall survival (OS). These meta-analyses together involved 42 clinical trials and 21,006 patients in total. Specifically, the question the ODAC discussed and voted on was “Does the data presented support the use of MRD as an intermediate clinical endpoint for accelerated drug approval in multiple myeloma?”
As a bit of background, the MMRF, in collaboration with Dr. Landgren and the FDA, has been supporting yearly meetings on this topic since 2014. There is a clear need for new therapies in myeloma, and with new immunotherapies currently lengthening the lives of patients and improving overall response rates (ORR), it has become more difficult to accumulate significant PFS data in trials in a reasonable timeframe, which is currently required for FDA approval; this can sometimes take up to 10 years, and many patients are unable to wait that long for new effective therapies to be approved. Using MRD measurement at a specific timepoint in a trial, 9 months and/or 12 months (+/- 3 months) after treatment is initiated, may provide assessment of sustained MRD, which is a hallmark of deep response to the clinical regimen.
After careful presentation of the data by both groups and an extended discussion with the FDA of the take-aways from the data, the ODAC panel voted 12-0 in favor of the use of MRD as an intermediate endpoint to support accelerated approval. What this means:
MRD testing may become more commonplace, but for now is mainly available only in major academic medical centers. For more information about this topic or anything else myeloma-related, please contact our patient navigators at 1-888-841-6673, Mon-Fri 9AM – 7PM ET, or by email at [email protected].
In most cases, myeloma cells release monoclonal antibodies (M-protein) into your blood and urine. In rare cases, myeloma cells do not make any monoclonal antibodies, a condition called non-secretory myeloma. It can be difficult to diagnose patients with non-secretory myeloma because they have no M spike. While treatment for non-secretory myeloma is often the same as for other types of myeloma, it is more difficult to monitor treatment efficacy since doctors cannot use a simple blood test to detect the M protein.
This is an advantage of having multiple ways to measure MRD. For the clonoSEQ test, a patient needs a baseline bone marrow biopsy sample to establish the presence of an individual’s DNA sequence in the myeloma cells that can then be tracked over time. Flow cytometry does not require a baseline sample from the patient, so this is an alternative test to measure MRD if the initial bone marrow biopsy sample is not available. Flow cytometry can be used to simply count the number of myeloma cells from a recent bone marrow biopsy.
Currently there is no test that is FDA approved to measure MRD from a peripheral blood sample. There are several studies that are evaluating the use of blood-based test to measure the levels of M-proteins or circulating tumor DNA; that is a DNA fragment released by myeloma cells during cell death. Additional studies are needed to determine if a blood-based MRD test could be introduced in the clinical in the near future.
The age and the performance status of the patient play a role in determining which treatment is selected. Someone who is frail and/or has a poor performance status may be better suited for a bispecific antibody. Whereas a younger patient with a good performance status could be a better candidate for CAR T-cell therapy. There is currently no limit on the age of a patient who can receive bispecific antibody therapy. Healthcare professionals should have a discussion with the patient to see what is in line with the goals of the patient.
That is the million-dollar question. Findings from recent clinical trials have shown that the overall response rate was higher in patients who have received CAR T therapy first. Generally, the myeloma community believes that you can use CAR-T first and then use bispecific antibody therapy following relapse. If we treat patients with a BCMA-directed bispecific antibody first, the efficacy of a follow-up BCMA-directed CAR-T therapy may not be as strong. However, every situation is unique. For example, one doctor had a patient who had rapidly progressive disease and needed treatment immediately with a bispecific antibody while the CAR-T was being developed.
While we have moved the needle and improved outcomes for patients with standard risk disease, there is a long way to go when it comes to improving outcomes in patients with high-risk myeloma. That is why we have the MMRF HORIZON platform trials. We need new trials with new designs to see how bispecific antibodies can improve the outcomes of patients with high-risk disease. There is a lot of interest in the community to see how these newer trials can address the unmet need of this patient population.
Multiple myeloma is a complex cancer, different in every patient. This complexity makes it difficult to predict what therapy will work best for each patient. Knowing a patient’s prognosis at the time of their diagnosis can help their care team decide which therapy would be most effective for first line treatment.
Differences in myeloma in each patient can be traced back to the complex DNA changes (also known as the “genomic landscape”) in each patient’s myeloma cells. This information can only be measured in tumor cells collected during the bone marrow biopsy. Researchers have long looked to catalog what these changes are, and which ones are important to a patient’s overall survival. This type of work requires a large dataset of DNA sequences from many myeloma patients, their clinical history (i.e., what they were treated with and how well the treatment worked) and their demographic data. No single clinical center in the world sees enough patients to generate a data set like this on its own.
