Earlier, I spoke about the relatively rapid CAR T‑cell process (from apheresis to CAR T-cell infusion) as it happened during clinical trials: When potentially eligible patients came to the center, they signed informed consent, underwent eligibility assessment and within 2-3 weeks could undergo apheresis. After apheresis, the patient’s cells were processed and returned to the treatment center typically within 4-5 weeks. Unfortunately, this does not reflect the way CAR T-cell therapy is currently working in the real world.

When I see a patient today who is eligible for CAR T‑cell therapy, the first thing I disclose is that a slot may be available for apheresis within 6-8 weeks (or longer, depending on the wait list). Thus, we must decide what treatment is appropriate while awaiting apheresis to keep their disease under control and to keep their T‑cells in good shape for the apheresis procedure.

We typically stop therapy 2 weeks prior to the apheresis. After the apheresis procedure, we have to think about bridging therapy. Currently, when we send cells for manufacturing, we receive them back in 6-10 weeks (compared with 4 weeks in the clinical trials). Thus, patients may need 2 or 3 cycles of bridging therapy while we are waiting for that manufactured product. We also think about the possibility of manufacturing failure and whether we would reapherese the patient if that should occur. 

We generally plan for patients to stop all bridging therapy at least 7-14 days before LD therapy to avoid increased risk of adverse events. After patients receive their CAR T-cell infusion, they stay in the treatment center area for the 1‑month acute phase.

Real‑world data in patients with R/R MM who received SoC ide-cel were recently presented by a CAR T-cell consortium of 11 US centers.¹⁸ They reported manufacturing failures in 12 (6%) of the 196 patients who underwent leukapheresis. Among those, 7 were successful on their second try, resulting in a manufacturing failure rate of 2.5%.

Among the 196 leukapheresed patients, 159 (81%) received ide-cel infusion. This represents nearly 20% of patients who dropped out because of their MM or because of comorbidities. Among the infused patients, 120 (75%) would have been ineligible for the phase II KarMMa study based on comorbidities or exposure to prior therapies (several had prior BCMA-targeted therapy). This was a true real-world population that was more debilitated than those seen in the original clinical trials.

Of interest, the safety and efficacy data were very similar to the KarMMa data. CRS occurred in 82% of the patients (3% grade ≥3), and neurologic toxicity was seen in 18% of patients (6% grade ≥3). The ORR in this population was 84%, with 42% of patients achieving CR, and the median PFS was 8.5 months. Often, real‑world data do not recapitulate what was seen in the clinical trial because of a less healthy patient population, but these data did.

In the real world, we have to select the right patients for CAR T‑cell therapy based on several factors. Obviously, comorbidities are at the top of this list. Some comorbidities that limit autologous stem cell transplant also limit CAR T‑cell therapy, such as symptomatic congestive heart failure, ischemic heart disease, arrythmias, or severe pulmonary disease requiring oxygen supplementation. However, age is not an exclusion criteria for CAR T‑cell therapy. We and others have treated patients in their 80s, and if 90-year-old patients are fit and could survive sepsis, they potentially could be eligible. There are now reports of patients on dialysis receiving CAR T-cell therapy, although this is not standard, and patients with severe renal dysfunction who are unable to receive fludarabine may be better with bispecific antibodies. That said, patients with moderate renal dysfunction can receive dose-reduced fludarabine for LD therapy and be considered for CAR T-cell therapy with adequate support.

Additional characteristics include having more indolent disease or lower tumor burden, such that patients can wait for their apheresis slot and CAR T-cell manufacturing (ie, either the pace of their disease allows an off-treatment interval or they can receive therapy that is adequate to hold their disease while they wait).

Patients also should have had limited exposure to alkylator‑based therapies. Many of the patients whose manufacturing failed or made a product that did not meet FDA specifications have had recent exposure to high‑dose alkylator‑based therapy (eg, cyclophosphamide-based or melphalan‑based therapy).

