In the current MM treatment paradigm, patients are usually categorized at baseline by whether or not they are eligible for stem cell transplant, which informs decisions on induction, consolidation, and maintenance therapy.^1,2 Unfortunately, few patients are cured after initial therapy, and most patients experience disease relapse and go on to receive multiple cycles of relapse‑based therapy. After having received 3-4 prior lines of therapy, patients become candidates for novel therapies, such as BCMA‑targeted CAR T‑cell therapy and other novel immunotherapies, as salvage therapy. Today’s discussion focuses on the patients in this space, known as triple-class exposed, although in the future, patients may be able to receive these novel immunotherapies in earlier lines of therapy.

CAR T‑cell therapies have been in development for the past 5-10 years, but they have only been approved by the FDA for MM since March 2021. The structure of the CAR gene is very simple: The gene codes for an extracellular tumor antigen–binding domain, typically a single-chain variable fragment (scFv) from a monoclonal antibody, that binds to a target antigen on the surface of a cancer cell.3 Both approved CARs target BCMA, but other MM targets are in development. A transmembrane domain links the tumor antigen–binding domain to the intracellular signaling domain. Approved CARs in MM utilize dual intracellular signaling with 4‑1BB  and CD3‑zeta signaling domains that cause T‑cell activation after binding BCMA to the tumor cell.

The CAR gene is delivered to T‑cells (either autologous T‑cells from the patient or allogeneic [donated] T‑cells) via a lentiviral vector and is integrated at random into the chromosomal DNA. The resulting gene product is then expressed and displayed on the T‑cell surface, giving that specific T‑cell a receptor targeting the tumor antigen.

There are several underlying principles for autologous T‑cell therapy. A patient undergoes leukapheresis, typically utilizing a 10- to 15-liter procedure (~3 hours) to collect buffy coat–containing T-cells that are then sent for manufacturing.⁴ During manufacturing, CD3+ T-cells are isolated and then activated in vitro prior to CAR gene transfer using a retroviral vector, followed by expansion of the T‑cells to complete the therapeutic product.

Treatment strategies are tailored to each individual patient after his or her initial CAR T‑cell consult.⁵ After evaluation to ensure that he or she qualifies for CAR T-cell therapy with no exclusionary comorbidities, the patient undergoes the apheresis procedure. At present, it can take 6-10 weeks to receive the manufactured CAR T‑cell product, and patients may need bridging chemotherapy during that waiting period. It is essential that patients maintain a low or stable tumor burden during manufacturing, but we avoid CAR T‑cell therapy in patients with comorbidities resulting from treatment. Thus, bridging therapy balances the risk of disease progression with the risk of treatment-related adverse events. 

Once an approved product has been manufactured, the patient undergoes lymphodepletion (LD) chemotherapy, targeting the host immune system to prevent rejection of the incoming CAR T‑cells. LD has been relatively uniform in patients with MM, with most protocols utilizing daily cyclophosphamide and fludarabine infusions for 3 days, starting 5 days prior to the start of CAR T‑cell therapy. Patients then have 2 days of rest to allow for metabolism of these therapeutics before they receive the CAR T‑cells, usually in a single infusion. LD therapy can be administered in the inpatient or outpatient setting, depending on the center and patient preference. Most centers admit patients for CAR T-cell infusion or soon thereafter so that they can monitor the patients closely for toxicity (eg, cytokine-release syndrome [CRS] or immune effector cell–associated neurotoxicity syndrome [ICANS]) and initiate mitigation strategies promptly. Patients are also at risk for cytopenias and infection. It is mandatory that the patient and caregiver are within close proximity to the treatment center for the first 30 days after CAR T‑cell therapy so that toxicity can be monitored closely.

There are currently 2 FDA-approved BCMA-targeted CAR T-cell therapies for MM: idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel).^6,7 Both are indicated for the treatment of adult patients with R/R MM after ≥4 prior lines of therapy, including an immunomodulatory agent (IMiD) (lenalidomide or pomalidomide), a proteasome inhibitor (bortezomib or carfilzomib), and an anti-CD38 monoclonal antibody (daratumumab or isatuximab).

Ide cel was initially approved based on the phase II KarMMa study in patients with R/R MM who had received ≥3 prior lines of therapy including an IMiD, proteasome inhibitor, and anti-CD38 antibody and were refractory to their last line of therapy.⁸ In this study, among the 140 enrolled patients, 128 received ide-cel at one of 3 dose levels (150 million, 300 million, or 450 million cells) in a single infusion. 

The patients were heavily pretreated, with a median of 6 prior lines of therapy, and 84% were triple class refractory. All treated patients were refractory to their last line of therapy, 35% had high risk cytogenetics, and 39% had extramedullary disease. 

The primary endpoint was overall response rate (ORR), and secondary endpoints included time to response, duration of response (DoR), progression-free survival (PFS), overall survival (OS), achievement of minimal residual disease (MRD) negativity, and quality of life. 