We began our multi-year CoMMpass study back in 2011 to build such a dataset. It is the largest and most complete dataset of its type in myeloma, and more than 605 researchers around the world have used this dataset to form and test their hypotheses. CoMMpass holds the detailed genomic and clinical data of over 1000 newly diagnosed patients from 76 centers in 4 countries. These patients agreed to join this research study, enrolled over the course of 4 years and were followed for 8 years; the data is freely available to researchers worldwide. Numerous papers are published yearly using CoMMpass data, and it has been invaluable in helping to develop early risk and prognosis models in myeloma patients.
Recently, Dr. Francesco Maura of the Sylvester Comprehensive Cancer Center at the University of Miami, and colleagues from various institutions, published a new model of genomic classification and prognosis in multiple myeloma. The model was developed using detailed clinical, genomic, and therapeutic data from 1933 patients, 1062 of which were from the CoMMpass dataset. Using this data, the investigators developed a model called Individualized Risk Model for Myeloma (IRMMa) that found 12 genomic groups with high prognostic accuracy compared to earlier models. The IRMMa model was then confirmed on 256 patients enrolled in the GMMG-HD6 clinical trial and was used to show which patients benefitted significantly from autologous stem cell transplant (ASCT) vs. those who saw limited benefit. The model performed well, with good overlap seen between observed risk and risk predicted by the model for each patient. This machine learning model is now publicly available for other myeloma researchers, who are encouraged to add their own patient data to it. Further testing is necessary before this preliminary model becomes a clinical test. It is only through analyzing large data sets that researchers can accurately identify predictive signatures that could guide clinical decision-making.
In conclusion, predictive models of this type require large datasets for their accurate development. The MMRF built the CoMMpass dataset for exactly this purpose, and this treasure trove of myeloma data is now bearing fruit. It is hoped that additional data added to the IRMMa model will sharpen its predictive ability so that eventually, every newly diagnosed patient will receive the best, most effective therapy for their own unique type of myeloma.
1. With the difficulty in a timely diagnosis of multiple myeloma (MM) for underserved patient populations, including Black African Americans and Hispanics, what are the early symptoms that a patient can share with their health care provider (HCP)?
There are significant disparities with regards to the timely diagnosis of MM in underserved patient populations. While many symptoms of MM such as fatigue and bone pain are nonspecific and can be seen in many other conditions, patients should see a doctor to determine the cause of these symptoms. It is very important for patients to be advocates for their own health and to be persistent in finding a cause for their symptoms.
2. Given the disparity in treatment of MM in certain underserved patient populations, what is the standard of care that patients should be asking for?
Unfortunately, there are barriers to appropriate therapy that contribute to application of treatment approaches for underserved patient populations that are inconsistent with current recommended practice. Currently there is a no one-size-fits-all treatment option for MM. There are very broad guidelines doctors adhere to when selecting treatment for each individual patient. A newly diagnosed patient should be treated with either a 3- or 4-drug regimen as first-line therapy. There are different factors that would favor the use of either the 3- or 4-drug combination. All patients should be evaluated to see if they are eligible for a stem cell transplant. Supportive care should be provided to every patient. Supportive care is treatment that addresses the symptoms and complications of a disease rather than the disease itself. Examples include bisphosphonates for bone health, antibiotics for infections, and pain control measures.
In the relapse setting, it is very important for patients to ask their doctor why a certain treatment is being chosen, and if possible, patients should be included in the decision-making process. Also, it is vital that patients seek the opinion of a myeloma specialist during key treatment decision points, such as when relapse necessitates a change in therapies.
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!
Norwalk, Conn., December 7, 2023 – The Multiple Myeloma Research Foundation (MMRF) announced today that data from its landmark CoMMpass Study and Immune Atlas fueled 12 oral presentations to be presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego from December 9-12. In total, 34 different presentations use MMRF data. These advances represent important and continued innovation in multiple myeloma research.
“Our investment in the generation, analysis, and sharing of robust research and clinical data is fundamental to our relentless effort to drive progress in multiple myeloma treatment and ultimately a cure for each and every patient,” said Michael Andreini, President and CEO at the MMRF. “For over a decade, CoMMpass data has been analyzed by more than 300 researchers worldwide, making it one of the most highly published datasets in myeloma.”
Among the 34 CoMMpass abstracts to be highlighted at ASH are findings related to predictive biomarkers, disease progression, therapeutic resistance, risk assessment, genetic profiling to interpret the outcomes of early intervention for high-risk smoldering myeloma, and precision medicine.