In addition, I look for patients who have had limited exposure to high‑dose steroids (eg, dexamethasone), which can affect the quality of the lymphocytes that we send to apheresis. I like for patients to have been off alkylator‑based therapies for at least 4-6 weeks before apheresis and at least 2-4 weeks off of high‑dose steroid therapy.

I also like to see patients with an absolute lymphocyte count (ALC) >0.5 x 10³/µL, although some studies have allowed patients with lower ALC. With ALC <0.2 x 103/µL, it is very difficult to collect an adequate product from that patient.

Another thing I discuss with my patients who are selected for CAR T-cell therapy is the possibility of manufacturing failure. There is a 5% to 15% chance that we will not receive an adequate product to move forward with the CAR T‑cell therapy, and patients should know that ahead of time. Patients should also be informed that they will need to stay near the treatment center for 30 days after infusion and that they will need 24/7 caregiver support during that period, which is challenging for some but very important for good outcomes.

Once patients are scheduled for apheresis, it is time to consider bridging therapy.

It is important to assess disease status by performing  a standard International Myeloma Working Group disease assessment. Patients typically undergo routine blood tests, a PET/CT scan (especially for patients who have had previous extramedullary disease), and bone marrow biopsy. These tests will help us evaluate bridging therapy after apheresis is complete.

Disease burden is an important component. The goal is to debulk or prevent disease progression to bulky disease prior to CAR T‑cell therapy. Patients with high disease burden at the time of CAR T-cell infusion tend to have more toxicity with LD therapy and a greater incidence of more advanced and higher-grade CRS, ICANS, and hematologic toxicity post–CAR T‑cell infusion.  

Also under consideration are unresolved toxicities that patients have at the time of apheresis, as these may limit certain bridging therapies. It is optimal to begin LD and CAR T-cell therapy with adequate blood cell counts, so can we give them a bridging therapy that has a lower incidence of cytopenias? Can we avoid drugs that produce nephrotoxicity, allowing the use of full-dose fludarabine for LD?

The choice of bridging therapy is more of an art than a science, and not a lot of data are available to guide therapy in all circumstances. In the phase II KarMMa and phase Ib/II CARTITUDE-1 trials, the FDA required that the bridging therapy be selected from agents to which the patient had previously been exposed to avoid a major MM response during bridging that would prevent assessment of the response to CAR T‑cell therapy.

In the phase II KarMMa study, 88% of the patients received bridging therapy, but only 4% achieved  response.8 The types of bridging therapy were quite varied—73% of patients received glucocorticoids (70% dexamethasone), 42% received proteasome inhibitors (23% carfilzomib, 20% bortezomib), and 41% received alkylator‑based therapy (37% cyclophosphamide). Monoclonal antibodies were also used in 30% of patients (28% received daratumumab), and 23% received IMiDs (19% pomalidomide).

In the phase Ib/II CARTITUDE‑1 study, 75% of the patients received bridging therapy including but not limited to corticosteroids (65%), alkylating agents (33%), IMiDs (27%), bortezomib (27%), carfilzomib (17%), and daratumumab (16% in different combinations).10 In this study, more patients had a response (45%) to bridging therapy.

In the real world, any anti-MM agent can be used for bridging, including those to which the patient has not yet been exposed, but the optimal regimen has yet to be defined

One retrospective study from Germany evaluated real-world use of daily cyclophosphamide, etoposide, and dexamethasone (CED) for 4 days as salvage and bridging therapy in patients with R/R MM.¹⁹ Six patients received CED as bridging therapy to CAR T-cell infusion. Five of the 6 had apheresis performed after the first cycle of CED, but all successfully went on to receive more cycles as bridging therapy and were able to proceed to CAR T-cell therapy. No major conclusions can be drawn from such a small study, but alkylator-based therapy is in frequent use as bridging.

