Coordination of Care for Patients With Heavily Pretreated Relapsed/Refractory Multiple Myeloma Receiving CAR T-Cell and Bispecific Therapies

Beth Faiman,¹ PhD, MSN, APN-BC, BMTCN, FAAN, FAPO, Haleigh Mistry,² MS, PA-C, and Mikhaila Rice,³ PharmD, BCPS, BCOP
From ¹Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland, Ohio; ²Department of Lymphoma & Myeloma, MD Anderson Cancer Center, Houston, Texas; ³Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio.
Authors’ disclosures of conflicts of interest are found at the end of this article.
Correspondence to: Beth Faiman, PhD, MSN, APN-BC, BMTCN, FAAN, FAPO, Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland, Ohio. E-mail: faimanb@ccf.org

Introduction

Multiple myeloma (MM) is a disorder of clonal bone marrow plasma cells. For most individuals diagnosed with multiple myeloma, it remains an incurable but highly treatable condition (Faiman, 2022). Since 2012, numerous agents representing various drug classes have been approved for use in the United States. These include a second-generation immunomodulatory drug (lenalidomide and pomalidomide), proteasome inhibitors (carfilzomib and ixazomib), an anti-SLAM7 monoclonal antibody (elotuzumab), anti-CD38 monoclonal antibodies (daratumumab and isatuximab) and an XPO inhibitor (selinexor; Faiman et al., 2016). (Additionally, panobinostat, melphalan flufenamide, and belantamab mafadotin have been withdrawn from the US market in this setting.) Recently, additional therapeutic options have become available, which include bispecific antibodies (BsAb) and chimeric antigen receptor T-cell therapy (CAR-T). Unfortunately, the vast majority of patients will require subsequent treatments after their first line of therapy with drugs from various classes. After a series of remissions and relapses, patients often become refractory to traditional therapies, which confers a poor prognosis of months, rather than years of life (Cornell et al., 2021).

BCMA is a member of tumor necrosis factor receptor (TNFR) superfamily 17 and has emerged as a major therapeutic target in relapsed/refractory multiple myeloma (RRMM; Tai and Anderson, 2015). BCMA is an attractive target for the destruction of plasma cells, as it is expressed on late memory B cells that are committed to plasma cell differentiation but is not expressed on healthy plasma cells (Cho et al., 2022; Shah et al., 2020). To understand the best approaches in the management and treatment of patients with RRMM, it is critical to distinguish between the two main types of available BCMA-directed therapies currently approved in the US and internationally for treatment of RRMM. This includes CAR-T, a one-time cellular therapy with important pre- and post-treatment considerations, and bispecific antibodies (BsAb), which are a type of non-cellular immunotherapy administered at regular intervals (weekly or biweekly) at an outpatient infusion center. The ideal model of care would be for patients who were prescribed either therapy to safely receive post-treatment monitoring or ongoing care in the community. As CAR-T is a one-time infusion and BsAbs are off-the-shelf products designed to be administered in the community, effective coordination of care is critical with both approaches.

BCMA-directed CAR T-Cell Therapy

Two anti-BCMA CAR T-cell therapies, idecabtagene vicleucel and ciltacabtagene autoleucel, are approved by the US Food and Drug Administration (FDA) to treat patients with RRMM who have received at least 4 prior therapies. It is important to note that the process of CAR T-cell therapy is lengthy and begins with early patient referral to a CAR T center and patient identification. The 4 phases for CAR T-cell harvesting and infusion are: (1) the pre-CAR T-cell phase, which includes patient referral, screening, staging, and fitness, financial, and disease assessment; (2) immune effector cell collection by white blood cell apheresis (leukapheresis); (3) lymphodepletion, infusion of CAR T cells, and supportive care treatment; and (4) follow-up. These will be described further in detail. It is during the referral phase when the lines of communication between referral center and the community practice should be established. In addition, patient and caregiver education commences and is reinforced throughout the process. Components of education include frequency of visits, side effects to expect, and supportive care treatments that may be required (such as antibiotics or blood transfusions). Once pre-screening, patient fitness, and other factors have been confirmed, the patient then undergoes harvesting and separation of T cells through apheresis.

