Multiple Myeloma Treatment Advances: Five Things to Know 

For patients with multiple myeloma, a treatable but incurable cancer that affects blood plasma cells, there are many new options for treatment that are producing better, and increasingly long-lasting outcomes. Approved options include immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies. More recently, immunotherapies such as CAR T-cell therapies and bispecific antibodies have been approved.  

There also are therapies under investigation that show similar promise for patients with relapsed/refractory multiple myeloma, newly diagnosed multiple myeloma, and a pre-cancerous condition called smoldering myeloma, with a beneficial impact felt across the whole spectrum of disease. 

“This is a very encouraging time for our patients,” says Paul G. Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber. “We have many new medicines to work with, but we still have much more work to do because myeloma remains a difficult-to-treat disease with important subsets of patients who fare less well, despite significantly improved survival overall.”  

Multiple immunotherapy options for relapsed/refractory myeloma 

Immunotherapy refers to treatments that use the body’s own immune system to combat diseases such as cancer. 

• CAR T-Cell Therapy: Currently, there are two CAR T-cell therapies approved for relapsed/refractory multiple myeloma. These therapies (ide-cel and cilta-cel) have been approved for several years. Dana-Farber and other specialized medical centers have the expertise and resources needed to administer these medicines.  

These therapies have shown very positive results in practice, says Dana-Farber hematologic oncologist Omar Nadeem, MD, clinical director of the Myeloma Immune Cell Effector Cell Therapy Program, even in patients who have received many lines of previous treatments. Cilta-cel is approved for use in patients after one prior line of therapy, and ide-cel after two, based on positive results from clinical trials led by Dana-Farber and other experts. 

CAR T-cell therapy may not be appropriate for patients who have disease that is advancing rapidly, or those who might not be able to tolerate the serious side effects that can accompany CAR T-cell therapy. The therapy also may require time away from home if the patient doesn’t live near a medical center that provides it.  

• Bispecific Antibody Therapy: There are also several bispecific antibody therapies approved for relapsed/refractory multiple myeloma. These therapeutics are also showing promising response rates and can be an option for patients. 

Your Dana-Farber care team can help you determine if one of these options is right for you.  

“It depends on where the patient is in the lifetime of their disease, their health status, and personal logistics. All of that comes into play when we think about the best immunotherapy options for patients,” says Nadeem.  

Next-generation immunomodulatory drugs known as CelMoDs show promise for relapsed/refractory myeloma 

Drugs such as thalidomide, lenalidomide, and pomalidomide, have been integral to standard of care combination therapy for patients with myeloma over the last 10 to 20 years. These drugs leverage cellular recycling systems to remove proteins that myeloma cells need through a process called targeted protein degradation. They also help the immune system work potently against myeloma in addition to direct killing of the myeloma cells.  

Now, a next-generation medicine in this broad category, a once-daily pill called mezigdomide, is showing great promise in early phase clinical trials. In 2023, Richardson and colleagues reported in the New England Journal of Medicine impressive responses to mezigdomide in combination with dexamethasone in patients with relapsed and refractory multiple myeloma which had stopped responding to all currently available therapies, including immune treatments.  

Phase 3 trials of mezigdomide are now underway and results in various combinations both with oral novel agents, proteasome inhibitors, and monoclonal antibodies continue to show great promise. Importantly, these responses are being seen after immune therapies have failed, as well as in patients with resistant disease to all other major drug classes, which meets an urgent unmet medical need in relapsed and refractory disease.   

Similar work with iberdomide, also a once daily pill in the CelMoD class, has shown benefit and is moving into the newly diagnosed and early relapse settings. 

In addition, active trials of mezigdomide in combination with other promising drugs, such as low-dose selinexor, another potent oral anti-cancer medicine that is especially effective in high-risk myeloma, are currently open and enrolling patients at Dana-Farber, with promising early results. 

Another ongoing early phase study with a novel oral degrader (C4755) in relapsed, refractory myeloma (in partnership with Massachusetts General Hospital and other centers) continues to show activity and a manageable safety profile, supporting the potential value of this overall approach for patients. 

