Referrals From Community to Academia Enhances Multiple Myeloma Outcomes

Samer A. Al Hadidi, MD, MS, FACP

Frits van Rhee, MD, PhD

Appalanaidu Sasapu, MD, FACP

As part of an Around the Practice® program focused on the University of Arkansas Medical for Medical Sciences (UAMS), CancerNetwork® hosted a panel discussion on multiple myeloma. The program was brought together to discuss the advantages associated with effective collaboration and communication between community and academic cancer centers in treating patients with multiple myeloma. The panel also discussed the referral process, comparing the use of bispecific antibodies vs CAR T-cell therapies in patients with multiple myeloma, and managing toxicities related to treatment with bispecific antibodies.

The Panel was led by Samer A. Al Hadidi, MD, MS, FACP, assistant professor of Medicine at UAMS. Panelists included Frits van Rhee, MD, PhD, professor of medicine and clinical director of UAMS Myeloma Center; and Appalanaidu Sasapu, MD, FACP, a hematologic oncologist at the CARTI Cancer Center in Little Rock, AK.

From Community to Academia Referral Process

Al Hadidi: What is the importance of collaboration and patient care between academic and community practice when caring for patients with multiple myeloma?

van Rhee: That is an important topic because one has to realize that many patients live far away from academic centers, and although they can get more complex or intensive therapies at an academic center, they will get most of their ongoing therapy locally from the community oncologist. Good communication and seamless transition of care are vital for a good outcome. There has to be fluent communication between the community oncologist and academic physician. We also take some very practical measures. We try to fax any instructions that we have to the community oncologist, and in fact, sometimes faxes get lost in a doctor’s office. That’s not too uncommon. We give the patient the instructions with a printed form customized to that specific patient, and we give instructions on what we think is important for immediate follow-up care.

Al Hadidi: You mentioned a few things that you are doing, including personalized patient communication and reaching out to the community oncologist. There is a team supporting this. Can you tell us more about that?

van Rhee: We have 2 doctors, but a good team does not operate just by the mere existence of doctors. We have our nursing team, our nurse practitioners, transplant coordinators, and a phone nurse where people can call directly, and we also have a nationally known social work program that helps to support our patients. [The team] is not just a doctor. There are many team members who are involved in delivering care, both locally and helping the patient from a distance. Then we also have our medical record system, where patients can communicate with us directly and we can answer any questions that they have. In addition, many of us give out our cell phones, rightly or wrongly, and emails, so there are multiple lines of communication.

Al Hadidi: With all these complexities of the system, how do you ensure everything works in place to serve that purpose?

van Rhee: It is important to realize what therapy the patient is going to receive back home. It is also important to realize what type of practice the patient goes back to. Very large private practices, such as the one where Dr. Sasapu works, are staffed with hematologists who are familiar with multiple myeloma care. Some of the smaller community practices may have physicians who are mostly focusing on breast cancer and colon cancer, etc. The level of instruction and detail that is required needs to be tailored to the setting where the patient goes back.

Al Hadidi: How can you streamline the referral process from, say, your institution to an academic center? How does that process go?

Sasapu: As Dr. van Rhee [said], he gave us details about the work they do in academia. I do agree that there should be streamlined communication which is predefined and works for everybody. There should be an intake coordinator at the academic center, and that person will be the single point of contact for all communications. When we send a referral from the community to academia, that point of contact will receive the communication. Then they will have a checklist of documents that [academia will need] for that patient. Then we will be happy in the community setting to send all those records. If our nurses have that single point of contact–– the email address, the phone number–– having that conversation initiated once will help my team at the community clinic and also the patient have that smooth communication. Having the constant communication without any gaps is important.

Al Hadidi: What other resources could have been available to you to help in making this process easier?

Sasapu: Whenever we identify a patient who will be eligible for these novel therapies, including bispecifics or CAR T-cell therapy, I, as a physician, will initiate that referral. I will send my nurse and the scheduler a note saying that this person should be sent to this academic center, but I might not say what therapy that patient would need, because I would let the academic center decide which therapy is going to be eligible for a patient. Once that referral is sent, we send all the records and the latest clinic notes to that point of contact, hopefully. After that, we check on that referral a few days later to make sure that the academic center received all the documents that they needed to avoid any miscommunication. At the same time, we will keep the patient in constant communication, saying that we have done the referral 3 days ago. We just checked on it, and they have confirmed the receipt of all the reports and the referral. That way the patient has the trust [of] all the providers taking care of them.

