Shaji Kumar, MD

Shaji Kumar, MD, a professor of medicine and a consultant in the division of hematology at Mayo Clinic in Rochester, Minnesota, discusses the incidence and management of infections in patients receiving teclistamab-cqyv (Tecvayli) or other bispecific agents for relapsed/refractory multiple myeloma.

Teclistamab, a B-cell maturation antigen [BCMA­]–targeted bispecific T-cell engager, was approved based on the phase 1/2 MajesTEC-1 trial (NCT03145181; NCT04557098). One significant adverse event (AE) reported in the trial was infection, which occurred in 76.4% of patients, with 44.8% reporting grade 3 or 4 infections. Kumar says that opportunistic infections are seen in patients who are heavily immunosuppressed due to the disease and the effect of therapies. He says this makes it important to monitor patients as they receive teclistamab in routine practice.

Risk of infection may be related to BCMA-targeted therapies depleting B cells and plasma cells, leading to hypogammaglobulinemia, which was reported in 74.5% of patients in the trial. Kumar says that identifying infections early and giving intravenous immune globulin (IVIG) to patients who have low serum immunoglobin are important management practices for teclistamab.

 One important set of [AEs] that has been noted with teclistamab and other bispecific antibodies has been infections. Now [over] two-thirds of the patients on teclistamab had infections and almost half of them—that means a third of the patients got a grade 3 or 4 infection. Now what has been concerning is some of these infections are what we call opportunistic infections that are seen in heavily immunosuppressed patients. So clearly, we need to get a better handle on that particular set of AEs. And I think careful monitoring as patients start getting this drug in the routine practice is going to be very important.

 Now part of that is probably related to the fact that the BCMA is also present on the B cells and these therapies lead to profound depletion of the B cell population, and normal plasma cells, leading to significant hypogammaglobulinemia. So identifying infections early on, treating them aggressively, as well as trying to prevent infections with IVIG infusions in patients who are profoundly hypogammaglobulinemic, all are going to be important part of the management of these patients.

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Shaji Kumar, MD, discusses the incidence and management of infections in patients receiving teclistamab-cqyv or other bispecific agents for relapsed/refractory multiple myeloma. 

Managing Infections During Bispecific Therapy for Multiple Myeloma

The main message would be that oncologists should be aware of the potential adverse effects, both short term and long term. I think we are going to be dealing with 2 situations. One obviously is very small community practices that cannot or do not have the infrastructure that allows them for close monitoring in the hospital. In that case, it might be better for those patients to be referred to a larger institution to at least get initiated on therapy for the first cycle or 2. Then potentially, these patients can come back and do community practice to get these drugs. I think the in-between approach is the larger community hospitals, where the facilities are accessible, and it’s a matter of the training and putting the logistics in place for these patients to be monitored in the hospital. Then, of course, larger facilities that are very well acquainted with these kinds of adverse events and have extensive experience with cellular therapy. Those sites probably already have the technology required for treating patients with this, in terms of both the outpatient and inpatient facilities.

The key message is to figure out which patients need the therapy. Identifying those patients who have had 4 or more lines of therapy and can benefit from teclistamab is important. The next step is making sure they go to the right setup so they can get started on this treatment. Once they’re on the treatment, it’s very important for us to be closely monitoring these patients for infections.

In terms of future challenges, as we already said, patients with myeloma continue to need new therapies. Thankfully, there are a lot of new treatments being developed both in terms of cellular therapies—not only chimeric antigen receptor T cells against different targets but also natural killer cells that are mortified to target the tumor cells. There are bispecific antibodies that are going after different targets, and trispecific antibodies are also being developed. In addition, there are targeted small molecules, including the cell ... or the venetoclax for patients with t11;14 translocation, as well as some new therapies being developed that are targeting the t4;14 translocations. Overall, there are a lot more effective global therapies, such as immunotherapy and more targeted therapies, going after specific subtypes of myeloma.

Dr Shaji Kumar outlines advice for community oncologists and discusses unmet needs for treating patients with R/R multiple myeloma.

Advice to Community Oncologists Treating with Bispecifics and Unmet Needs in MM

The approval of teclistamab comes with the Risk Evaluation and Mitigation Strategy program, which also requires very close monitoring of these patients. One way to do that is to admit the patients during the increased dosing to a hospital, where we can watch them closely. Teclistamab has 2 increased doses, then the final dose. Each of those doses can be associated with cytokine release syndrome CRS, so patients do need to be watched for a couple days after each dose. You can either admit them to the hospital or monitor them extremely closely in an outpatient setup, especially if we have technology that allows for remote monitoring of the patients so that once they spike a fever or develop any of the symptoms that are typical of CRS, those patients can be immediately hospitalized and treated with steroids or teclistamab as needed.

