Multiple myeloma is a plasma cell malignancy that accounts for approximately 1% of new cancer diagnoses per year. The development of a combination approach of mainstay therapies including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti–CD-38 antibodies has greatly improved up-front remission rates and response duration and prolonged overall survival in the past decade. However, for patients who have been heavily exposed to or are triple or penta-refractory to these classes of therapy, survival is under 1 year.

 Therefore, the emergence of cellular-based therapies represents a major opportunity to improve outcomes in the heavily pretreated and refractory myeloma population.

Chimeric antigen receptor (CAR) T-cell therapies approved by the FDA for several relapsed and refractory B-cell lymphomas are presently under investigation in a variety of treatment line settings for multiple myeloma. As more patients in the community become eligible for CAR T-cell therapies, community oncologists will need to be increasingly familiar about the various products, including their immediate and longer-term risks. In addition, it is key to understand the optimal time for referring these patients to an academic institution, as well as how to manage the requisite post CAR T-cell therapy in the community setting.

The State of Current BCMA-Directed CAR T-Cell Therapy

The major CAR T-cell therapies in trials for multiple myeloma are directed toward B-cell maturation antigen (BCMA), a surface antigen expressed on B cells starting from their period of development in the germinal centers onward and persisting through the time of plasma cell differentiation. BCMA is minimally expressed in normal human tissues but is heavily expressed on myeloma plasma cells. This allows for safe and intentional targeting of neoplastic myeloma cells using CAR T-cell technology.

The first FDA-approved commercial CAR T-cell therapy will likely arrive in the first quarter of 2021. Patients enrolled on the initial BCMA CAR T-cell trials were required to have had 3 or more prior lines of therapy with exposure to a PI, an IMiD, and an anti-CD38 monoclonal antibody.

The earliest trial was the KarMMa-1 study (NCT03361748) of idecabtagene vicleucel (ide-cel, previously bb2121), which demonstrated an overall response rate (ORR) of 73% and a median progression-free survival (PFS) of 8.8 months in all dose levels. Additionally, a median PFS of 12.1 months was observed in the highest dose level of CAR T cells (450 × 10

 Patients on this trial (n = 128) had a median of 6 prior lines of therapy, and 84% were triple refractory.

A concurrent trial, CARTITUDE-1 (NCT03548207), studying JNJ-4528 (ciltacabtagene autoleucel in China), also targeting BCMA, demonstrated an unprecedented 100% ORR in patients, with 86% achieving stringent complete response (sCR), the deepest response level by International Myeloma Working Group criteria.

 In the most recent evaluation of PFS, 86% of patients on CARTITUDE-1 had not progressed in disease at a median follow-up time of 9 months.

 New data for JNJ-4528 and the other CAR T-cell therapies being investigated will be made available during the 2020 American Society of Hematology Annual Meeting and Exposition in December and should further reinforce the potential for CAR T-cell therapy to deliver deep and durable responses to patients with multiple myeloma who are heavily pretreated.

What Type of Patients Might Benefit the Most From CAR T?

As in the case of BCMA, antigens for CAR T cells are chosen for their unique expression in tumor tissue and low expression in 

normal, healthy tissue. The complications that occur in patients receiving CAR T-cell therapy will be largely specific to the targeted antigen. Patients must undergo a multistep process to safely and effectively undergo CAR T-cell treatment and should know up front about the process involved.

The initial step involves leukapheresis, or collecting the patient’s T cells. Once this is completed, the patient must wait 3 to 5 weeks for typical manufacturing of their CAR T cells at a production facility. If required, patients typically can undergo bridging chemotherapy during this waiting period to maintain their disease, particularly if myeloma progression is accelerating. Once the patient’s CAR T cells are produced, the patient will undergo lymphodepletion (typically with fludarabine/cyclophosphamide) for 3 days before being infused with prepared CAR T cells. Patients must have sufficient health reserve to withstand the potential adverse effects (AEs) associated with CAR T-cell therapy, including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Therefore, early referral to an academic center is key to getting these patients on therapy at the optimal time.