Al Hadidi: Do you see a difference in patient outcomes when such collaboration exists, where both academia and community practice help in taking care of patients?

van Rhee: Yes, I do. The outcomes are better when there is integrated care between academic centers and the community. We can deliver some of the more complicated and intensive therapies better because there is more dedicated infrastructure. Once these more intensive or complicated treatments have been completed, then we cannot keep the patient in Little Rock. They need to transition back to their local oncologist, and that is where they receive further therapy. In that regard, it is also important to realize that multiple myeloma is not just one therapy, it is usually a whole therapy plan of which only 1 aspect is being implemented at the academic center, and further therapy and ongoing therapy needs to be done locally.

Sasapu: I strongly agree. Having that collaborative talk between academia and the community is helpful for patient outcomes. As you mentioned, in the clinical trials, there are several new novel molecular therapies that are [being evaluated]. Not everybody will be eligible for the standard-of-care therapies, but when you have a clinical trial, we, as community oncology teams, should let patients know that there is an option there. If we do not know what option is available, doing that referral early to the academic center, and letting the academic center team decide which trial is good for this patient vs standard of care, is important.

Al Hadidi: What are some of the challenges that you deal with during this process of the referral system?

van Rhee: One of the main challenges is first establishing a rapport with the patient. The initial contact between the oncologist and the patient is important. There are also socio-economic barriers to receiving care. This can [entail] travel or staying locally at lodging. That is an aspect where our social work department plays an important role. There can be financial support from various organizations. The patient, by coming to an academic center, can not only establish this rapport with the doctor and the team but also benefit from some of the social support measures that are available. That will alleviate their fear or their worry about coming to an academic center, and they quite rightly, sometimes worry about the cost associated with this travel and sometimes staying in town.

Utilizing Approved Therapies in a Clinical Setting

Al Hadidi: We have 3 bispecific antibodies approved in multiple myeloma; 2 of them targeting BCMA [elranatamab-bcmm (Elrexfio); phase 2 MagnetisMM-3 (NCT04649359)]; teclistamab-cqyv (Tecvayli); phase 2 MajesTEC-1 (NCT04557098)] and 1 targeting GPRC5D [talquetamab-tgvs (Talvey); phase 1 MonumenTAL-2 (NCT05050097)].^1-6 We [likely] have more in development in clinical trials. Dr. Sasapu, how do you envision this referral process at your institution? Do you refer all patients who are intended to get bispecifics to academia to help with step-up dosing and so on? What is your process?

Sasapu: There are a lot of bispecifics available for later lines of therapy. We have the CAR T-cell therapies available for the second line and beyond. It is complicated and complex for a community oncologist to decide which patient would get what. To simplify the referral process, what I have been doing is when my patient has gotten the standard of care therapy in the frontline, and then they need a special therapy, either the bispecific vs other treatments, which are delivered at an authorized treatment center, I will send a referral saying that patient would need treatment for the therapy. [This would] help us to guide which therapy is suitable for this patient. I will let the academic team decide which patient would benefit from which therapy, but I do tell them at the contact or the final contact before they go to see the academic that there are therapies available. [There are] bispecifics, or non-bispecific, other one-time therapies. I will set up expectations for the patients from my side when they go to academia. The ball will be in [the court of] the academic side of it.

Al Hadidi: Who are the patients that you think are eligible to [receive] bispecific antibodies? When do you think of starting those patients [on them]?

Sasapu: Looking at the FDA approval for bispecifics, they are all approved in third-line therapies [and beyond]. I look at the patient’s comorbidities. If they are not a candidate for conditioning chemotherapy, which is a part of the requirements for CAR T-cell therapy, either because of their poor organ function or frailty, or if they have social factors that are impeding them not to to stay locally for 4 weeks or so for the [treatment] or some other lodging issues, those patients are [ones] who fit the bispecific category better. I still would let the academic center decide whether that particular patient I sent for referral is suitable for a bispecific vs a clinical trial.

REMS Program

Al Hadidi: Those bispecific antibodies, the approval process comes with this REMS [Risk Evaluation and Mitigation Strategy mandate], which requires yourself and some of your staff to be certified to be allowed to prescribe such medications.

