The Important Role of Cell Therapy in Multiple Myeloma: Three Reasons Why It’s Here to Stay

Surbhi Sidana, M.D., Assistant Professor and Myeloma Disease Group Lead, Blood and Marrow Transplantation and Cell Therapy Division, Stanford University School of Medicine

During my tenure as a hematologist/oncologist treating patients with multiple myeloma, I’ve had a front-row seat to the latest wave of cancer treatment strategies, including chimeric antigen receptor (CAR) T cell therapy, and have seen first-hand the impact these therapies can have on patients in need of additional options. Every day, I see multiple myeloma treatment innovation come to life—which all began as I trained in a program known for multiple myeloma patient care.

As a physician, it has been inspiring to see how many patients’ lives have been impacted by therapeutic approaches that push the boundaries in multiple myeloma. A key example of how treatment can help change the outlook for patients is Abecma® (idecabtagene vicleucel), the first CAR T cell therapy approved for relapsed or refractory multiple myeloma. Abecma is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.¹ Please see the Important Safety Information section below, including Boxed WARNINGS for Abecma regarding Cytokine Release Syndrome (CRS), Neurologic Toxicities (NT), Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), and Prolonged Cytopenia.

Patients with relapsed or refractory multiple myeloma who have been exposed to all three major drug classes have faced high unmet need and have limited treatment options.² With the introduction of CAR T cell therapy, the efficacy and safety of this highly personalized approach has been demonstrated in clinical trials and additional data has emerged in the real-world setting, generating interest from the healthcare community around CAR T cell therapy in this indication.³ With that, here are three reasons why I believe cell therapy has been successful and is here to stay in the multiple myeloma treatment paradigm.

#1: High response rates: Efficacy with Abecma has been demonstrated in clinical trials, and we’re learning more in the real-world setting

The U.S. Food and Drug Administration (FDA) approved Abecma in 2021 based on data from the pivotal open-label, single-arm Phase II KarMMa clinical trial of 127 patients with relapsed or refractory multiple myeloma who had received at least three prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody.¹

Among the efficacy evaluable population of 100 patients who received Abecma within the dose range of 300 to 460 x 10^6 CAR-positive T cells, the overall response rate (ORR) was 72% (95% CI: 62-81) and 28% of patients achieved a stringent complete response (95% CI: 19-38).¹ The median duration of response was 11 months (95% CI: 10.3–11.4).¹ Follow-up analysis in 100 patients from the KarMMa study approximately 27 months after infusion showed a median progression-free survival (PFS) of 11.1 months (95% CI, 6.08-12.22).⁴

Safety results in the pivotal trial among the 127 patients who received Abecma showed that CRS, a systemic inflammatory response, occurred in 85% (108/127) of patients.^1,5 Grade ≥3 CRS occurred in 9% (12/127) of patients, with Grade 5 CRS reported in one patient.¹ The median time to onset was one day (range: 1-23 days) with a median duration of seven days (range: 1-63 days).¹ NT occurred in 28% (36/127) of patients, including Grade ≥3 events in 4% (5/127) of patients.¹ The median time to onset of NT was two days (range: 1-42 days).¹ NT resolved in 33 of 36 patients (92%) with a median time to resolution of five days* (range: 1-61 days).¹ Among all patients in the trial, fatal adverse reactions occurred in 6% of patients.¹

Now, two years following the FDA approval of Abecma, it’s important to evaluate the real-world data available, as many of my on-label patients would not have met all of the stringent trial criteria. My colleagues and I recently published real-world data in the Journal of Clinical Oncology from a retrospective, multicenter, observational study of 159 patients with relapsed or refractory multiple myeloma, who had received 4 or more prior lines of therapy and were administered Abecma, showed best ORR of 84%.³ This is very heartening to see, as 75% of patients in the real-world data cohort would not have met the parameters to participate in the clinical trial.³

Safety results showed any Grade CRS occurred in 82% (n=131) of patients and Grade ≥3 CRS occurred in 3% (n=5) of patients. Additionally, any Grade NT occurred in 18% of patients (n=29) and Grade ≥3 NT occurred in 6% (n=9) of patients.³ Thirty (19%) patients died by data cut-off, 20 due to myeloma progression and eight due to non-relapse mortalities, which included two cases of Grade 5 CRS.³ Limitations of this study include its retrospective design, limited follow-up, and heterogeneity in institutional standards for toxicity management across different centers and, thus, the data should be interpreted in this context.³

