They will present research findings at the 2024 annual meeting of the American Society of Hematology (ASH), which will be held Dec. 7-10 in San Diego.
“We’d like to develop a curative treatment for multiple myeloma, and we are at the point where that’s possible,” said C. Ola Landgren, M.D., Ph.D., who leads the Sylvester Myeloma Research Institute.
Key research questions include how to best combine treatments, overcome resistance and tailor therapy to the individual. Scientists are also addressing how to track disease best to optimize outcomes, including through highly sensitive techniques that measure minimal residual disease (MRD).
Below are some of the key ASH presentations involving Landgren and his collaborators.
New Drugs, New Questions - How we do it: New combinations reshaping treatment decision-making in newly diagnosed multiple myeloma
Landgren will chair this key symposium, discussing what the advent of new therapies means for the field and how to apply new data to clinical situations.
One area of discussion will focus on combination therapies containing immunotherapy drugs called CD38-targeting antibodies, which are highly effective in many newly diagnosed patients. Researchers, for instance, will discuss which combinations should be used in different clinical scenarios.
Another major question is whether to offer bone marrow or hematopoietic cell transplantation to patients with a strong initial response to the new drugs. “Does everyone eligible need a transplant?” asked Landgren.
Finding the Best Combination - Efficacy of Elranatamab (ELRA) in Combination with Carfilzomib (CFZ) and Dexamethasone (DEX) in the Phase 1b MagnetisMM-20 Trial in Relapsed or Refractory Multiple Myeloma (RRMM)
Immunotherapy is not only changing outcomes in newly diagnosed patients but also benefiting patients with relapsed multiple myeloma or myeloma that does not respond to first-line treatment (refractory disease). Such patients often receive “bispecific antibodies” that bind to both immune cells and multiple myeloma cells.
Landgren and his team are studying how to best combine bispecific antibodies with other treatments in relapsed or refractory disease. His colleague Michael Tomasson, M.D., from the University of Iowa, will present data on an ongoing collaborative phase 1b clinical trial testing the bispecific antibody elranatamab in combination with two other drugs (carfilzomib and dexamethasone). The findings show “demonstrated clinical efficacy” and “predictable” safety signals.
“Everyone is wondering, what are the optimal partner drugs for the new bispecific antibodies? What do the dosing schedules look like? How often do you have to give these drugs in combination, for how long do you treat to achieve deep and durable responses, and so forth? That's what this study is about,” said Landgren, the senior researcher on the multicenter trial.
Minimizing Side Effects - Tocilizumab Prophylaxis for Patients with Relapsed or Refractory Multiple Myeloma Treated with Teclistamab, Elranatamab or Talquetamab
Bispecific antibodies yield high response rates, but most patients also experience side effects, including cytokine release syndrome (CRS) and a neurotoxicity syndrome.
Sylvester researchers are studying whether these side effects can be reduced by giving patients the drug tocilizumab prior to bispecific antibody treatment. At ASH, Sylvester researcher Andrew Kowalski, PharmD, reports low rates and low severity of CRS and neurotoxicity in 72 patients treated with this approach, with data in sync with previous studies.
The findings could potentially lead to a reduced need for inpatient hospital visits in the step-up dosing phase, which are currently part of standard of care to monitor for side effects during the first phase with bispecific antibody treatments. “We are not yet there, but we are heading in that direction,” said Landgren.
Overcoming Resistance - Convergent Evolution Towards CD38 Biallelic Loss Is a Recurrent Mechanism of Resistance to Anti-CD38 Antibodies in Multiple Myeloma
While new immunotherapies have increased survival rates, resistance to treatment often eventually develops. Understanding how resistance occurs and how to respond to it is a major precision medicine goal, and multiple researchers at Sylvester are pursuing it.
One common mechanism of resistance for CD38-targeting drugs is loss of the cellular target. Sylvester physician-scientist Benjamin Diamond, M.D., will present a comprehensive genetic analysis of multiple myeloma cells to understand how CD38 loss occurs. One key finding was that some relapsed patients (3/50) acquired genetic mutations inactivating CD38 in both cellular chromosomal copies. Such detailed analyses of the mechanisms of resistance can guide treatment decisions.
Overcoming Resistance - Genomic Determinants of Clinical Outcomes in Multiple Myeloma with t(11;14)(CCND1;IGH) Treated with Venetoclax
The drug venetoclax is a current example of precision therapy since it is given to patients with certain chromosome rearrangements. But not all of these patients respond. Sylvester physician-scientist Marcella Kaddoura, M.D., and her colleagues performed a deep genetic analysis in such patients to ask why. The data showed mutations associated with poor responsiveness to the drug. The findings highlight how genomic profiling can help better select patients for venetoclax treatment.
Overcoming Resistance - Intrinsic Tumor Drivers and Immune Escape Mechanisms in CD19 CAR T-Cell Therapy Resistance for Aggressive Large B Cell Lymphoma
Landgren and his colleagues are also studying the drivers of resistance in other related blood cancers to look for similarities and differences in mechanisms of resistance to modern immunotherapies. Sylvester researcher Bachisio Zicchedu reports on the genetic mechanisms of resistance to CAR T-cell therapy in diffuse large B cell lymphoma. The findings could lead to new ways to circumvent resistance.