The mean ORR for all patients receiving ide-cel at all dose levels was 73%, with a difference in response based on dose: The patients receiving 300 million cells had an ORR of 69%, and those receiving 450 million cells had an ORR of 81%.^8,9 The responses occurred rapidly (median time to response: 1 month), and the median time to complete response (CR) was approximately 3 months.

Median follow-up for the update of this study was 24.8 months, and 26% of all treated patients achieved MRD negativity. Among patients who achieved CR or better (n = 42), 79% of them achieved MRD negativity.

The PFS for all treated patients was 8.6 months (95% CI: 5.6-11.6) and was very similar regardless of 3 or ≥4 prior lines of therapy (8.6 and 8.9 months, respectively).^8,9

The median OS for all treated patients was 24.8 months, which is quite a dramatic improvement in this patient population for whom an OS of fewer than 12 months could be expected. 

There were some adverse events with ide-cel, the most common being cytopenias. Neutropenia occurred in 91% of patients, thrombocytopenia in 64% of patients, and anemia in 70% of patients.^8,9 CRS was the other common adverse event, occurring in 84% of patients, with most cases being grade 1/2, and only 5% of patients with grade ≥3 CRS. 

Neurotoxicity was seen in 18% of patients, again mostly grade 1/2 and reversible, with only 4% of patients having grade ≥3 toxicity. 

The other available CAR T-cell therapy is cilta-cel, which was approved based on the results of the phase Ib/II CARTITUDE 1 study in patients with R/R MM.^10-12 Trial participants had received ≥3 prior lines of therapy or were double refractory to an IMiD and proteasome inhibitor and had previously received an IMiD, proteasome inhibitor, and anti CD38 antibody. 

Among the 113 enrolled patients, 97 received cilta-cel infusion. The target dose range was based on body weight (750,000 CAR T cells per kg of recipient weight) resulting in 40-50 million CAR T-cells, which is slightly lower than in the KarMMa study. 

Again, this was a heavily pretreated population, with a median of 6 prior lines of therapy; 87.6% of patients were triple class refractory, 99% were refractory to their previous line of therapy, 24% had high risk cytogenetics, and 13% had extramedullary disease.

The primary endpoint for the phase II part was ORR, with secondary endpoints including DoR, PFS, OS, and achievement of MRD negativity. 

Patient responses after cilta-cel therapy were impressive. ORR was 97.9% (95% CI: 92.7-99.7), with 95% of patients achieving very good partial response, and 82.5% (95% CI: 73.4-89.4) achieved a stringent CR.¹²

Responses were rapid (median time to first response: 1 month), and the median time to best response was 2.6 months. No patient had stable disease as best response. With extended follow-up, the median DoR has now been reached at 33.9 months (95% CI: 25.5-not estimable).

With 33 months of follow-up, the median PFS has now been reached at 34.9 months (95% CI: 25.2-not estimable).¹² Median PFS among patients achieving CR or better is slightly longer at 38.2 months (95% CI: 34.9-not estimable). Median OS has not been reached, but the estimated OS at 3 years is 62.9%.

Similar to the KarMMa trial, hematologic adverse events were the most common after cilta-cell treatment: 96% of patients had neutropenia, 81% of patients had anemia, and approximately 80% had thrombocytopenia. Most of these adverse events grade 3/4,^11,12 and all were reversible, although some cytopenias lasted 1 month or longer.

CRS was also common, occurring in 95% of patients, most of whom had grade 1/2, with 5% of patients having grade ≥3 toxicity. The median time to onset of CRS with cilta-cel was 7 days, which was longer than what was seen with ide-cel (median time to CRS onset: 1 day). 

Neurotoxicity occurred in 21% of patients, and approximately 9% had grade ≥3 toxicity. Most neurologic symptoms were (ICANS), which typically presents as confusion and word finding abnormalities, and were transient and reversible. 

Other neurotoxicities were seen in 12% of patients (9% grade ≥3), some of which were late neurotoxicities, cranial neuropathies, and parkinsonian like symptoms with cogwheeling and rigidity. The median time to onset of late neurotoxicity was 27 days. For ICANS, the median time to onset was approximately 8 days and was usually seen together with CRS.

CAR T-cell therapies induce novel toxicities that have not been seen previously with other anti‑MM therapeutics and that present unique challenges.¹³ Patients need to be cared for by healthcare professionals who can recognize these unique toxicities.

Also, all physicians, pharmacists, nurses, and other mid‑level providers should receive CAR T‑cell therapy education and training, and they should go through a Risk Evaluation and Mitigation Strategy program. These specialized centers must also have appropriate consult services with infectious disease, neurology, intensive care specialists, and rapid access to emergency services.

Most toxicity associated with CAR T-cell therapy is seen during the acute phase between 0 and 30 days, which is why patients are required to stay near the treatment center during this time.¹⁴ Some centers are able to treat grade 1 CRS as an outpatient, but other centers treat patients with grade ≥1 CRS as an inpatient. All patients who have ICANS are hospitalized for the duration of their symptoms and to receive supportive care.