We’ve also learned more about patient history and characteristics that impact responses to Abecma, which help guide better patient selection and treatment practices in this population of triple-class exposed** patients who have received at least four prior lines of therapy. Notably, we’re seeing that the type and timing of prior therapies matter, specifically regarding prior BCMA-directed therapy, which can decrease efficacy of Abecma compared to patients who received Abecma without prior anti-BCMA therapy, based on use in the real world.³ We also have data that show alkylating therapies can reduce the number of CD3+ T cells during apheresis, compared to cells from patients who have never been exposed to alkylators.⁶ This reduction in T cell composition may negatively impact the successful production of CAR T cell therapy.⁶ My colleagues and I are navigating the challenges of understanding which patients may optimally respond to treatment with Abecma, and further studies are needed to better understand treatment, consolidation and maintenance with CAR T.

#2: Single infusion: CAR T cell therapy offers the potential for multiple myeloma treatment-free intervals

Optimal care plans for patients reflect their values and needs, often balancing therapeutic efficacy with safety, tolerability and lifestyle considerations. In my experience, the ability to spend time with family and pursue activities they enjoy is what many patients value most when working to get their multiple myeloma under control. When we look at a CAR T cell therapy like Abecma, it is a single-infusion treatment with the potential to offer patients treatment-free periods while responding to Abecma; however, there are important risks to consider and the treatment process has many steps, including leukapheresis, manufacturing, administration and adverse event monitoring.¹

After leukapheresis and manufacturing of the CAR T cells, patients are given a short course of chemotherapy to help prepare the body to receive the engineered cells.¹ Then, at the treatment center, patients receive their personalized CAR T cells, which then expand systemically and bind to the target cells.¹ All patients are monitored closely by their care team for four weeks for possible side effects, which may be severe, life-threatening or even fatal.¹ These side effects can include but are not limited to CRS and NT, which can happen in the first few days to several weeks after a patient’s CAR T cells are infused into their body.¹ Time at the treatment center and follow-up visits will vary based on the individual patient.¹

After making the choice to receive this treatment, some of my patients have shared that they enjoy the flexibility that CAR T cell therapy has given them, potentially eliminating the need for frequent appointments and continuous cycles of maintenance treatment, as long as their disease remains in control. The potential for prolonged duration of response and treatment-free intervals may give patients time to do the activities they love, which has meant a lot to me and my patients.¹

#3: Multidisciplinary care teams: Enhanced collaboration in healthcare has set the foundation to support patients in their CAR T experience

The COVID-19 pandemic elucidated a common theme in healthcare that cannot be overlooked: the critical role of collaboration. Similarly, CAR T cell therapy is a complex process that requires a similar level of collaboration. It demands a multidisciplinary care team that communicates frequently and effectively to allow us to follow the progress of a patient's cells from apheresis to manufacturing to delivery, which are all key milestones in the process. Personally, I have found that awareness of and education on the use of CAR T in multiple myeloma is expanding, and it is important to continue this education, from guidelines for toxicity management to the development of survivorship plans.⁷ I look forward to seeing further collaboration between treatment centers, manufacturers and patient advocates to educate communities about different treatment options and provide resources and support to those undergoing innovative treatments like CAR T cell therapy.

It has been a privilege to watch the multiple myeloma treatment paradigm evolve during the past decade. The future for CAR T cell therapy in multiple myeloma is very exciting—we are seeing this in real-world practices and continue to generate and review evidence on the effect of CAR T cell therapy in patients. As a treating physician, my goal is to treat the disease and address the specific needs of each patient. CAR T helps make that a reality through the very nature of this personalized approach. I’m hopeful that the outcome of ongoing efforts to improve our understanding of CAR T cell therapy will continue to advance patient care—the health and lives of our patients depend on it.

*For patients who experienced NT, including 3 patients with ongoing NT, the median duration of CAR T cell-associated NT was 6 days (range: 1 to 578 days).

**Triple class exposed defines patients who have received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

INDICATION

ABECMA (idecabtagene vicleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, AND PROLONGED CYTOPENIA

• Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with ABECMA. Do not administer ABECMA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
• Neurologic Toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with ABECMA. Provide supportive care and/or corticosteroids as needed.
• Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS) including fatal and life-threatening reactions, occurred in patients following treatment with ABECMA. HLH/MAS can occur with CRS or neurologic toxicities.
• Prolonged Cytopenia with bleeding and infection, including fatal outcomes following stem cell transplantation for hematopoietic recovery, occurred following treatment with ABECMA.
• ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS.

