Ajai Chari, MD, on the Challenges of Bringing CAR T, Bispecifics to Patients With Multiple Myeloma

In recent years, dramatic clinical trial results in multiple myeloma have dominated plenary sessions and news conferences at major cancer meetings. Physicians and patients have choices that include quadruplet therapy in frontline treatment with anti-CD38 therapy—either daratumumab (Darzalex) or isatuximab (Sarclisa), and a backbone of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone.1-3 Meanwhile, there are multiple choices of bispecifics or chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed or refractory disease.4

Ajai Chari, MD | Image credit: AJMC

Bringing this bounty of treatment options from clinicals to real-world treatment can have its own challenges, however. For insights on this process,

The American Journal of Managed Care® (AJMC) spoke with Ajai Chari, MD, director of the Multiple Myeloma Program and professor of clinical medicine, University of California, San Francisco (UCSF), on what goes into clinical decision-making in multiple myeloma and how physicians overcome barriers in real-world settings.

This interview is lightly edited for clarity.

AJMC: What are the biggest operational challenges in bringing CAR T-cell therapies to the clinic, and how can health care systems streamline their adoption?

Chari: The overarching starting point would be these are unprecedented [therapies] in terms of their activity in relapsed/refractory myeloma. We’re seeing 60% to 100% response rates with remissions lasting 1 to 3 years in patients who literally could have been hospice bound. The question is, how do you deploy that to the entire patient community? And [it] has different operational challenges.

With CAR T, I think the best way to summarize it is: How do we decrease the “brain-to-vein” time? What that means is 80% of patients [with myeloma] in the US are being treated in the community. From the moment that a community doctor thinks about CAR T for a patient, and because this is only being done at specialized centers, they have to be referred to the academic center; the academic center has to do the consultation; then you have to submit for insurance approval; then there needs to be an apheresis slot; then the cells need to be collected—the T cells need to be collected and sent off. That can take anywhere from 4 to 6 weeks currently. And then when those cells are ready, then you have lymphoid depletion, chemotherapy, and then you actually get to a CAR T.

When you think about not just brain-to-vein time, because people want to historically talk about apheresis to CAR T infusion. It’s really brain-to-vein, which is community doctor to the CAR T. I think that process is inherently cumbersome, and what that means is you cannot have patients who are rapidly progressing go through CAR T. [What] we’ve seen in randomized phase 3 [trials] is that when you do CAR T vs standard of care for the first few months, there’s a crossover in...progression, presurvival, and overall survival. What’s happening is the patients who can’t wait to get to CAR T are having progression complications and even deaths prior to CAR T or during the CAR T.

Thus, a key issue in CAR T is you need to pick the right patients—those who can tolerate high-grade CRS [cytokine release syndrome]—so probably not the frail elderly or those with significant heart failure or renal failure. That would be my response for operational challenges with CAR T.

The last part, from a payer perspective, is these are very expensive products. They’re $500,000 to $700,000 list price. But in return for that, you do have a long treatment-free interval, potentially up to 3 years or longer. It’s quite cost-effective when you think about it like that. But the only thing is, people think it’s a one-and-done [treatment], but it’s not that simple. We talked about getting to CAR T, but after CAR T, there’s IVIG [intravenous immunoglobulin] transfusions, supportive care, [and] antibiotics. It can take up to 6 months to really be completely visit free. But in the long term, you’ve saved all the expensive chemotherapy that needs to be given routinely in a chronic disease.

AJMC: Who should receive a bispecific therapy? And what are the operational challenges of bringing these therapies to the clinic?

Chari: This is the opposite of CAR T, because it really belongs in the community. I’ve always said that no one with relapsed/refractory myeloma who’s eligible for bispecifics should be denied a bispecific. When the drugs were first approved, who got it at my institutions? People who couldn’t get it in a study: those with heart failure, dialysis, CNS [central nervous system] myeloma. There was no patient that I wouldn’t feel comfortable giving a bispecific to because it has a rapid onset of activity: 1 month. The remissions or PFS [progression-free survival] lasts up to a year. And the [adverse] effects are manageable, because you just stop the drug.

I’ve often made the analogy that CAR Ts are like a Rolls-Royce or Bentley, and bispecifics are Toyota Corollas. Toyota Corollas make the world go round, and that’s why they are the No. 1 most sold car in the world. The Bentleys are great if you can get it. But let’s face it, in the US, only 20% of [autologous] transplant patients eligible for auto transplant get it, and CAR Ts are even more restricted and more expensive. So, the vast majority of patients aren’t going to get a CAR T.

By contrast, the vast majority of patients can get a bispecific. And what people need to remember is that we now have, I think at last count, 9 bispecifics approved in oncology and hematology. This is the wave of the future, and community doctors either need to get on board or they’ll get left behind. More importantly, their patients will get left behind because bispecifics today are like the monoclonals of 30 years ago. Initially, when rituximab (Rituxan) and daratumumab came around, everybody was concerned about infusion and related reactions and long appointment times, and we got over that. Now, no one bats an eye. We’re going to get there [with bispecifics], but we’re in a very steep learning curve that we need to do this.

I think the operational challenges here are, first and foremost, training in myeloma—that bispecifics have a REMS program—a risk evaluation mitigation strategy. The providers need to be trained [and] the facilities need to be trained. Step-up doses need to be done to avoid the [adverse] effects of CRS and ICANS [immune effector cell–associated neurotoxicity syndrome]. That can either be done in academia and then the patients go back to the community, or it can be done entirely in the community.