Immediate and Longer-Term Complications of CAR T-Cell Therapy

CRS is the most common acute AE that occurs in patients treated with CAR T-cell therapy. It occurred in nearly 9 out of 10 patients in the KarMMa-1 and CARTITUDE-1 trials, though severe CRS occurred only in 5% to 7% of patients.3,5 CRS is the phenotypic presentation of a supraphysiologic production of cytokines prompted by immune cell activation, including T cells, macrophages, and monocytes (

 ). Preclinical models have shown that macrophages amplify CRS severity and are the source of several of the culprit cytokines of CRS, including interleukin (IL) 6, IL-1, and IFN-γ. CRS onset occurs variably depending on the CAR construct used.

For example, CRS occurred at median 1 day after infusion of ide-cel, whereas CRS occurred at median 7 days after infusion of JNJ-4528. Our primary treatment for CRS is tocilizumab (Actemra), a monoclonal antibody directed against IL-6; its use does not diminish efficacy of CAR T cells. Subsequent agents such as the IL-1 receptor antagonist anakinra (Kineret), anti–IL-5 monoclonal antibody siltuximab (Sylvant), and corticosteroids may be employed for severe cases of CRS.

The second notable AE associated with CAR T-cell therapy is ICANS, which is defined by the American Society for Transplantation and Cellular Therapy as “a disorder characterized by a pathological process involving the central nervous system….Symptoms or signs can be progressive and may include aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, seizures, and cerebral edema.”

 A primarily encephalopathic picture appears when patients develop ICANS, which typically occurrs later than CRS. The primary treatment for ICANS involves corticosteroids such as dexamethasone, initially every 6 hours with a quick taper as symptoms start resolving.

Signs and symptoms of neurotoxicity should be screened at least daily during the acute CAR T-cell treatment period and can be assessed with validated tools such as those from CAR T-cell therapy-associated TOXicity (CARTOX) Working Group or the Immune-Effector Cell-Associated Encephalopathy (ICE) tool.6 Severe neurotoxicity occurred at only a 3% rate in KarMMa-1 and CARTITUDE-1 and can be treated readily if caught early with close monitoring.

Other common AEs such as cytopenia and infection may occur during and after the period of CAR T-cell infusion and expansion. Anemia, thrombocytopenia, or neutropenia may occur for months after the initial treatment 

period, and clinicians should utilize supportive transfusions and/or granulocyte colonystimulating factor and thrombopoietin mimetics as indicated.

Cytomegalovirus quantitative polymerase chain reaction should be checked monthly. If the patient is persistently neutropenic, opportunistic infections should be considered. Intravenous immunoglobulin should be administered before initial lymphodepletion, but also every month for 6 months after CAR T-cell infusion and during winter months if the patient has a history of recurrent infections. In addition, patients should be vaccinated at 1-year post CAR T-cell therapy; a recommended vaccine schedule is included in 

Table 2. Recommended Vaccine Schedules After CAR T-Cell Therapy

The multiple myeloma treatment landscape is rapidly evolving, with many exciting new therapies on the forefront for relapsed and refractory multiple myeloma. CAR T-cell therapy is a 1-time treatment that allows patients to achieve deep and durable remissions without the need for the usual continuous cancer-directed treatments. The aforementioned trials and therapies have paved the way for subsequent iterations of cellular therapies. These include non–BCMA-targeted CAR T cells; next-generation CAR T cells with improved costimulatory domains for improved safety, efficacy, or faster production; and allogeneic CAR T cells derived from pluripotent stem cells available off the shelf to patients. In the coming year, as commercially available myeloma CAR T-cell therapies are approved, it will be even more important for community oncologists to better understand these therapies so they can offer them to their patients.

Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. 

. 2019;33(9):2266-2275. doi:10.1038/s41375-019-0435-7

Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. 

. 2019;380(18):1726-1737. doi:10.1056/NEJMoa1817226

Munshi NC, Anderson LD, Shah N, et al; KarMMa Study Investigators. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): initial KarMMa results. 

. 2020;38(suppl 15):8503. doi:10.1200/JCO.2020.38.15_suppl.8503

Madduri D, Usmani SZ, Jagannath S, et al. Results from CARTITUDE-1: a phase 1b/2 Study of JNJ-4528, a CAR-T cell therapy directed against B-cell maturation antigen (BCMA), in patients with relapsed and/or refractory multiple myeloma (R/R MM). 