Warnings and Precautions:

Cytokine Release Syndrome (CRS): CRS, including fatal or life-threatening reactions, occurred following treatment with ABECMA in 85% (108/127) of patients. Grade 3 or higher CRS occurred in 9% (12/127) of patients, with Grade 5 CRS reported in one (0.8%) patient. The median time to onset of CRS, any grade, was 1 day (range: 1 - 23 days) and the median duration of CRS was 7 days (range: 1 - 63 days). The most common manifestations included pyrexia, hypotension, tachycardia, chills, hypoxia, fatigue, and headache. Grade 3 or higher events that may be associated with CRS include hypotension, hypoxia, hyperbilirubinemia, hypofibrinogenemia, acute respiratory distress syndrome (ARDS), atrial fibrillation, hepatocellular injury, metabolic acidosis, pulmonary edema, multiple organ dysfunction syndrome, and HLH/MAS.

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS.

Fifty four percent (68/127) of patients received tocilizumab (single dose: 35%; more than 1 dose: 18%). Overall, 15% (19/127) of patients received at least 1 dose of corticosteroids for treatment of CRS. All patients that received corticosteroids for CRS received tocilizumab. Ensure that a minimum of 2 doses of tocilizumab are available prior to infusion of ABECMA.

Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs or symptoms of CRS and monitor patients for signs or symptoms of CRS for at least 4 weeks after ABECMA infusion. At the first sign of CRS, institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurologic Toxicities: Neurologic toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA in 28% (36/127) of patients receiving ABECMA, including Grade 3 in 4% (5/127) of patients. One patient had ongoing Grade 2 neurotoxicity at the time of death. Two patients had ongoing Grade 1 tremor at the time of data cutoff. The median time to onset of neurotoxicity was 2 days (range: 1 - 42 days). CAR T cell-associated neurotoxicity resolved in 92% (33/36) of patients with a median time to resolution of 5 days (range: 1 - 61 days). The median duration of neurotoxicity was 6 days (range: 1 - 578) in all patients including 3 patients with ongoing neurotoxicity. Thirty-four patients with neurotoxicity had CRS with onset in 3 patients before, 29 patients during, and 2 patients after CRS. The most frequently reported manifestations of CAR T cell-associated neurotoxicity include encephalopathy, tremor, aphasia, and delirium. Grade 4 neurotoxicity and cerebral edema in 1 patient, Grade 3 myelitis, and Grade 3 parkinsonism have been reported with ABECMA in another study in multiple myeloma.

Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs or symptoms of neurologic toxicities and monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after ABECMA infusion and treat promptly. Rule out other causes of neurologic symptoms. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed.

Counsel patients to seek immediate medical attention should signs or symptoms occur at any time.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): HLH/MAS occurred in 4% (5/127) of patients receiving ABECMA. One patient developed fatal multi-organ HLH/MAS with CRS and another patient developed fatal bronchopulmonary aspergillosis with contributory HLH/MAS. Three cases of Grade 2 HLH/MAS resolved. All events of HLH/MAS had onset within 10 days of receiving ABECMA with a median onset of 7 days (range: 4 - 9 days) and occurred in the setting of ongoing or worsening CRS. Two patients with HLH/MAS had overlapping neurotoxicity. The manifestations of HLH/MAS include hypotension, hypoxia, multiple organ dysfunction, renal dysfunction, and cytopenia. HLH/MAS is a potentially life-threatening condition with a high mortality rate if not recognized early and treated. Treatment of HLH/MAS should be administered per institutional guidelines.

ABECMA REMS: Due to the risk of CRS and neurologic toxicities, ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS. Further information is available at www.AbecmaREMS.com or 1-888-423-5436.

Hypersensitivity Reactions: Allergic reactions may occur with the infusion of ABECMA. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) in ABECMA.

Infections: ABECMA should not be administered to patients with active infections or inflammatory disorders. Severe, life-threatening, or fatal infections occurred in patients after ABECMA infusion. Infections (all grades) occurred in 70% of patients. Grade 3 or 4 infections occurred in 23% of patients. Overall, 4 patients had Grade 5 infections (3%); 2 patients (1.6%) had Grade 5 events of pneumonia, 1 patient (0.8%) had Grade 5 bronchopulmonary aspergillosis, and 1 patient (0.8%) had cytomegalovirus (CMV) pneumonia associated with Pneumocystis jirovecii. Monitor patients for signs and symptoms of infection before and after ABECMA infusion and treat appropriately. Administer prophylactic, pre-emptive, and/or therapeutic antimicrobials according to standard institutional guidelines.