Depending on which cellular product is planned for administration (idecabtagene vicleucel or ciltacabtagene autoleucel), a lentiviral or retroviral vector is used by the pharmaceutical manufacturer to deliver the gene to encode for the selected CAR into the patient’s T cells. The viral vector is designed to deliver the CAR transgene, in the form of RNA, into target T cells where it is then reverse-transcribed into DNA and incorporated into the patient’s genome. In the laboratory, the T cells first express the CAR, undergo transcription, then the T cells fully express the CAR target. Still in the laboratory, the CAR undergoes first expansion until the cells reach the target dose based on clinical trial results. The cells are inspected one final time to ensure they meet quality standards and specifications, then sent back to the infusion site in liquid nitrogen.

The acute CAR T-cell phase includes initial administration of lymphodepletion chemotherapy (usually fludarabine and cyclophosphamide). CAR-T cells are then reinfused either as an outpatient or an inpatient, depending on the product and institutional guidelines (Catamero et al., 2022; Shank et al., 2017; Van de Donk et al., 2021). The patient is then monitored for acute and long-term toxicities by nursing staff, clinicians, or in some cases- an approved caregiver (Sim et al., 2023; Mistry et al., 2023).

In contrast to other directed CAR-T therapies for leukemias and lymphomas, BCMA-directed therapies are currently approved only for RRMM patients who have had at least four prior lines of therapy, offering another therapeutic option where few effective options are available. Yet despite approval of two anti-BCMA CAR T-cell therapies by the FDA, the use of these therapies in clinical practice remains limited. Initially, this was due to supply chain issues that affected the processing and manufacturing of the CARs. To highlight this disparity, Kourelis and colleagues published in 2023 results of a survey highlighting that many large CAR-T referral centers only receive 1 or 2 patient slots per product per month. As of October 2023, manufacturers of both idecabtagene vicleucel and ciltacabtagene autoleucel still provide each institution approved to deliver CAR-T therapies to patients with a limited number of patient manufacturing slots each month. The limited availability of CAR-T demands that centers optimize allocation based on a balance between the trajectory of disease progression and patient fitness on a patient-by-patient basis to maximize both long-term survival and treatment tolerability (Kourelis et al., 2023). The lack of access to patient slots per institution has been a barrier to CAR-T since 2021, necessitating that each institution agree upon patient selection factors. The factors and processes of CAR-T selection vary by center. Common considerations include at least four prior lines of therapy, recent relapse requiring a salvage regimen, and limited life expectancy due to aggressive disease, with a lack of other effective therapy options or clinical trials. Of utmost importance is adequate performance status and life expectancy in order to receive CAR-T therapy on a reasonable timeline based on disease kinetics and health status (Faiman et al., 2023). While institutional access has improved in the last year, CAR-T is available only at Risk Evaluation and Mitigation Strategy (REMS)-approved institutions, thus there remains a need to expand these centers nationally for local access.  

BCMA-Directed Bispecific Antibodies

Teclistamab-cqyv is a first-in-class, humanized, BCMA x CD3-directed BsAb for treatment of RRMM. Its mechanism of action is unique as the drug binds to the CD3 receptor on the T-cell surface and to BCMA on MM cells, bringing these cells together and triggering release of pro-inflammatory cytokines that initiates destruction of target myeloma cells. The safety and efficacy of teclistamab were discussed in other articles within this Resource Center. Serious adverse events with teclistamab include cytokine release syndrome (CRS), immune cell effector neurotoxicity syndrome (ICANS), hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), hypogammaglobulinemia, prolonged cytopenias, and increased risk of infections (Faiman et al., 2023; Mistry et al., 2023). Macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH) are two potentially fatal overlapping syndromes caused by an overreactive immune response and immune system disorganization that can result in widespread inflammation and end-organ damage. Clinical signs of MAS/HLH include hyperferritinemia (with ferritin levels > 3,000 ng/mL), fevers, hypersplenism, and organ dysfunction (Janoudi & AlDabbagh, 2021). Both CAR T-cell and BsAbs carry a long-term risk of infection, including opportunistic and atypical infections (Mistry et al., 2023).