. 2019;134(suppl 1):577. doi:10.1182/blood-2019-121731

Berdeja JG, Madduri D, Usmani SZ, et al. Update of CARTITUDE-1: a phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy, in relapsed/refractory multiple myeloma. 

. 2020;38(suppl 15):8505. doi:10.1200/JCO.2020.38.15_suppl.8505

Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. 

. 2019;25(4):625-638. doi:10.1016/j.bbmt.2018.12.758

Articles

The emergence of cellular-based therapies represents a major opportunity to improve outcomes in the heavily pretreated and refractory myeloma population. 

CAR T-Cell Therapy for Multiple Myeloma: What Community Oncologists Need to Know

Deepu Madduri, MD, assistant professor, medicine, hematology and medical oncology, Mount Sinai Hospital, discusses the results of the phase Ib/II CARTITUDE-1 trial of the BCMA-directed CAR T-cell therapy JNJ-4528 in patients with heavily pretreated relapsed/refractory multiple myeloma.

View more from the 2019 ASH Annual Meeting

Videos

Dr. Madduri on the Results of the CARTITUDE-1 Trial in Multiple Myeloma

Deepu Madduri, MD, assistant professor, medicine, hematology and medical oncology, Mount Sinai Hospital, discusses the potential impact of CAR T-cell therapy in multiple myeloma.

There are several CAR T-cell products that are being explored in myeloma, most of which target BCMA. It’ll be important to wait for the data to come out of these trials because each product would preclude exposure to another in practice, explains Madduri. For example, if a BCMA bispecific monoclonal antibody is given, a bispecific CAR T-cell therapy cannot be given and vice versa. It will also be interesting to see what patients are chosen to participate in these studies, she adds. There is also a lot of ongoing research exploring CAR T-cell resistance, persistence, and relapse.

Every year, more therapies are being approved in myeloma. Most recently, the FDA approved selinexor (Xpovio) for the treatment of penta-refractory patients. Now, the phase I CRB-401 trial (NCT02658929) of bb2121 has completed enrollment. A biologics license application for the agent may be submitted to the FDA early next year, says Madduri.

Moreover, there are going to be commercially available CAR T-cell therapies, which is going to change the treatment paradigm very quickly. However, it remains to be seen whether patients who progress on BCMA bispecific monoclonal antibodies will derive any benefit from CAR T-cell therapy in the real-world setting.

Dr. Madduri on the Potential Impact of CAR T-Cell Therapy in Multiple Myeloma

Deepu Madduri, MD, assistant professor, medicine, hematology and medical oncology, Mount Sinai Hospital, discusses challenges in the transplant-eligible myeloma population.

One of the main challenges with transplant is getting the referrals to the institutions where they perform the procedure, says Madduri. As such, many patients who come from the community have been on lenalidomide (Revlimid) for longer than 4 to 6 cycles. Ideally, the best time to harvest a patient’s cells is within 4 to 6 cycles of lenalidomide therapy, explains Madduri. Being on lenalidomide beyond that can decrease the stem cell harvest. To avoid this, patients must be assessed when they come to the clinic in order to determine whether they are candidates for transplant.

C. Ola Landgren, MD, PhD, of Memorial Sloan Kettering Cancer Center, published a paper showing that patients who have received 4 to 6 cycles of induction get a bone marrow biopsy.

If patients test negative for minimal residual disease (MRD), they continue their current induction therapy as part of consolidation. If they’re MRD-positive, they undergo transplant and are then put on maintenance, concludes Madduri.

Dr. Madduri on Challenges in Transplant-Eligible Patients With Myeloma

Deepu Madduri, MD, assistant professor, Mount Sinai Hospital, discusses the standard of care for transplant eligible patients with multiple myeloma.

In terms of current induction treatment, results from the IFM 2009 study indicated that transplant is superior to no transplant. Another area of active investigation is consolidation, maintenance, and minimal residual disease (MRD) negativity, explains Madduri. As it stands, every patient with multiple myeloma is being tested for MRD negativity.

With regard to consolidation, physicians are investigating the importance of consolidation posttransplant. Some studies have demonstrated a progression-free survival benefit, but not as much of an overall survival benefit, adds Madduri. In terms of maintenance, lenalidomide (Revlimid) is the standard of care following transplant. However, lenalidomide may not be sufficient for patients with high-risk disease. In that case, physicians can defer to prior studies that have shown that bortezomib (Velcade) maintenance is a good choice for high-risk patients as well as for those with renal insufficiency, concludes Madduri.