There are also patients who, following CRS, have continued inflammatory markers even though their fever may resolve. The inflammatory markers may be associated with a rapidly progressive ferritin or evidence of liver test abnormalities or disseminated intravascular coagulation on laboratories with hypofibrinogenemia. This is a hallmark of a hemophagocytic lymphohistiocytosis–like syndrome that can occur after CAR T‑cell therapy. This needs to be treated with anti‑inflammatory therapies, typically corticosteroids with or without other anticytokine therapies, and some patients have received anakinra in attempt to decrease the effects of interleukin‑1.¹⁵

Patients in the acute phase have neutropenia and, typically, hypogammaglobulinemia and are at risk for a broad number of infections, including bacterial infections, sepsis, pneumonia, fungal infections, fungemia, and mold infections of the lung. When patients are neutropenic, they generally receive antifungal medications as prophylaxis and undergo more exhaustive investigations for viral, bacterial, or fungal infections if they have a febrile‑like syndrome.

Tumor lysis syndrome can occur, with patients having high disease burden and rapid progression at highest risk. Appropriate prophylaxis measures should be initiated in these patients.

In the late phase after CAR T‑cell therapy (>30 days), patients may have persistent cytopenias or may require other anti‑inflammatory drugs (eg, corticosteroids) or cyclophosphamide for complications such as late neurologic toxicity. These patients may have persistent aplasia and hypogammaglobulinemia and may be receiving immunosuppressive agents and, consequently, continue to be at risk of infections. Most late infections tend to be viral reactivations, although several cases of Pneumocystis jiroveci pneumonia (PJP) have also been seen. These patients need to receive prophylaxis for varicella zoster virus and continue with it for 1 year or longer if they still have significant lymphopenia. Prophylaxis for PJP can be continued for the first 6-12 months or longer if the patient still has low CD4+ T-cell counts. Delayed CRS or inflammatory episodes can occur but are rare. Local physicians taking care of these patients should consult with the CAR T-cell center if these signs or symptoms occur.

Several studies have reported increased risk of secondary malignancies in recipients of CAR T-cell therapy. This may be because of the alkylator‑based therapy prior to receiving CAR T‑cell infusion, or even as a secondary effect of post–autologous stem cell transplant and high‑dose melphalan. Patients are living longer and therefore potentially have a higher risk, so they should undergo age-appropriate routine screening for secondary malignancies in the post–CAR T-cell follow-up.

Management of CRS relies heavily on supportive care.^14,16 After patients receive CAR T‑cell infusion, their vital signs are closely monitored including their temperature. The first indication of CAR T‑cell–associated CRS is generally a fever >38°C, often associated with chills or rigors and, if severe, hypotension and hypoxemia. CRS typically occurs on postinfusion Day 1 after ide-cel and Day 7 after cilta-cel. CRS tends to last 2-4 days, and supportive care is important during that time. Most patients receive acetaminophen with or without IV fluids, depending on their blood pressure.

Most centers initiate tocilizumab for any grade ≥2 CRS, and some centers, including mine at the University of California, San Francisco (UCSF), have adopted an early use strategy, initiating at onset of the first fever or at grade 1 CRS. We hope that early intervention will limit development of more severe CRS and may decrease the incidence and severity of subsequent neurologic toxicity. Steroids are also commonly used, sometimes before and sometimes after tocilizumab, especially in patients who have recurrent fevers. For patients who have severe (grade 3/4) CRS, higher‑dose steroids—as high as methylprednisolone 500 mg given IV twice daily for 3 days—are used. Of note, immunosuppressive treatment of CRS has not been shown to impair response to CAR T-cell therapy.

Regarding treatment for ICANS, all patients receive prophylaxis for seizures, which can occur after CAR T‑cell therapy with any neurologic toxicity.

At onset of neurotoxicity, most patients are followed closely with the immune effector cell–associated encephalopathy (ICE) test, where patients are asked questions multiple times per day.¹⁷ The 10‑point ICE test draws upon components of a mini-mental state exam, assessing orientation, ability to name some objects, and ability to follow commands and includes a handwriting component. Neurotoxicity is graded based partly on the ICE exam score and on how patients appear during the evaluation.

Patients who have ICANS associated with CRS will typically receive tocilizumab, adding steroids if the neurotoxicity persists. If they have ICANS alone or following CRS that has already been treated with tocilizumab, those patients will receive corticosteroids alone.

Patients with severe ICANS, neurologic toxicity or seizures, and so on, who are unresponsive to therapies are treated with high‑dose methylprednisolone (500 mg twice daily for 3 days or longer).

Most of these therapies are given until a patient responds and shows signs of improvement and then can be tapered over a few days after the particular symptom (CRS or ICANS) improves.

The treatment of late neurotoxicities, including cranial nerve palsies and movement and neurocognitive treatment-emergent adverse events, is less well defined and should be done in collaboration with the CAR T-cell therapy specialist and neurology.