Elranatamab, the most recent BCMA x CD3 bispecific antibody, confers a similar mechanism of action and safety information as teclistamab. Approval was based on results of the single arm, Phase 2 MagnetismMM-3 study. In this trial, patients who received at least 4 prior lines of therapy and had no prior BCMA-directed therapy were included in the study. A 57.7% overall response rate was observed. Similar adverse events (CRS/ICANS) were observed. As such, a step-up dose is recommended as with teclistamab.

Another approved agent, talquetamab, is a bispecific GPRC5D-directed CD3 T-cell engager indicated for the same heavily pretreated (at least 4 lines of previous therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody) population as teclistamab and elranatamab. But for the purposes of this article, we will mainly focus on the 2 BCMA-directed agents. 

It is important to educate patients and caregivers early on in the BsAb process. Treatment with BsAb can be modeled after the phases of CAR-T therapies. As with CAR-T, most referral centers begin patients on the drug as the infrastructure allows for safe monitoring for acute toxicities during step-up dosing. The FDA has mandated a REMS program for teclistamab to ensure adequate education on serious adverse effects, such as CRS and ICANS, through which all prescribers and pharmacies must be registered prior to providing teclistamab to patients. As with the first phase of CAR-T, establishing lines of communication between the referral center and community center is important. Financial clearance and drug supply should be confirmed prior to administration of first dose, and an inpatient admission (typically lasting 7–9 days to allow for adequate monitoring during the step-up dosing period) should be arranged since most institutions currently lack infrastructure for adequate outpatient initiation and monitoring.

Choosing Between BsAb and CAR T-Cell Therapy

Based on the risk of serious adverse effects during the step-up dosing and beyond, patients must be carefully selected to receive either BsAb or CAR-T therapies. Considerations include physical fitness, adequate organ function, proximity to the treatment area, and caregiver support (Catamero et al, 2022; Dima et al., 2023; Hungria et al., 2023). The risks, benefits, and alternatives to any treatment must be carefully discussed with the patient and their family or support system.

Much discussion has surrounded the important issue of choosing between BsAb and CAR-T, which includes proper sequencing of therapy. At what point should a BsAb or CAR-T therapy be indicated? In a patient who has received 4 or more lines of therapy and has failed an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 directed monoclonal antibody, both therapies should be considered. This choice is best made through shared decision-making (SDM). SDM is an important aspect of patient engagement in which the healthcare provider invites the patient, caregivers, and/or designated support person to collaborate on major and minor healthcare decisions. Providers consider the data from clinical research, personal experience, and patient preference to arrive at a critical decision (Faiman, 2022).

The benefits of SDM are well documented. Studies have evaluated the financial and emotional benefits when providers and patients communicate, as well as improved patient-reported affective-cognitive outcomes. These benefits include increased patient autonomy and decreased decisional regret as well as increased adherence to treatment (Faiman and Tariman, 2019). Because patients can incur financial and physical toxicities from both CAR-T and BsAb therapy, SDM discussions should always be incorporated into provider practice. Data to support the sequencing of one therapy versus another have been discussed within this series. Patient disease status (such as a rapid and aggressive relapse) and disease kinetics (slow biochemical relapse versus rapid, symptomatic relapse), as well as the time needed to fulfill the CAR T-cell process, are some of the strongest reasons why patients may choose an off-the-shelf, readily available BsAb instead of CAR-T (Catamero et al., 2022; Hungria et al., 2023; Rice, 2023). Biochemical relapse in multiple myeloma is characterized by a gradual increase in monoclonal paraprotein level but no myeloma-related clinical symptoms or organ dysfunction, whereas in symptomatic or clinical relapse a rapid increase in plasma cells or onset of myeloma-related symptoms occurs (Rajkumar et al., 2014). To illustrate this process, let us examine a patient case scenario and suggestions for best practice recommendations.