We recently reviewed our experience at UCSF, looking at 70 bridging attempts among 64 patients with R/R MM who proceeded to CAR T‑cell therapy.²⁰ Manufacturing failure occurred in 9 patients (13%). We looked at 3 regimens for bridging therapy: 41% of patients received IV hyperfractionated cyclophosphamide twice daily; 33% received lower-dose weekly cyclophosphamide, either oral or IV; and 26% were given non‑cyclophosphamide–based therapy (proteasome inhibitors or IMiDs and dexamethasone). Dexamethasone was included in most of our cases (87% of the patients), and radiation therapy was given to 11% of patients.

We found that patients who received the more intensive cyclophosphamide‑based therapy had more cytopenias post CAR T‑cell therapy.²⁰ In fact, they also had a slightly worse median PFS (5.0 vs 12.5 months; P = .16) and a significantly worse median OS (15.3 vs 30.0 months; P = .01) compared with patients who received weekly cyclophosphamide. Although this was not a randomized study, the data suggest that patients requiring intensive IV cyclophosphamide‑based bridging chemotherapy may be less likely to benefit from CAR T‑cell therapy. Other conclusions are also possible, but it is important to note that chemotherapy causing significant cytopenias is associated with slower count recovery after CAR T-cell therapy.

I will discuss 2 cases that illustrate how we think about bridging therapy proceeding to CAR T-cell infusion. These are real patients who we treated at UCSF. 

The first case is a 67-year-old patient diagnosed in 2016 with light-chain only MM, and creatinine clearance of 3.5 mL/min at presentation. They had standard risk disease with β2-microglobulin 4.5 mg/L, albumin 3.5 g/dL, and 1q21 gain on fluorescence in situ hybridization, so they had International Staging System (ISS) 2 and Revised-ISS 2 MM. 

They received the following treatment: Frontline was lenalidomide/bortezomib/dexamethasone, autologous transplant, and then lenalidomide maintenance. They came off the bortezomib after 6 months because of neuropathy and came off lenalidomide after approximately 18 months because of cytopenias. They were off therapy and being followed approximately 12 months later when they had evidence of relapse. They went on to receive ixazomib/lenalidomide/dexamethasone as salvage therapy. They were lenalidomide sensitive at that point and wanted an all oral regimen. Their PFS was <1 year and went on to receive third-line therapy, daratumumab/pomalidomide/dexamethasone. Again, they have a PFS of <1 year, so they went on to receive carfilzomib/cyclophosphamide/dexamethasone and were on therapy for less than 6 months. This patient is now triple class refractory and in progression after 4 prior lines of therapy. 

This is the patient’s fourth relapse, but their baseline labs are in good shape and they have a good performance status: creatinine clearance 1.5 mL/min, hemoglobin 10 g/dL, and platelets 75 x 10⁹/L. Those counts are adequate to undergo CAR T-cell therapy, making this patient a perfect candidate. They do have evidence of extramedullary disease with a 3 x 8 cm mass in the solus muscle. 

Before their last line of carfilzomib/cyclophosphamide/dexamethasone, their light chains were 500 mg/L. After cycle 2, they went to 150 mg/L but started to go back up to 225 mg/L after cycle 3 and were back at 400 mg/L after cycle 4. If I see this patient with evidence of disease progression, what should I do? Their light chains have almost doubled in 4 weeks, and I have a slot available 6 weeks from now. 

I am worried that it will be difficult to hold nephrotoxicity and their disease not only for apheresis in 6 weeks but also for bridging chemotherapy. For this patient, I would consider giving therapy now to try to hold their light chains, hopefully giving them stable disease between now and apheresis. There are a few options that we can try in this type of patient. Sometimes we can give selinexor and dexamethasone for 4-6 weeks, or we could give pulse dexamethasone for the next 4 weeks and give 2-3 weeks off dexamethasone before going into apheresis. Then these patients would also need bridging therapy. Depending on what I gave leading up to apheresis, I may repeat it during bridging if it was very successful. If not, these patients potentially could receive a higher dose of cyclophosphamide based therapy (fractionated or weekly IV) to bridge them until their infusion product is available.