The second toxicity is the Immune Effector Cell–Associated Neurotoxicity. Again, most of the neurological toxicity has been in the context of CRS, so if you’re monitoring these patients closely for CRS, we should also be capturing those and treating them appropriately. For those patients, predominantly steroid-based therapies would be important. There are other measures that can [also] be invoked.

The other toxicity one must be aware of is hematological toxicity. We do see cytopenia in these patients. Some patients can have cytopenia that may go beyond that initial 2 or 3 weeks. Those patients must be monitored closely. Knowing these are potential adverse events is going to be important for monitoring. Then one of the biggest concerns, as we already talked about, is the risk of infection. These patients must be on adequate antibiotic prophylaxis, particularly prophylaxis against 

 pneumonia, fungal infections, and viral reactivation. If these patients have unexplained symptoms with cytopenia, fever, or other symptoms that are concerning for CMV [cytomegalovirus], we certainly need to be checking the CMV tighter just to make sure there’s no reactivation of CMV. Some adverse effects are unique to this class of drugs, but awareness is the key to monitoring them.

Dr Kumar shares his perspective on the impact of management and monitoring strategies used to minimize the risk of adverse events in patients treated with teclistamab and other bispecifics.

Monitoring and Management of Adverse Events Associated with Bispecifics in MM

Unfortunately, myeloma continues to relapse. Even with the teclistamab or the CAR [chimeric antigen receptor] T cells, we are still looking at patients who continue to relapse. We need additional therapies for patients with myeloma. Thankfully, there are several bispecific antibodies in development that are not only targeting BCMA [B-cell maturation antigen] but also other antigens, such as FcRH5 in the case of cevostamab or GPRC5D in the case of talquetamab. All these bispecific antibodies, irrespective of the target, appear to have an activity that’s quite similar with almost two-thirds of the patients getting some response. Again, the responses are reasonably durable, lasting for upward of a year for most.

What we must understand over the next few years is how we sequence these different bispecific antibodies. Do we use different bispecific antibodies based on the target? Do we use them in sequence, or do we go after the same target but using different platforms such as CAR T-cell therapy, bispecific antibodies, or antibody-drug conjugates? Much needs to be learned, particularly in the context of bispecific. There are clinical trials looking at combinations, particularly with monoclonal antibodies, which might be the way we end up using bispecific in the future, in combination and potentially for a limited duration of time.

Fortunately, we have several platforms we can use to target the BCMA. We know it’s a well-validated target antigen in myeloma. A lot of it is determined by the availability of therapies while we have an antibody-drug conjugate like belantamab approved, as well as teclistamab and 2 CAR T cells approved for BCMA. A lot of the treatment choices are often driven by availability, particularly that of the CAR T. There’s limited availability for CAR T, and that is often preferred in the setting of a patient like whom we just talked about.

Unfortunately, a large proportion of those patients may not be able to access CAR T, either because we don’t have available slots or because they are in a smaller community practice without cellular therapy facilities. For those patients, bispecific antibodies are the best option, primarily in the sense of the good response rate we have seen.

If that is not an option, then certainly BCMA-targeted antibody-drug conjugates, such as belantamab, would be of value. There are phase 3 trials looking at combining belantamab with other standard-of-care agents, such as protostome inhibitors and immunomodulatory drugs. Hopefully, those trials will also provide some guidance in terms of when to use a specific combination, whether it be an antibody-drug conjugate or bispecific antibody.

Dr Shaji Kumar highlights bispecifics under development and how BCMA-targeting therapies impact patient selection for the treatment of R/R multiple myeloma.

Bispecifics Under Development for The Treatment of R/R Multiple Myeloma

The activity we have seen with the bispecific antibodies is quite good. Bispecific antibodies are not something new in the cancer space. They have been around for awhile, but teclistamab represents the first bispecific antibody that has been approved for the treatment of multiple myeloma. As a class, the bispecific antibodies all work in a similar fashion. They are, as the name describes, bispecific, so the antibody has specificity both for CD3 that is on the T cell and a tumor antigen, which, in the case of teclistamab, is a B-cell maturation antigen. However, it can be different, such as FcRH5 for cevostamab or GPRC5D for talquetamab. Essentially, the antibody brings the tumor cells in close proximity with the immune cells, leading to an immune synapse formation and even tumor cell death.

The activity with the bispecific antibodies across the board with all these, including teclistamab and others that are in clinical trials, are promising response rates of upward of 60% in patients who are quite refractory to the available therapies. Given all the other options we may have available—the bispecific antibodies and, in this case, teclistamab—make good sense as the next line of treatment.