Learn more about the history of these medicines in multiple myeloma in Dana-Farber’s Unraveled podcast.  

Efforts continue to expand options for relapsed/refractory myeloma 

Belantamab mafodotin, an antibody-drug conjugate, is being studied in clinical trials and in an expanded access program for patients in the U.S. Favorable results were reported in recent pivotal phase III combination studies of belantamab mafodotin in combination with bortezomib and dexamethasone (the DREAMM-7 study), and pomalidomide with dexamethasone (the DREAMM-8 trial), with striking clinical benefit seen in patients with relapsed and refractory myeloma.  Importantly, belantamab mafodotin provides an off-the-shelf treatment in the outpatient setting without some of the potentially challenging toxicities of other therapeutic strategies in this patient population. 

Additional studies at Dana-Farber include: 

• The phase 2 ISABELA trial of belantamab mafodotin plus isatuximab, pomalidomide, and dexamethasone in patients with at least one prior line of therapy. 
• The phase 1 trial of an EP300/CBP bromodomain inhibitor called OPN-6602, a promising novel agent being tested for the first time in humans. 
• Melflufen, a potent peptide drug conjugate, is fully approved in Europe and elsewhere, including Asia, for advanced myeloma and works particularly well in patients with extramedullary disease. Future directions in the US include studies of a next generation peptide drug conjugate as part of a new program exploring this treatment strategy and informed by laboratory studies at Dana-Farber. 

Learn more about clinical trials for multiple myeloma at Dana-Farber. 

Investigations of new options for newly diagnosed myeloma underway 

In 2024, a regimen combining daratumumab with bortezomib, lenalidomide, and dexamethasone was approved for patients with newly diagnosed multiple myeloma. 

Several studies are exploring ways to improve treatment for newly diagnosed disease: 

• With the success of CAR T-cell therapy in patients who have received many lines of treatment, investigators are interested in learning if CAR T-cell therapy might be a good choice for patients immediately after diagnosis. Dana-Farber investigators have launched a large phase 3 clinical trial comparing induction therapy followed by stem cell transplant to CAR T-cell therapy in newly diagnosed patients to help guide the selection of initial therapies.  
• In addition, Jacob Laubach, MD, MPP, is leading a phase 2 study of the combination of isatuximab, lenalidomide, bortezomib, and dexamethasone in transplant-eligible patients with newly diagnosed multiple myeloma.   
• Iberdomide, another CELMoD currently under clinical development, is of interest in newly diagnosed myeloma. It has proven to be effective in patients with relapsed/refractory disease and has a favorable risk and toxicity profile. Dana-Farber’s Yuxin Liu, MD, is planning to open an investigator-sponsored trial of isatuximab plus iberdomide, bortezomib, and dexamethasone in patients with newly diagnosed multiple myeloma. 

Learn more about treatment for multiple myeloma at Dana-Farber.  

Multiple therapies are in trials for smoldering multiple myeloma 

Multiple myeloma is a cancer that affects the immune system. Smoldering myeloma is a precursor condition that sometimes develops into multiple myeloma. Prior to the transition, the immune system is still healthy and hasn’t been affected by the cancer. 

Dana-Farber experts are interested in learning if immunotherapies might be more effective if given to patients early, as an intervention before smoldering multiple myeloma becomes multiple myeloma. Investigations are underway: 

• In 2023, Irene Ghobrial, MD, reported early results of phase 2 clinical trial showing that bispecific antibody therapy in patients with smoldering myeloma drove the precursor condition to undetectable levels.  
• The Center for Early Detection and Intervention at Dana-Farber is investigating whether other therapies, including combination therapy and CAR T-cell therapy, might benefit patients with smoldering multiple myeloma that is of high risk of developing into multiple myeloma. In 2024, Nadeem and colleagues reported early results of the CAR-PRISM (PRecision Intervention Smoldering Myeloma) phase 2 clinical trial, the first to investigate CAR-T cell therapy in patients with high-risk smoldering myeloma who have received no previous therapies. Six out of six patients had a complete response, and none experienced high-grade side effects. 

Learn more about clinical trials for smoldering multiple myeloma at Dana-Farber.