Case Scenario

Imagine you are an advanced practitioner who works in a community oncology practice. You have a 63-year-old patient diagnosed in January 2019 with IgA kappa, standard-risk MM who does not harbor adverse findings on fluorescent in situ hybridization (FISH) such as del(17p), t(4;14), and 1q21 gain or amplification. The patient receives lenalidomide, bortezomib, and dexamethasone (RVD) for 4 cycles, then is referred to a larger center for an autologous hematopoietic stem cell transplant (ASCT) after 3 cycles of therapy. At day 90 post-ASCT, the patient begins lenalidomide maintenance and achieves a complete response (CR), with disappearance of any monoclonal protein in his serum or urine.

He does well on lenalidomide maintenance for 13 months, then develops biochemical disease progression with the reappearance of a monoclonal protein in his serum and doubling of kappa free serum light chains within a period of 4 months. You discuss data that supports the use of daratumumab in combination with pomalidomide and dexamethasone (DPd). He proceeds with this regimen.

After 11 months, the patient develops low-back pain, and skeletal imaging reveals an L3 plasmacytoma. After a short course of radiation, you switch his regimen to carfilzomib, cyclophosphamide, and dexamethasone (KCd). As he now has progressed to his third line of therapy and continues with persistent leukopenia, you obtain an updated bone marrow biopsy (BMBx) with FISH analysis. The BMBx shows 70% clonal kappa-restricted plasma cells and a gain of chromosome 1q. Although he is hesitant to travel to a referral center for treatment, you encourage him to return to the same center where he underwent ASCT for a second opinion as to whether a BsAb, CAR T-cell therapy, or a clinical trial would be indicated after this third line of therapy.

After his referral visit, the AP at the referral center phones and shares your concerns about short remissions. You discuss his case, and the referral center suggests he continue with KCd, with regular follow up by in-person visits or telehealth due to distance. You aim to streamline the referral process and establish a point of contact at the referral center (whom to notify if there is a change in his condition), and provide your contact information and that of the nursing, pharmacy, and medical teams. Fortunately, you both share the same electronic medical record (EMR), which allows for shared access to documents to enhance patient/provider and intra-institutional communication.

Now that he is progressing on KCd and does not have time to wait for manufacture of his CAR T-cells, you discuss the case with the referring institution, asking how to best coordinate initiation of BsAb therapy due to rapid disease progression and off-the-shelf availability of product. You do not have a REMS program for teclistamab at your institution. The referral center obtains a prior insurance authorization for teclistamab; see Rice, 2023), and plans to admit the patient for the step-up dosing. Since his IgG level is 242 mg/dL, you obtain approval for intravenous immunoglobulin (IVIg) and administer a dose prior to hospital admission to minimize risk of infection. The IVIg will be continued on a monthly basis as long as serum IgG level is less than 400 mg/dL. The referral center provides a standard order set for you to use following his hospital admission for step-up dosing to begin on Cycle 2, day 1. You work with the pharmaceutical manufacturer and the pharmacy at your center to become REMS certified so you will be able to prescribe and administer teclistamab to your patient. Finally, you reassure the patient that you will remain in contact with the referral center just as you had before, during, and after his ASCT, and notify him of your discussions regarding coordination of his care. You also discuss with the patient that you will continue with frequent laboratory monitoring and monitoring for adverse events, including infection, as this can commonly be seen with BsAbs.