The MajesTEC-1 trial [NCT04557098] is the pivotal trial that led to the approval of teclistamab for the management of multiple myeloma. This included a phase 1 portion that first identified the recommended phase 2 dose of teclistamab given as a single agent. That was 1.5 mg/kg subcutaneously, weekly, with increased doses of 0.06 and 0.3 mg/kg. In MajesTEC-1, a fairly large number of patients were enrolled on that study, and the overall response rate was 62%. That included nearly 60% of the patients who have eGFR [estimated glomerular filtration rate] and almost a third of the patients who achieved a complete response or better. A significant proportion of the patients who achieved a complete response also were emerging negative in their assessment.

MajesTEC-1 was a phase 1/phase 2 study that looked at, first, the identification of the recommended phase 2 dose 4 teclistamab, followed by a phase 2 study that explored the first tolerated dose in these patients. There were 40 patients who were enrolled in the phase 1 study, which eventually determined that the recommended phase 2 dose is 1.5 mg/kg given subcutaneously. The phase 2 portion of the study at the recommended phase 2 dose enrolled a total of 125 patients.

This was a fairly heavily pretreated group of patients, with a median age of 64. Many of these patients had extramedullary disease, almost 17%, and almost a quarter of these patients were highly cytogenetic. These patients had many prior lines of therapy. There was a median of 5 prior lines of therapy, with almost three-quarters of the patients having had 4 or more lines of therapy. Most of the patients, 82%, had a prior transplant, including a few with allogeneic stem cell transplants. All these patients were triple-class exposed, and almost 75% of the patients were triple-class refractory. The overall response rate was 63%, and that included 59% of the patients who have eGFR or better and almost 40% of the patients who are in complete response. The minimal residual disease negativity rate at the 10–5 cutoff was 27% in the intent-to-treat patient population.

When you look at the overall response across different patient subgroups, you can see it benefited all patients, including some who were high risk, even though the response rates were lower in those who were International Staging System stage 3 compared with those who were stage 1. In addition, there was not as much benefit seen in patients who had extramedullary plasmacytomas, which continue to be a challenge in relapsed disease. When you look at the responses, they were quite durable. Again, we don’t have median progression-free survival for this cohort, but we have patients who have been on therapy for over 2 years at this point in time. When you look at the duration of response, the median was approximately 18 months, and the 12-month event-free rate was approximately 68%. When you look at this cohort of patients who are in complete response or better, the median duration of response was even longer for those groups of patients.

The median overall survival for this group of patients was 18.3 months. In terms of toxicity, the drug was fairly well tolerated. Cytokine release syndrome [CRS] was the most common toxicity encountered, and it was seen in approximately 72% of the patients. Thankfully, most of it was grade 1 or 2 and was managed with steroids and other supportive parameters in most patients, with some needing teclistamab, as well. The hematological toxicity—again, neutropenia was the most common, seen in approximately 70% of the patients, followed by thrombocytopenia, lymphopenia, and anemia. There was some gastrointestinal toxicity, injection site reactions, cough, and headache that were reported in several patients.

One of the adverse effects that clearly needs more review is the infection that was seen in these patients. Nearly three-quarters of the patients had infections, with nearly half of the patients having a grade 3 or 4 infection. There were also 19 deaths due to adverse events—almost 12 COVID-19–related deaths. Clearly, the infection is something we need to be very cognizant of as patients are getting started on teclistamab.

One-third of the patients ended up receiving teclistamab, but others were able to be managed with other measures. The median time to onset of CRS was approximately 2 days, and it lasted for anywhere from 1 to 9 days in these patients. Neurotoxicity was seen, but the overall rate was fairly low—mostly grade 1 or 2. Overall, there were 5 patients, with a total of 9 events. Most of this occurred concurrently with CRS, and all of them were fully resolved. MajesTEC-1 demonstrates the value of teclistamab in a heavily pretreated patient population, such as our patient whom we just talked about.

Dr Shaji Kumar reviews key efficacy and safety outcomes of the updated data from MajesTEC-1, evaluating teclistamab in patients with R/R multiple myeloma. 

MajesTEC-1 and Teclistamab in Patients with Relapsed-Refractory (R/R) Multiple Myeloma

Hi, my name is Shaji Kumar. I’m a hematologist at Mayo Clinic in Rochester, Minnesota. Thank you for joining us today. I’m going to talk about a patient scenario first, then talk about the treatment choices we made, and then go into a discussion regarding the rationale and how to manage this patient on that specific therapy.

