Elotuzumab

iStock/ Mohammed Haneefa Nizamudeen Traditionally carrying a dire prognosis, the treatment paradigm for multiple myeloma is changing, with CAR T therapies, bispecifics and more contributing to multifaceted regimens unique to each patient’s needs. 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. The Multiple Myeloma 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.” CAR T Cell Therapies: Carvykti vs. Abecma 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. A Shift in Expectations 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.”

ABBV-383 is a B-cell maturation antigen (BCMA) bispecific antibody T-cell engager being evaluated in relapsed/refractory multiple myeloma (r/r MM) The CERVINO Phase 3 trial will evaluate the efficacy, safety, and tolerability of ABBV-383 monotherapy compared with standard available therapies (SATs) in patients with r/r MM who have received at least two lines of prior therapy NORTH CHICAGO, Ill., June 5, 2024 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced that the first patient has been treated with investigational ABBV-383 in the CERVINO Phase 3 study. ABBV-383 is a distinctive B-cell maturation antigen (BCMA) and CD3 bispecific antibody T-cell engager composed of bivalent BCMA-binding domains allowing for high BCMA-avidity and a low-affinity CD3 binding domain.1 ABBV-383 is being evaluated in a Phase 3, multicenter, randomized, open-label study compared with standard available therapies in patients with r/r MM who received at least two lines of prior therapy. "Despite notable advances in treatment, most patients with multiple myeloma will eventually relapse. Patients with advanced disease, especially in the community setting, often have limited access to novel treatment options and existing options have a high treatment burden, including frequent dosing," said Dr. Peter Voorhees, clinical professor of medicine, director of plasma cell disorders, Atrium Health Levine Cancer Institute. "The CERVINO Phase 3 trial is designed to evaluate the efficacy of ABBV-383 with monthly dosing and we look forward to seeing the data as it emerges." Multiple myeloma is a blood cancer characterized by abnormal proliferation of plasma cells, which can cause end-organ damage and is the second most commonly occurring blood cancer in the world.2 An estimated 176,000 people globally were diagnosed with multiple myeloma in 2020, and 117,000 people died from the disease.3 "The start of the CERVINO Phase 3 trial marks an important step forward in AbbVie's continued commitment to advance new oncology treatments and elevate the standard of care for blood cancer patients," said Mariana Cota Stirner, M.D., vice president, therapeutic area head oncology, hematology, AbbVie. "ABBV-383 is being evaluated with monthly dosing from the beginning of treatment, with the goal of maximizing treatment simplicity for physicians and patients, if proven in the clinical trials." About the CERVINO Study CERVINO (NCT06158841) is a global, Phase 3, multicenter, randomized, open-label, parallel-group study evaluating ABBV-383 in adult patients (≥18 years) with r/r MM and an Eastern Cooperative Oncology Group performance status ≤2 who received at least two prior lines of therapy, including exposure to a PI, an IMiD, and an anti-CD38 mAb. Patients who received prior BCMA-targeted therapy will be excluded. Patients will be randomized 1:1 to receive intravenous ABBV-383 60mg Q4W or the investigator's choice of SAT (carfilzomib + dexamethasone, elotuzumab + pomalidomide + dexamethasone, or selinexor + bortezomib + dexamethasone), and will continue treatment until confirmed progressive disease or other discontinuation criteria are met. The dual primary end points are progression-free survival and overall response rate. Secondary end points include overall survival, complete response (CR) or better, very good partial response or better, rate of minimum residual disease negativity, and change in disease symptoms and physical functioning. Approximately 140 sites globally will enroll approximately 380 total patients. Additional information about the study can be found at under the identifier NCT06158841. About ABBV-383 ABBV-383 is an investigational distinctive BCMA x CD3 bispecific antibody T-cell engager composed of bivalent high-avidity BCMA-binding domains, a low-affinity CD3-binding domain designed to reduce cytokine release, and a silenced Fc tail designed for an extended half-life that may support once every 4-week (Q4W) dosing. Clinical relevance of these structure activity relationships has not been established. BCMA is highly expressed on the surface of malignant plasma cells in multiple myeloma, making it an ideal target for therapy. BCMA plays a crucial role in the survival of myeloma cells by promoting their growth and inhibiting their apoptosis (programmed cell death).4 About AbbVie in Oncology At AbbVie, we are committed to transforming standards of care for patients living with difficult-to-treat cancers. We are advancing a dynamic pipeline of investigational therapies across a range of cancer types in both blood cancers and solid tumors. We are focusing on creating targeted medicines that either impede the reproduction of cancer cells or enable their elimination. We achieve this through various, targeted treatment modalities including Antibody Drug Conjugates (ADCs), Immuno-Oncology, and bi-specific and CAR-T platforms. Our dedicated and experienced team joins forces with innovative partners to accelerate the delivery of potential breakthrough medicines. Today, our expansive oncology portfolio is comprised of approved and investigational treatments for a wide range of blood and solid tumors. We are evaluating more than 20 investigational medicines across some of the world's most widespread and debilitating cancers. As we work to have a remarkable impact on people's lives, we are committed to exploring solutions to help patients obtain access to our cancer medicines. For more information, please visit us at . About AbbVie AbbVie's mission is to discover and deliver innovative medicines and solutions that solve serious health issues today and address the medical challenges of tomorrow. We strive to have a remarkable impact on people's lives across several key therapeutic areas – immunology, oncology, neuroscience, and eye care – and products and services in our Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at . Follow @abbvie on LinkedIn, Facebook, Instagram, X (formerly Twitter), and YouTube. Forward-Looking Statements Some statements in this news release are, or may be considered, forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions and uses of future or conditional verbs, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those expressed or implied in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," of AbbVie's 2023 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission, as updated by its subsequent Quarterly Reports on Form 10-Q. AbbVie undertakes no obligation, and specifically declines, to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law. 1 Foureau DM, Bhutani M, Robinson M, et al: Ex vivo efficacy of BCMA-bispecific antibody TNB-383B in relapsed/refractory multiple myeloma. EJHaem 1:113-121, 2020 2 International Myeloma Foundation. What is Multiple Myeloma? 3 Cancer.Net. Multiple Myeloma: Statistics. . 4 Cho SF, Anderson KC, Tai YT: Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy. Front Immunol 9:1821, 2018 SOURCE AbbVie