Sasapu: These bispecifics and CAR T-cell therapies, do have some unique toxicities, which we do not see with the standard of care or other therapies that include cytokine release syndrome [CRS], neurotoxicity, or [immune effector cell-associated neurotoxicity syndrome] ICANs. To mitigate and evaluate the risk, there is a specialized program called REMS. What the REMS [mandate] means is that providers, [including] physicians, nurses, and the pharmacy team and whoever is on call that includes all the doctors and mid-level providers–– everybody should have the training on how to identify these toxicities, like CRS or ICANS and other adverse effects. They also should know what to do when they have these toxicities, educating the patient, and educating the caregivers, is part of this REMS program to be able to deliver these special bispecifics. There is a requirement that the treatment center should have REMS certification and then intermittently check up on it.

Al Hadidi: In your practice, is there a difference with step-up dosing between those agents, and [what they are]?

van Rhee: It is exciting that we have these therapies available, and they are a game changer in the treatment of relapsed multiple myeloma because they are effective. This will undoubtedly prolong the life of patients with relapsed disease. When it comes to the CAR T cells, we generally reserve them for patients who are in a more fit condition. [When] they [receive] chemotherapy, some of the [adverse] effects are initially more severe. [These include] fevers, some confusion, and neurological toxicity.

Bispecifics are immediately available off the shelf and patients who are frail can have these. In terms of what treatment you give first, it now appears that, if a patient is eligible, the sequence of first doing CAR T cells and then bispecifics is probably the best one, because if the patient has prolonged exposure to an antibody and then relapses, the multiple myeloma may have undergone mutations which makes the CAR T-cell therapy ineffective. The sequence should be CAR T cells and then bispecifics.

There is more than 1 bispecific antibody available. There are 2 [elranatamab and teclistamab] that have the same target, called B-cell maturation antigen [BCMA]. The other target is GPRC5D. BCMA is also expressed in normal plasma cells, and the job of normal plasma cells is to make antibodies, so once you deliver that therapy, patients are even more immunocompromised. For that group of patients, prophylaxis of infection needs to be ongoing and is important. Drugs preventing shingles and protecting against certain types of pneumonia, and what is called intravenous immunoglobulin [IVIG] antibody preparation infusions are important.

The other therapy [talquetamab] which targets GPRC5D, has its own unique set of [adverse] effects. Some of this target is expressed, not only on plasma cells, but it can also cause alteration of taste. Sometimes patients get a sore mouth, what we call a mucositis-type picture. They lose weight, they can have nail changes, and they can get skin rashes. That drug is a little bit harder to tolerate. When the choice comes between the bispecific antibodies, that target BCMA, or the other one that targets GPRC5D, most physicians will first go for the bispecific antibody that targets BCMA.

Location and its Impact on Referrals

Al Hadidi: How do you decide to use a bispecific treatment?Is there a difference in treatment decisions for patients who are in-state and out-of-state? In Arkansas, we do see a sizable [number of] patients out of state that come to your [practice].

van Rhee: In principle, there is no difference in treatment between patients who are in-state and out-of-state. Patients who are out of state need to travel here. They stay here and [receive] lodging and have their initial workup and assessment here, and then they get either initial treatment here, or perhaps they come back later for a transplant or for other therapy. In principle, the approach is the same. What therapy we deliver is to a large extent determined also by the physical fitness of the patient. The aim of treatment for an 80-year-old is a little bit different than the aim for a 40-year-old. Eighty-year-old patients want to keep the disease under control and maintain a very good quality of life. If a patient is 40 years old, then we would like to cure the patient, and this is already feasible nowadays, with quite intensive therapy.

The exciting thing is that these novel therapies are moving earlier on into the treatment. One of the [approved] CAR T cells can be given at first relapse. We are also taking part in a clinical trial where patients can receive CAR T cells as part of their frontline therapy instead of a transplant, and we just enrolled our first patient in this international trial. We are going to see a paradigm shift where some of the older treatments in the future may be replaced by these novel immunotherapies, and they are going to be used early on. There are a number of trials ongoing with the bispecific antibodies. They are currently approved for patients in fourth-line therapy but are undoubtedly also going to be given much earlier.

In terms of a patient being out of state, it is even more crucial to have excellent rapport with the referring physician. When you think about CAR T-cells, the main time of immunosuppression is 2 or 3 months. The immunosuppressive effect of the bispecific antibodies is more ongoing. All these prophylactic measures are important. It is [also] important for the treating academic physician to realize what type of practice the patient is coming from. If the patient is coming from a large practice, like Dr. Sasapu, they are aware of these antibodies and their [adverse] effects and what they need to monitor them. Some of them also come from smaller practices where the main focus is on solid tumors, breast cancer, or lung cancer, and they may only have a few patients with multiple myeloma, and they are not that familiar with this new class of drug. Therefore, it is important that we communicate about potential [adverse] effects, how these patients need to be monitored, and what prophylactic measures should be implemented.