One oral presentation from the Immune Atlas team reports on the results of single-cell RNA sequencing of bone marrow cell samples from 263 multiple myeloma patients enrolled at time of diagnosis in the CoMMpass Study. Using single cell transcriptomics, researchers captured the TIME (tumor immune microenvironment) and correlated specific immune cell populations and phenotypes with relapse risk and poor prognostic outcomes. These results suggest that immune subpopulations may be an essential novel aspect for improving current risk stratification models. These single-cell data are also part of a prognostic analysis of myeloma subtypes reported in a second oral presentation, in which collaborators at Genentech develop more refined subtypes using this Immune Atlas data, with improved characterization of early relapse.
“The Immune Atlas data have shown how immune function provides additional information beyond tumor subtyping, refining our understanding of risk and potentially advancing prognostication and strategies for clinical trials,” said George Mulligan, PhD, Chief Scientific Officer at the MMRF. “We will continue to push the envelope of innovative science in our urgent pursuit of better clinical strategies and more effective treatments for each and every patient with multiple myeloma.”
The CoMMpass Study is an ongoing study of patients with active multiple myeloma, who enrolled at diagnosis and are being followed for eight years. The study maps patients’ tumor genomic profile to clinical outcomes with the goal of developing a more complete understanding of both disease biology and the patient’s response to treatments. With its inclusion in more than 300 published or presented studies, CoMMpass represents the largest longitudinal genomic dataset in multiple myeloma and has led to groundbreaking discoveries that have transformed how researchers understand the biology of the disease. The MMRF makes the CoMMpass data available to researchers globally and updates results at regular intervals.
The MMRF Immune Atlas is a collaboration to study the immune system in multiple myeloma and establish a “gold standard” immune profiling platform for use in multiple myeloma research studies. This information, from hundreds of patients, will be combined with the existing genomic and clinical data from our CoMMpass Study to develop a more comprehensive picture of myeloma disease biology. These resulting insights will be helpful in guiding optimal therapy for myeloma patients.
The Multiple Myeloma Research Foundation (MMRF) is the largest nonprofit in the world solely focused on accelerating a cure for each and every multiple myeloma patient. We drive the development and delivery of next-generation therapies, leverage data to identify optimal and more personalized treatment approaches and empower myeloma patients and the broader community with information and resources to extend their lives. Central to our mission is our commitment to advancing health equity so that all myeloma patients can benefit from the scientific and clinical advances we pursue. Since our inception, the MMRF has committed over $500 million for research, opened nearly 100 clinical trials, and helped bring 15+ FDA-approved therapies to market, which have tripled the life expectancy of myeloma patients. To learn more, visit www.themmrf.org.
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C.J. Volpe
Director, PR and Communications
203-652-0453
[email protected]
Norwalk, Conn., November 15, 2023 — The Myeloma Investment Fund (MIF), the Multiple Myeloma Research Foundation’s (MMRF) venture philanthropy subsidiary, today announced an investment in Reverb Therapeutics to explore the potential of its antibody-based Amplifier™ platform for the treatment of multiple myeloma with endogenous cytokines that naturally occur within the body.
Reverb is a seed-stage oncology company with a highly differentiated platform approach to cytokine therapy. Its Amplifier™ platform uses antibodies to localize endogenous cytokines to immune cells in the tumor microenvironment (TME) and overcome toxicity issues of exogenously delivered cytokines. Instead of using heavily engineered exogenous cytokines to treat diseases, which present challenges such as systemic toxicity and immunogenicity, Reverb’s antibodies redirect endogenous cytokines already in the body to cells of interest. With this round of funding, the MIF joins Reverb’s founding and lead investor Amplitude Ventures to support the company’s initial debut of its platform for the potential treatment of multiple myeloma and other cancers.
“We look forward to our partnership with Reverb Therapeutics and the potential of its Amplifier platform as a treatment for multiple myeloma,” said Michael Andreini, President and CEO at the Multiple Myeloma Research Foundation. “The MIF is committed to identifying and accelerating the most innovative treatment approaches for myeloma patients and we are excited by the potential of this novel approach to cytokine therapy.”
“We are excited about the power that the Myeloma Investment Fund brings to Reverb Therapeutics,” said David de Graaf, PhD, Founder and CEO of Reverb Therapeutics. “Having the scientific and clinical team at the MMRF available to an early-stage company is unique. We can translate their knowledge, focus, and dedication to improve the lives of multiple myeloma patients into impactful therapies such as our IL-15 programs.”