Phases of Patient Care: Before BsAb and CAR T-Cell Therapy

The case example describes successful coordination of care prior to BsAb therapy and plans for management after the step-up doses. The steps outlined in this case may be extrapolated to CAR-T. Also, you are introduced in the case to the various touch-points and phases in the treatment of patients with RRMM using BsAb or CAR T-cell therapy. Each therapeutic approach shares the components of necessary referral to an approved treatment center and care coordination strategies before and immediately after the therapy. While the BsAb is administered on a regular schedule as an outpatient, CAR T-cell therapy includes a multi-step process and release of care to the referral center, similar to ASCT. The 4 key phases for CAR T-cell harvesting and infusion are: (1) the pre-CAR T-cell phase, which includes patient referral, screening, staging, and fitness, financial, and disease assessment; (2) immune effector cell collection by white blood cell apheresis (leukapheresis); (3) lymphodepletion, infusion of CAR-T cells, and supportive care (treatment); and (4) follow-up (Figures 1 and 2).

Figure 1. Suggested model for a bispecific antibody patient pathway (varies by center). BsAb = bispecific antibody; IVIg = intravenous immunoglobulin; CRS = cytokine release syndrome; ICANS = immune effector cell-associated neurotoxicity syndrome; HLH = hemophagocytic lymphohistiocytosis; MAS = macrophage activation syndrome; REMS = Risk Evaluation and Mitigation Strategy; HSV = herpes simplex virus.

Figure 2. Components of a CAR T-cell therapy patient pathway. PJP = Pneumocystis jiroveci pneumonia; ED = emergency department; CRS = cytokine release syndrome; IVIg = intravenous immunoglobulin. Adapted from Alexander et al. (2021); Buitrago et al. (2019); BMS (2021); Catamero et al. (2022); Janssen (2022); Hungria et al. (2023).

Transfer of the Patient to a Referral Center to Receive BsAb or CAR T-Cell Therapy

Regardless of whether the patient receives a BsAb or CAR T-cell therapy, effective communication is critical. When patients from the community are seen and evaluated by a referral center, it is highly important for the patient and care team at each institution to discuss how the centers will communicate and with whom. Some centers have EMR capabilities and choose to watch the EMR for updates, while others prefer communication by facsimile. Currently, most small and large hospitals and medical centers will have dedicated nurse coordinators or a care team with a person who serves as a point of contact. With the importance of timing and care coordination, a quick phone call and documentation of telephone communication between the patient and each care center is acceptable. Moreover, once a strong relationship is established between clinicians at academic and community cancer programs, communication and referrals are often streamlined. Building on existing pathways, such as with our case scenario, is an excellent way to encourage a patient to obtain a second opinion, and to enhance two-way communication between patient and providers (Association of Community Cancer Centers, 2022; Hungria et al., 2023).

Post-acute adverse effects of BsAb and CAR T-cell treatment can include cytopenias, infection, B-cell aplasia and hypogammaglobulinemia, secondary primary malignancies (typically B-cell myeloid malignancies such as MDS/AML), neurologic toxicities, fatigue, and infertility. Ongoing disease monitoring on a monthly basis is required to assess for remission or relapse and to ensure patients maintain adequate organ function. It is also recommended that patients who receive BsAb or CAR-T remain in contact with a referral center in case another line of therapy or clinical trial is necessary.

Conclusion

BsAbs and CAR T-cell therapies carry some risk of toxicity, yet they can also provide benefits such as increased progression-free survival or prolonged remission status. Patient care coordination for these complex treatment modalities may be daunting at first, but care can become streamlined as methods of effective communication are established and continued throughout the patient journey. The best strategies for sequencing are as yet unclear, but a BsAb may also be good treatment option for patients who have progressed following CAR-T, in patients who are not eligible for CAR-T, and those who are unable to wait for CAR-T collection and production due to disease progression. Given the novel mechanisms of action, unique side effect profiles of these therapeutic modalities, and potentially life-threatening toxicities, nursing, patient, and provider communication, education, and collaboration are critical to effectively coordinate, provide safe care, and ameliorate potential poor outcomes. Ongoing studies are continuing to evaluate best practices in the management of and supportive care for these patients.

Acknowledgment

Writing assistance was provided by Larry Rosenberg, PhD. 

Disclosure

Dr. Faiman has served as a consultant for Amgen, BMS, Janssen, and Pfizer. Dr. Rice has served on the advisory board for Janssen. Ms. Mistry has no conflict of interest to disclose.

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