Tracking Disease - Circulating Tumor DNA As a Minimally Invasive Predictor of Early Relapse in Multiple Myeloma
The effectiveness of therapy is increasingly being monitored through molecular assays to measure minimal residual disease. These assays are designed to detect minute numbers of cancer cells in the body.
Bone marrow is typically used for MRD analysis, but Sylvester researchers are exploring the possibility of using blood, which offers the advantage of less invasive and more frequent sampling. At ASH, Sylvester researcher Palak Bajaj showed that tumor DNA is readily detected in blood and can yield key data about the course of disease, including MRD and the accumulation of new mutations.
Improved MRD testing will be essential for better-monitoring patients in the future, developing new therapies, and supporting precision medicine tailored to the individual.
Finding Root Causes - Increased Risk of Monoclonal Gammopathy of Undetermined Significance in US Military Service Members: A Case-Control Study of 1,589 Service Members Deployed to Either Iraq, Germany, or Not-Deployed Ex-US with or without Reported Burn Pit and Toxic Smoke Exposure
Environmental factors are known to play a role in the development of multiple myeloma, and Landgren has long investigated them — from Agent Orange exposure among U.S. service members in Vietnam to toxin exposures among first responders at the World Trade Center after 9/11.
At ASH, Dickran Kazandjian, M.D., the associate director of the Myeloma Research Institute, will present his findings on U.S. military service members exposed to burn pits while deployed to Iraq or Afghanistan. He and his colleagues are asking if fumes and smoke from the pits increase the risk of developing a precursor condition to multiple myeloma.
Bringing it All Together
These are just some of the dozens of studies that will be presented at ASH by Landgren and the Sylvester myeloma team and external collaborators.
Several research angles are needed to build on the success of newer immunotherapies and targeted drugs to yield better outcomes in multiple myeloma with fewer side effects, said Landgren.
“We are developing immunotherapy-based, chemotherapy-free regimens for patients diagnosed with multiple myeloma, and we are driving precision medicine to better select patients and to overcome resistance and to identify patients who may not first respond,” he said. “We are also drivers of MRD for clinical management. We are talking about a segue toward a cure for multiple myeloma.”
More than 70 researchers at the Sylvester Myeloma Research Institute are actively studying these areas and others. The institute also supports more than 20 clinical trials.
Landgren envisions a future where patients routinely receive therapy tailored to the features of their cancer and where disease is vigilantly monitored at the molecular level for response to treatment.
“In order to take it to the next level, you need to drill deeper. You have to be more sophisticated in your approach to the disease and how to better treat all the different subtypes of disease that our patients have,” said Landgren. “We are exiting the one-size-fits-all era, and we are entering an era of precision medicine for myeloma.”
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How We Do It®: New Combinations Reshaping Treatment Decision-Making in Newly Diagnosed Multiple Myeloma
Friday, December 6, 2024: 7:00 PM-10:00 PM PST
Room 30 (San Diego Convention Center)
1024 Efficacy of Elranatamab (ELRA) in Combination with Carfilzomib (CFZ) and Dexamethasone (DEX) in the Phase 1b MagnetisMM-20 Trial in Relapsed or Refractory Multiple Myeloma (RRMM)
Monday, December 9, 2024: 5:15 PM PST
Hall B (San Diego Convention Center)
Tocilizumab Prophylaxis for Patients with Relapsed or Refractory Multiple Myeloma Treated with Teclistamab, Elranatamab or Talquetamab
Monday, December 9, 2024: 3:00 PM PST
San Diego Ballroom AB (Marriott Marquis San Diego Marina)
592 Convergent Evolution Towards CD38 Biallelic Loss Is a Recurrent Mechanism of Resistance to Anti-CD38 Antibodies in Multiple Myeloma
Sunday, December 8, 2024: 12:45 PM PST
San Diego Ballroom AB (Marriott Marquis San Diego Marina)
249 Genomic Determinants of Clinical Outcomes in Multiple Myeloma with t(11;14)(CCND1;IGH) Treated with Venetoclax
Saturday, December 7, 2024: 2:30 PM PST
San Diego Ballroom AB (Marriott Marquis San Diego Marina)
232 Intrinsic Tumor Drivers and Immune Escape Mechanisms in CD19 CAR T-Cell Therapy Resistance for Aggressive Large B Cell Lymphoma
Saturday, December 7, 2024: 2:45 PM PST
Pacific Ballroom Salons 15-17 (Marriott Marquis San Diego Marina)
252 Circulating Tumor DNA As a Minimally Invasive Predictor of Early Relapse in Multiple Myeloma
Saturday, December 7, 2024: 3:15 PM PST
San Diego Ballroom AB (Marriott Marquis San Diego Marina)
4669 Increased Risk of Monoclonal Gammopathy of Undetermined Significance in US Military Service Members: A Case-Control Study of 1,589 Service Members Deployed to Either Iraq, Germany, or Not-Deployed Ex-US with or without Reported Burn Pit and Toxic Smoke Exposure
Monday, December 9, 2024, 6:00 PM-8:00 PM PST
Halls G-H (San Diego Convention Center)
(EMBARGOED UNTIL DEC. 9, 2024, AT 9 PM EST)
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