Bispecific Treatment Referrals and Adverse Effect Management

Al Hadidi: How do you investigate this when you decide on referring the patient for bispecific treatment?

Sasapu: In Arkansas, most of the cancer care is delivered in the rural setting, and also at the community oncology level. Since Arkansas [consists of] mostly rural areas, there are social factors that play a role in terms of what type of therapy we can deliver to them. When it comes to referral for novel therapies like CAR T and bispecifics, even for autologous or allogenic [transplant], these factors play a big role. We do have a social worker who will look into the initial social situation.

We will try to provide whatever resources we have at our center, at the CARTI Cancer Center, but at the same time, that alone should not stop me or any community oncologist to not to send the referral to academia, but we tell the patient what to expect and set up the expectations. Then when we communicate to the referring center or the university or academia, we tell them [about] the situation. The patient needs local lodging, does not have good transportation, and needs help with financial resources. Needing a caregiver for a long time or for repeated follow-ups is going to be a big issue. Those factors do play a role in what we can offer to these patients.

Al Hadidi: Is there anything that you want to share with us about the [adverse] effects that you are seeing with bispecific use in your patient?

van Rhee: With the bispecific antibodies, CRS, which is caused by the activation of immune cells, gives rise to fever and sometimes a drop in blood pressure does occur. [However], it is significantly less severe than in patients treated with CAR T cells. Also, the incidence of confusion and other neurological toxicities is much lower. Nevertheless, these [adverse] effects do occur, and that is why step-up dosing is utilized.

Step-up dosing means that the patient gets small doses before they get their first full dose, and that reduces the chance that any of these [adverse] effects occur. For some of our patients, we admit them, and we give the step-up dosing and the first full dose as an inpatient. For quite a few patients whom we think are suitable for this approach, we can do this as an outpatient, providing they are fairly fit and do not have a large myeloma tumor burden. One of the most important [adverse] effects beyond the initial phase with the bispecific antibody is the risk of infection.

The risk of infection arises twofold. First of all, the antibodies do not only kill the multiple myeloma cells. They kill the normal plasma cells as well. The patient stops making normal antibodies. Secondly, some of the other immune cells, which we refer to as T-cells, also get stimulated and they get tired. We call it exhaustion. There is a risk of more severe viral infection. The way we try to mitigate against these bacterial infections due to lack of antibodies is by giving IVIG and some prophylactic antibiotics. More of us in the multiple myeloma field try to space out these antibodies after the initial dosing.

For the teclistamab and elranatamab drugs, the initial dosing is weekly. We go fairly quickly after the patients had a very good response to dosing every 2 weeks, and later on to dosing every month. That is to prevent the wearing out of immune cells and to make sure that they still can react to normal challenges such as infections. There are also clinical trials going on with what we call fixed-duration treatment. That means the patients get the antibody for 6 months or 9 months, and then the treatment gets stopped and the patient is followed carefully for any recurrence, and then if that does occur, the patient can be restarted on the antibody treatment. The big advantage is that the normal plasma cells can recover, and the immune cells can recover as well. You allow the immune system to rebuild itself before, if needed, the next antibody treatment is given.

References

1. FDA approved teclistamab-cqvy for relapsed or refractory multiple myeloma. News Release. FDA. October 25, 2022. Accessed September 3, 2024. https://bit.ly/3Fgsi4s
2. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387:495-505. doi:10.1056/NEJMoa2203478
3. Pfizer's Elrexfio receives U.S. FDA accelerated approval for relapsed or refractory multiple myeloma. News release. Pfizer. August 14, 2023. Accessed September 3, 2023. https://bit.ly/3DTCRIY
4. Lesokhin AM, Tomasson MH, Arnulf B, et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med. 2023;29(6):2259-2267. doi:10.1038/s41591-023-02528-9
5. FDA grants accelerated approval to talquetamab-tgvs for relapsed or refractory multiple myeloma. News release. FDA. August 10, 2023. Accessed September 3, 2024. https://bit.ly/4cUjD4S
6. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a t-cell–redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 2022;387(24):2232-2244. doi:10.1056/NEJMoa2204591