Febrile neutropenia was observed in 16% (20/127) of patients after ABECMA infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care.

Viral Reactivation: CMV infection resulting in pneumonia and death has occurred following ABECMA administration. Monitor and treat for CMV reactivation in accordance with clinical guidelines. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against plasma cells. Perform screening for CMV, HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias: In the clinical study, 41% of patients (52/127) experienced prolonged Grade 3 or 4 neutropenia and 49% (62/127) experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Month 1 following ABECMA infusion. In 83% (43/52) of patients who recovered from Grade 3 or 4 neutropenia after Month 1, the median time to recovery from ABECMA infusion was 1.9 months. In 65% (40/62) of patients who recovered from Grade 3 or 4 thrombocytopenia, the median time to recovery was 2.1 months.

Three patients underwent stem cell therapy for hematopoietic reconstitution due to prolonged cytopenia. Two of the three patients died from complications of prolonged cytopenia. Monitor blood counts prior to and after ABECMA infusion. Manage cytopenia with myeloid growth factor and blood product transfusion support.

Hypogammaglobulinemia: Hypogammaglobulinemia was reported as an adverse event in 21% (27/127) of patients; laboratory IgG levels fell below 500 mg/dl after infusion in 25% (32/127) of patients treated with ABECMA.

Monitor immunoglobulin levels after treatment with ABECMA and administer IVIG for IgG <400 mg/dl. Manage appropriately per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

The safety of immunization with live viral vaccines during or after ABECMA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during ABECMA treatment, and until immune recovery following treatment with ABECMA.

Secondary Malignancies: Patients treated with ABECMA may develop secondary malignancies. Monitor life-long for secondary malignancies. If a secondary malignancy occurs, contact Bristol-Myers Squibb at 1-888-805-4555 to obtain instructions on patient samples to collect for testing of secondary malignancy of T cell origin.

Effects on Ability to Drive and Operate Machinery: Due to the potential for neurologic events, patients receiving ABECMA are at risk for altered or decreased consciousness or coordination in the 8 weeks following ABECMA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

Adverse Reactions: The most common nonlaboratory adverse reactions include CRS, infections – pathogen unspecified, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, encephalopathy, edema, pyrexia, cough, headache, and decreased appetite.

Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide.

References

1. Abecma Prescribing Information. Bristol Myers Squibb; March 2021.
2. Dhanasiri S, Hollier-Hann G, Stothard C, et al. Treatment patterns and outcomes in triple-class exposed patients with relapsed and refractory multiple myeloma: findings from the multinational ITEMISE study. Clinical Therapeutics. https://www.clinicaltherapeutics.com/article/S0149-2918(21)00386-6/fulltext. Published November 1, 2021. Accessed March 2023.
3. Hansen D, Sidana S, Peres L, et al. Idecabtagene vicleucel for relapsed/refractory multiple myeloma: Real-world experience from the Myeloma CAR T Consortium. Journal of Clinical Oncology. https://ascopubs.org/doi/abs/10.1200/JCO.22.01365. Published January 9, 2023. Accessed March 2023.
4. Data on file. BMS-REF-IDC-0002. Princeton, NJ: Bristol-Myers Squibb Company; 2021.
5. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al. Cytokine release syndrome. Journal for Immunotherapy of Cancer. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003181/. Published June 15, 2018. Accessed March 2023.
6. Rytlewski J, Madduri D, Fuller J, et al. Effects of prior alkylating therapies on preinfusion patient characteristics and starting material for CAR T cell product manufacturing in late-line multiple myeloma. American Society of Hematology. https://ashpublications.org/blood/article/136/Supplement%201/7/471183/Effects-of-Prior-Alkylating-Therapies-on. Published November 5, 2020. Accessed March 2023.
7. Yáñez L, Sánchez-Escamilla M, Perales M-A. CAR T cell toxicity: Current management and future directions. HemaSphere. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746032/. Published March 29, 2019. Accessed March 2023.

Abecma^© is a trademark of Celgene Corporation, a Bristol-Myers Squibb company.

© 2023 Bristol-Myers Squibb Company. 4/23. 2012-US-2300019.