The patient we have is a 63-year-old woman with a past medical history of hypertension, asthma, and a remote history of smoking, who presented to the clinic with back pain. At that time, testing was done. She was noted to be hypercalcemic, with a calcium of 12.3 mg/dL, and anemic, with a hemoglobin of 10.3—both of which were new compared with her baseline labs. She ended up getting an additional workup, including serum protein electrophoresis that demonstrated an M [monoclonal] spike of 1.4 g/dL. That was immunoglobulin G κmyeloma. The serum creatinine was 1.3 mg/dL. A bone marrow biopsy was performed and confirmed to be 20% to 30% chronic plasma cells, and the fluorescence in situ hybridization revealed translocation t4;14.

She was started on a combination of bortezomib, lenalidomide, and dexamethasone, which is the standard induction therapy for 4 cycles, followed by autologous stem cell transplant and lenalidomide maintenance following the stem cell transplant. She had a good duration of response for approximately 3 years on this therapy and subsequently progressed. After that time, she had several combinations, initially with daratumumab, pomalidomide, and dexamethasone subsequently with the carfilzomib-based combination. As her fourth line of therapy, she received a BCMA [B-cell maturation antigen]-targeted antibody-drug conjugate in the form of belantamab mafodotin.

Now she’s presenting with a relapsed disease, having gone through 4 prior lines of therapy, including a proteasome inhibitor, IMiD [immunomodulatory drug], an anti-CD38 monoclonal antibody, and most recently, an anti-BCMA antibody-drug conjugate. Based on the available therapies, you had a discussion with her and decided on treating her with teclistamab, which was recently approved for the management of patients with 4 prior lines of therapy. Now she’s started on this tip-up dosing of teclistamab. Typically, this drug has a starting dose of 0.06 mg/kg. Then 2 days later, you get an increased dose of 0.3 mg/kg, and 3 more days later, the patients will get the full dose of 1.5 mg/kg. These are all given subcutaneously.

When the patient becomes refractory to the 3 commonly used therapies, especially the anti-CD38 monoclonal antibody, the IMiD, and the proteasome inhibitor, we do have a good number of choices in terms of treatments we can apply. We have an XPO1 inhibitor, selinexor, that has been studied in combination with a variety of different standard-of-care drugs, and just in combination with dexamethasone. We have belantamab, a BCMA-targeted antibody-drug conjugate, which is active by itself, with a response rate of approximately 30% in this kind of patient. This patient has already received belantamab, so it’s no longer a choice. The other choices certainly include traditional chemotherapy combinations that may include alkylating agents and anthracyclines. Given the activity we have seen with teclistamab in the clinical trials and with its recent approval, that certainly becomes a logical choice for a patient like this, in terms of therapy.

It’s important for us to make sure the patient has a disease that is relapsing and requires therapy. It’s not uncommon, especially in the early relapses, to see a very slow increase in the M protein. It’s something we often refer to as biochemical relapse, which does not require an immediate institution of a new therapy for all patients. If it is not a high-risk disease and did not originally present with any high-risk characteristics, including neurological issues or renal failure, then it’s reasonable to consider following them very closely to see what the trend of increase in the biochemical parameters is.

If the M protein or the free light chain is increasing rapidly, with a doubling time of 3 months or less, it’s very reasonable to get started on therapy. Of course, patients who present with end organ damage in the form of recurrent CRAB [Carbapenem-resistant 

] features, whether it be new lytic lesions, renal insufficiency, hypercalcemia, or anemia, they clearly need to be started on therapy irrespective of the degree of biochemical progression they might have.

Finally, there are patients who may present with extramedullary disease or other clinical characteristics outside of CRAB features, which also point toward the need for therapy. It’s a combination of things, both in terms of myeloma-specific blood parameters and other findings that might come from imaging studies, all of which can contribute to that decision-making process as to when to start therapy for these patients.

Shaji Kumar, MD, presents a case of a 63-year-old woman with R/R multiple myeloma, shares his initial impression, and assess how clinical relapse impacts treatment decisions in patients with R/R multiple myeloma.

Shaji Kumar, MD | Authors

Articles

Managing Infections During Bispecific Therapy for Multiple Myeloma

Advice to Community Oncologists Treating with Bispecifics and Unmet Needs in MM

Monitoring and Management of Adverse Events Associated with Bispecifics in MM

Bispecifics Under Development for The Treatment of R/R Multiple Myeloma

MajesTEC-1 and Teclistamab in Patients with Relapsed-Refractory (R/R) Multiple Myeloma

Case Presentation: A 63-Year-Old Woman with Relapsed-Refractory (R/R) Multiple Myeloma