Reframing Multiple Myeloma: From Fatal to Chronic and Even Curable

Open any medical textbook and you’ll read that multiple myeloma is incurable. However, recent advancements by Johnson and Johnson, Bristol Myers Squibb and more are shifting the paradigm to something a lot more manageable, providing new hope for the 25,000 U.S. patients diagnosed with the blood cancer each year.

“[Multiple myeloma] has not been considered curable, but I think times are changing,” Saad Usmani, a myeloma specialist at Memorial Sloan Kettering Cancer Center, told BioSpace. “We are starting to call myeloma a chronically managed condition.”

When Usmani started in the space 15 years ago, survival for multiple myeloma was an average of two to three years following diagnosis. Now, he said, some patients are living 15–20 years or more as treatment options have advanced and expanded.

With CAR T cell therapies, antibody-drug conjugates and monoclonal, bispecific and trispecific antibodies plus other drug classes both on the market and in development pipelines, there is a growing variety of treatments to fit the unique biology of each patient’s needs—ultimately reaching for the ever-elusive cure.

J&J leads the way in this space. Half of all new medicines approved for multiple myeloma have come from the company and its partners, according to Mark Wildgust, vice president of global medical affairs at J&J. But with the multiple myeloma market projected to reach $38 billion by 2034, there is plenty of room for other companies—including BMS and Pfizer—to gain strong footholds in the market.

J&J’s top seller, Darzalex, is a CD38-targeted monoclonal antibody injected subcutaneously as a monotherapy or as a component of a patient’s multifaceted regimen. As of December, the drug was on track to rake in $12 billion in 2024. Sanofi is looking for a similar blockbuster in its anti-CD38 therapy Sarclisa, which was just approved in September.

In addition to Darzalex, J&J markets CAR T therapy Carvykti and bispecific antibodies Tecvayli and Talvey. The company also has a novel trispecific antibody in the pipeline, for which Wildgust said it expects data this summer.

Meanwhile, BMS sells CAR T therapy Abecma alongside three immunomodulators, Revlimid, Thalomid and Pomalyst, a portfolio it scooped up in its $74 billion buyout of Celgene in 2019. It also markets Empliciti, a monoclonal antibody developed with AbbVie.

In competition with Tecvayli and Talvey, Pfizer sells Elrexfio, which targets BCMA CD3. Regeneron also has a BCMA CD3-targeted bispecific, linvoseltamab, in development. In a Phase III trial, treatment with the candidate elicited a 46% complete response rate with 92% of those patients s negative for minimal residual disease after 12 months. Linvoseltamab was denied FDA approval in August 2024 due to third-party issues with its manufacturing site and Regeneron is currently awaiting another inspection.

While the market may seem crowded, not all of these products are in direct competition, as many are approved for different lines of treatment and diverse patient populations.

In July 2024, Darzalex was approved for frontline treatment, joining proteasome inhibitors from Takeda and Amgen. Sanofi’s Sarclisa is also approved for patients newly diagnosed with the disease. CAR T therapies, on the other hand, can be used only after at least one treatment has failed, since the FDA greenlit Carvykti in the second line in April 2024. At the same time, the regulator approved Abecma in the third line, while bispecifics are still approved only for patients who have received at least four prior lines of therapy.

Such a range of options is valuable because when it comes to multiple myeloma, experts agree that a multifaceted treatment regimen is key.

“There is no golden bullet that will address any cancer,” Usmani said. “You will have a strategy that attacks the cancer with different components.” CAR Ts, bi- and trispecifics, antibody-drug conjugates, proteosome inhibitors, cereblon modifying agents and steroids each manipulate the immune system and target cancer in different ways.

“It’s like being a cook. We’re working on how to best put them together in sequence to get the desired outcome that we need—the recipe,” Usmani said.

And the recipe may be different depending on the type of myeloma, which is a heterogeneous disease with multiple molecular subgroups. The recipe could also depend on the age of the patient, he added, as multiple myeloma predominantly affects older people.

Even if CAR T therapy ultimately becomes a first-line treatment, the regimen would begin with a combination of chemo-immunotherapies to bring the disease level down by 80-90%, Usmani said. Then, the CAR T would “come and clean the rest of it up.”