But it is a steep learning curve if you’ve never dealt with these kinds of [adverse] effects, and the label has that patients need to be monitored for up to 48 hours. How are you going to do that in a community setting? Are you going to do it as all-admission, in which case, who’s covering these patients? Are you going to do it as a hybrid, where you give the drug in outpatient [and] you admit them for the monitoring? Or do you do it all outpatient? Those are all things that we’re trying to work out.

For bispecifics to truly have the impact that they can, they need to be given in the community because the frail, elderly patients aren’t coming to academia to get the products, and they will have a huge impact on patient outcomes if it can be done in the community.

AJMC: Given the complexity of CAR T and bispecific treatments, what steps are being taken to ensure consistent patient eligibility and monitoring protocols, especially in cases of high-risk disease?

Chari: In terms of eligibility, I would say for CAR T, the patient must be fit, [have] no significant comorbidities, and can basically tolerate a high-grade CRS, so no hypotension, hypoxia, etc. With bispecifics, as I alluded to, I don’t think there is any contraindication to bispecifics. Where you can get into selection for bispecifics is if you’re planning on doing it as an outpatient, don’t take bulky disease, make sure that the patients don’t have comorbidities, that they’re not frail elderly, that they have a caregiver and are reliable for communication. But short of that, you could do all of that in inpatient, and after that’s done, it’s basically a subcutaneous or an intravenous medication given intermittently, like any other product.

In terms of protocols, [with] CRS, those of us who were involved in the clinical trials remember the days when every product seemed to have a different algorithm. Even within myeloma, for one of the bispecifics, you gave this for grade 1 CRS and that for grade 2, and the other one was completely different.

At UCSF, where I practice, we’ve decided to standardize that. And because there are now 9 bispecifics, and the inpatient team cannot be sitting there and calling the doctor for each disease, we have a one-size-fits-all algorithm for CRS, for ICANS. [We give] Tylenol and [tocilizumab], and then if that doesn’t work, add the [dexamethasone]. If that doesn’t work, add the anakinra.

I think you need to have a simple protocol. If you can, also build into your electronic medical records [EMRs] the drop-downs for all of these medications. If somebody’s never given tocilizumab, they don’t know that it’s 8 mg/kg. You can just click on a button, and it’s ordered, and the pharmacy mixes it. It needs to be given quickly, too. By putting it in an EMR, it should hopefully flag pharmacy and nursing to give it. Speaking to the interdisciplinary care, I think having those kinds of protocols helps standardize the management of these [adverse] effects.

Lastly, make sure that when there are transition points between academia and community, you’ve summarized what happened in the hospital. In a good discharge summary, you’ve summarized the dosing that should happen in the next immediate few days to weeks to months. Then the supportive care, IVIG, antimicrobial prophylaxis, all of that really needs to be spelled out.
And then the patients also need to be educated so that should they ever have fevers when they go to the emergency [department (ED)], they either show their wallet card or tell the [ED], “I’m on this medication,” so that [ED] doctors don’t think, “Oh, this is just another fever, or it’s flu and COVID-19.” Well, it may be something different. Those are the systems issues that I would suggest.

AJMC: Are there any key patient factors clinicians should consider before administering triple or quadruple therapy vs other treatments?

Chari: In general, when we think about selecting a regimen in any
oncologic indication, you have to think about patient factors, disease factors, and treatment factors. The treatment factors include dosing intensity, lowering the dosing schedule, and frequency. Patient factors are the comorbidities [and] the frailty.

If a patient can’t move quickly, then that’s a sign. There [are] emerging data about doing a gait speed test, for example. And if you’re not moving quickly, you might be at higher risk of blood clots with some of the drugs that we use that cause thrombosis, like [immune-modulating drugs].

When it comes to the disease factors, we still have not overcome high-risk disease: [International Staging System stage 3], high-risk genetics. Those might be patients who would want to consider quadruplet [therapy], even if they’re an older patient, because the myeloma might be the great limiting issue in their lifespan. On the other hand, somebody who’s a very standard risk [and] has minimal symptoms may not necessarily need a quadruplet for long.

The last point I’ll make is, one of the challenges we have when we
extrapolate clinical trial data in the real world is that, in general, parental drugs are probably only given for 50% to 60% of the duration of study drugs. We have these beautiful phase 3 studies published in the New England Journal of Medicine, but then when you go to the bedside in the clinics, no one’s giving that duration of therapy. We have to really ask some of these new quadruplet studies that give twice-weekly bortezomib for 6 months, less frequently, or for a year and a half, “Are you really going to ask your older patients to be doing that for that long?” And my guess is, probably not.

I think making sure that dosing, schedule visits, time toxicity, [and] financial toxicity are the things to think about that are also being considered when we treat our myeloma patients.

References
1. Sonneveld P, Dimopoulos MA, Boccadoro M, et al; PERSEUS Trial Investigators. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390:(4):301-313. doi:10.1056/NEJMoa2312054
2. Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial. Nat Med. 2025;31(4):1195-1202. doi:10.1038/s41591-024-03485-7
3. Facon T, Dimopoulos MA, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;391(17):1597-1609. doi:10.1056/NEJMoa2400712
4. Multiple myeloma drugs. International Myeloma Foundation. Accessed May 1, 2025. https://www.myeloma.org/multiple-myeloma-drugs