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About the Myeloma Investment Fund
The Myeloma Investment Fund is a venture philanthropy fund that invests in promising companies, clinical assets, and technologies in oncology to drive the development of new therapies for multiple myeloma. The MIF collaborates closely with portfolio companies to help them advance multiple myeloma research. This evergreen fund is supported entirely by philanthropy; all profits will be reinvested back into research for more effective treatments until there is a cure for every patient. For more information, visit www.myelomainvestmentfund.org
About the Multiple Myeloma Research Foundation
The Multiple Myeloma Research Foundation (MMRF) is the largest nonprofit in the world solely focused on accelerating a cure for each and every multiple myeloma patient. We drive the development and delivery of next-generation therapies, use data to drive optimal and more personalized treatment approaches, and empower myeloma patients with information and resources to extend their lives. Central to our mission is our commitment to advancing health equity so that all myeloma patients can benefit from the scientific and clinical advances we pursue. Since our inception, the MMRF has raised over $500 million for research, opened nearly 100 clinical trials, and helped bring 15+ FDA-approved therapies to market, which have tripled the life expectancy of myeloma patients. To learn more, visit www.themmrf.org.
About Reverb Therapeutics
Based in Vancouver, Reverb Therapeutics is the leader in the development of treatments for cancer and other diseases using the body’s natural endogenous cytokines. Reverb’s Amplifier™ Antibody platform avoids the systemic toxicity normally associated with cytokine treatments by increasing cytokine levels only in targeted tissues. Elements of Amplifier antibodies are reusable, allowing Reverb to rapidly scale its pipeline across multiple disease areas. Learn more about opportunities to work with Reverb by contacting [email protected].
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Multiple Myeloma Research Foundation Media Contact:
C.J. Volpe, Director, PR and Communications
203-652-0453
[email protected]
Non-BCMA targeting bispecific antibodies are a relatively new class of therapeutics. In our Patient Webinar on October 11, 2023, Drs. Ajai Chari (UCSF) and Suzanne Trudel (University of Toronto, Princess Margaret Hospital, Ontario, Canada) provided fascinating updates on this emerging class of agents.
Bispecific antibodies belong to the drug class known as T-cell engagers, which also includes CAR T-cells. Unlike CAR T-cells, which are engineered (over the course of 4-6 weeks) from a patient’s own T-cells to better recognize and kill myeloma cells, bispecific antibodies are an “off-the-shelf” treatment that can bind to both myeloma cells and to T cells at the same time, bringing them in close proximity so that the T cells can recognize and kill the myeloma cells. There are now three bispecific antibody therapies approved in the US for myeloma patients who have received at least four previous lines of therapy; two of these bind to BCMA on the surface of myeloma cells, and one binds to a molecule called GPRC5D on the surface of myeloma cells.
Dr. Chari began by discussing Talvey (talquetamab), a GPRC5D-targeting bispecific antibody approved for use in the US. Historically speaking, the bispecific antibody drug class offers increased activity in highly pre-treated myeloma patients (those who have already received 4 or more lines of therapy). The relative activity of a number of different drugs in this patient population is seen in this slide:
In comparison to current standards of care, such as Pomalyst/dexamethasone, it is clear from this figure that the three currently approved bispecifics—teclistamab (Tecvayli), talquetamab (Talvey), and elranatamab (Elrexfio)—have superior activity in this patient population in terms of both progression-free survival and duration of response (NR means the duration of response was not reached, as so many patients were still responding at the time the data was collected). Dr. Chari also mentioned that of the 288 patients enrolled in the Talvey Phase1/2 trials, 51 had received prior therapy with T-cell engagers, and their response rate compared to those who had not previously received such therapy was only slightly lower (65% vs 73%).
Regarding side effects and adverse occurrences, Dr. Chari provided some further fascinating facts on Talvey not demonstrated on a slide. Dr. Chari stated that patients who experienced more severe side effects (particularly skin rashes and nail issues) also responded better to Talvey. As a result, there is a correlation between side effects and pharmacological action, which may give patients who are experiencing discomfort from side effects optimism that the medication may work for them. He added that patients with the most severe adverse effects can benefit from other treatments or dose decrease, and that generally, these side effects do get better with time.
Next, Dr. Trudel discussed cevostamab, a FcRH5-targeting bispecific antibody that is still in clinical trials. Two noteworthy pieces of information emerged from her presentation:
Thank you to these two amazing doctors, and also to our patient speaker, Nick Lenoir, for sharing their knowledge! Nick was especially interesting, as he is currently receiving treatment with Talvey and is having issues with side effects, so he was very happy to hear that this meant he is more apt to respond to this therapy.
For more information on bispecific antibodies and other myeloma therapies, please visit our Treatment Options page https://themmrf.org/diagnosis-and-treatment/treatment-options/.