While Darzalex may be the current money-maker for J&J, Wildgust emphasized the value of CAR T cell therapy Carvykti. “If you were to look at the singular most efficacious myeloma product developed at Johnson & Johnson, I think it’s Carvykti,” he told BioSpace.

CAR T cell therapy involves extracting a patient’s own T cells and genetically modifying them in a lab to recognize and destroy cancer cells—in Carvykti and Abecma’s case, BCMA-expressing cells. Carvykti, co-developed by Legend Biotech, is in competition with BMS and 2seventy Bio’s Abecma. However, the therapies are not necessarily considered equals by practitioners.

“I’m always hesitant to comment on efficacy in the absence of head-to-head data, but this is a clear case where I think even BMS would admit their product’s performance is inferior to Carvykti,” Ran Reshef, a professor of medicine and clinical lead for the CAR T Cell program at Columbia University Irving Medical Center, said during a recent William Blair investor call, adding that real-world data clearly shows Carvykti’s superiority.

However, in an email to BioSpace, a BMS spokesperson said, “Data comparisons from separate trials investigating Abecma or Carvytki in certain patients with multiple myeloma are not appropriate, as each trial has different patient populations, study designs, and treatment comparators.”

Carvykti and Abecma could soon have new competition from Gilead Sciences and partner Arcellx, which in November 2024 touted strong response rates and promising survival outcomes from a registrational Phase II trial of anitocabtagene autoleucel in patients with relapsed or refractory multiple myeloma.

While there have been concerns and reports of delayed neurotoxicity among patients taking the therapies, particularly Carvykti, Reshef said this has not precluded him from using them in treatment. However, this has reframed the conversation, helping patients to understand the risk of potential long-term side effects that may not be reversible. So far, none of his patients have declined the therapy due to the risk.

“Carvykti is the only [CAR T] that’s proven a survival benefit,” Wildgust said, adding that J&J is “figuring out” how to manage the safety concerns associated with the drug.

Beyond survival benefit, CAR T therapies are at the forefront of the “treat to cure” mission, Wildgust said. He referenced a study conducted in China showing that five years after one dose of Carvykti, about 21% of patients were still alive without disease progression. J&J’s CARTITUDE-1 study is expected to read out this summer, providing a five-year progression-free survival rate.

“My anticipation is, we’re going to see a proportion of those patients are indeed cured,” Wildgust said.

With these treatment advances comes a shift in expectations for patients and providers alike. In April 2024, for example, an FDA advisory committee agreed that minimal residual disease (MRD) could be a viable surrogate endpoint in place of survival for accelerated drug approval in multiple myeloma. With patients surviving for longer periods of time, it has become impractical for companies to follow trials through to a survival readout.

“It’s a fancier way of measuring how deep the response is to treatment,” Usmani said. “If patients achieve MRD negativity, they get better progression-free survival, which is a surrogate for overall survival.”

There’s also the possibility of prevention on the horizon, as J&J is now targeting high-risk smoldering myeloma with Darzalex. Smoldering myeloma is an early stage of the disease in which abnormal plasma cells have begun to build up in the bone marrow, but without noticeable symptoms. It’s often found incidentally in a patient’s bloodwork. About half of smoldering myeloma cases with high-risk features will develop into active myeloma within two years, Wildgust said.

“Historically, patients with smoldering myeloma are watch and wait,” he said. “Actually, the patients will tell you it’s watch and worry. Watch and be scared.”

That could soon change. In a Phase III trial presented last month at the American Society of Hematology’s annual meeting, treating high-risk smoldering myeloma patients with Darzalex reduced the risk of disease progression or death by 51% versus active monitoring. The need for first-line treatment was also reduced by 42% in the Darzalex group compared to the monitored group. J&J has filed applications with both the FDA and European Medicines Agency to make Darzalex the first-ever treatment option for smoldering myeloma.

While it remains to be seen whether Darzalex becomes a preventive option for high-risk patients, both Usmani and Wildgust are optimistic that a cure for some multiple myeloma patients may be near.

“I think that this is an amazing time to be a myeloma investigator, trying to figure out how to develop strategies that get us to that functional curability in this older patient population,” Usmani said.

Meanwhile, J&J has undertaken the “audacious” mission to cure 50% of patients with myeloma, and “I don’t think we’re as far away from that as we might think,” Wildgust said. “I want a red pen, and I want to go find every medical textbook and cross out incurable because that’s where we’re going.”