A second patient, 78 years old, diagnosed in 2015, has standard-risk IgG-kappa MM. They have the 11;14 translocation and, at diagnosis, β₂-microglobulin 3 mg/L and albumin 3.5g/dL, resulting in ISS 1, Revised-ISS 1 disease. 

Treatment was lenalidomide/bortezomib/dexamethasone and then lenalidomide maintenance, with no transplant. They were off therapy, relapsed, and received elotuzumab/lenalidomide/dexamethasone with a nice response but over time progressed. Next, they received daratumumab/bortezomib/dexamethasone with a nice response but then progressed. For fourth-line therapy, they received doublet pomalidomide and dexamethasone, with good response but a short PFS (3 months). Then they received oral cyclophosphamide and dexamethasone, with another short PFS (~3 months), followed by carfilzomib and dexamethasone, and she is now in progression. 

This patient is older and now in their sixth relapse. Their labs at the time of CAR T-cell consult look good: creatinine clearance 1.1 mL/min, hemoglobin 11 g/dL, platelets 150 x 10⁹/L, and good Karnofsky performance status (90%). They relapsed after carfilzomib and dexamethasone, and we then reassessed their disease just before intended apheresis. Their bone marrow had approximately 50% plasma cells, and PET/CT showed innumerable lytic lesions but no extramedullary disease. 

If we look at the patient’s MM disease burden, their pre–carfilzomib/dexamethasone M protein was 2.2 with light chains of 105 mg/L. After cycle 4 (4 months later), their M protein is down to 0.5 g/dL, so they have a nice partial response, with kappa light chains at 25 mg/L. Then 4 months later, their M protein has slowly risen and it is now at 1 g/dL, and they have a kappa light chain of approximately 48 g/dL, in progressive disease. I have an available slot for this patient in 8 weeks. 

This second patient is a little easier to manage. We could potentially wait 8 weeks for their apheresis, and if there was no dramatic progression during that period, they might be able to wait 6-8 more weeks during the bridging therapy. Since this patient has an 11;14 translocation, we could potentially use venetoclax and dexamethasone as a targeted therapy, both in the lead-up to apheresis and for bridging. IV cyclophosphamide based therapy could also be used if it was necessary to try to debulk their disease.

What are our goals for bridging therapy? First, it is important to look at disease burden and disease kinetics. In my mind, patients with high disease burden need debulking therapy before going to CAR T cell therapy. If they have a rapid pace or rapid turnaround (ie, doubling times less than 1-2 months), those patients likely will need therapy before receiving LD chemotherapy. Debulking of their disease may reduce the risk of infection and CAR T cell–associated toxicities, including CRS and ICANS. On the other hand, patients who have low burden or slow growing disease may need minimal therapy (maybe 1 cycle) to maintain stable disease. Then, during the 6-8 weeks of bridging, I perform laboratories at least every 2-4 weeks to assess light chains and see if the pace of their disease is increasing during bridging. That way I can act quickly to add more bridging therapy if needed. 

During bridging it is important to avoid giving a treatment that may lead to more toxicity during the CAR T-cell therapy. Nephrotoxins should be avoided, and if patients already have cytopenias, I would avoid drugs that may potentially worsen them, such as alkylator based or selinexor based therapy. Keeping in mind that manufacturing failures can occur, I would limit lymphotoxic drugs if possible, just in case we need to try a subsequent collection.

Finally, and somewhat controversially, is the avoidance of BCMA targeted therapy leading up to apheresis or even leading up to LD during the bridging period. BCMA targeted therapy should be avoided because it may increase the risk of having a decreased response after the CAR T-cell therapy. This may be because of decreased receptor density of BCMA on the target cells, or it might be that the target cells that are left have very low BCMA expression. However, this is hypothetical, and the impact of using BCMA-targeted therapy before apheresis and bridging still remains unknown.