Dr. Madduri on the Standard of Care for Transplant Eligible Patients With Myeloma

Deepu Madduri, MD, assistant professor, Mount Sinai Hospital, discusses treatment after chimeric antigen receptor (CAR) T-cell therapy in patients with myeloma.

One of the biggest unmet needs in the myeloma treatment landscape is for the patients who need treatment after receiving CAR T cells, Madduri says, although there are strategies emerging in this setting. Most CAR T cell products are BCMA-directed, and BCMA antibody drug conjugates and other targeted therapies have been developed. An important question is whether the already penta-refractory patients who progress on CAR T cells have lost BCMA antigen, and if so, can they be treated with these other options? Research is still underway to better understand the mechanism of BCMA.

However, Madduri says, there is hope that CAR T cells will soon bring curative strategies to the treatment of these patients. Recently, at the 2018 ASH Annual Meeting, the anti-BCMA CAR T cell therapy bb21217 demonstrated an objective response rate of 83.3% with a very good partial response or better rate of 75% in patients with heavily pretreated relapsed/refractory multiple myeloma.

Deepu Madduri, MD, assistant professor, Mount Sinai Hospital, discusses treatment after CAR T-cell therapy in patients with myeloma.

Dr. Madduri on Treatment After CAR T Cells in Myeloma

Deepu Madduri, MD, assistant professor, Mount Sinai Hospital, discusses the use of checkpoint inhibitors in multiple myeloma.

Agents such as ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda) have been evaluated in patients with myeloma. Madduri says that nivolumab as a single-agent has not shown much activity, though. The phase I CheckMate-039 and phase II CA204142 trials, which are exploring nivolumab-based regimens in patients with relapsed/refractory myeloma, had their partial holds lifted in December 2017. The partial holds were put in place due to safety concerns seen with pembrolizumab in the phase III KEYNOTE-183 and KEYNOTE-185 trials.

In July 2017, the FDA placed a clinical hold on the KEYNOTE-183 and KEYNOTE-185 trials. These trials evaluated pembrolizumab combined with an immunomodulatory agent—lenalidomide (Revlimid) or pomalidomide (Pomalyst)&mdash;and dexamethasone. These holds came as a result of interim results that showed an increased risk of death for the pembrolizumab arm compared with the control arm.  

Madduri says that the FDA is now requiring a control arm in any trial of checkpoint inhibitors in myeloma, as to not increase mortality.

Deepu Madduri, MD, assistant professor, Mount Sinai Hospital, discusses the use of checkpoint inhibitors in multiple myeloma.
 

Dr. Madduri Discusses Checkpoint Inhibitors in Myeloma

Deepu Madduri, MD, assistant professor, Mount Sinai Hospital, discusses eligibly criteria for patients with multiple myeloma to receive chimeric antigen receptor (CAR) T-cell therapy.

There have been very promising data published recently on the use of CAR T-cell therapy for patients with myeloma, says Madduri. The anti-BCMA CAR T-cell therapy bb2121 was granted a breakthrough therapy designation for previously treated patients with relapsed/refractory myeloma in November 2017.

Madduri says that the biggest challenge with CAR T-cell therapy for these patients is slot limitation. There are many patients who want to receive CAR T-cell therapy, but it is a matter of how many slots are available, as well as eligibility. To be eligible for CAR T-cell therapy, a patient with myeloma must have received a proteasome inhibitor, an immunomodulatory drug, and a CD38 antibody. Additionally, the patient must have good hematological counts, and be relapsed and refractory. The patient cannot have had prior BCMA therapy. Madduri says that it is a matter of qualifying at the right time and the number of slots available.

Deepu Madduri, MD, assistant professor, Mount Sinai Hospital, discusses eligibly criteria for patients with multiple myeloma to receive chimeric antigen receptor (CAR) T-cell therapy.
 

Dr. Madduri on Eligibility for CAR T-Cell Therapy in Myeloma

Deepu Madduri, MD, assistant professor, Mount Sinai Hospital, discusses evidence supporting the use of a triplet regimen versus a doublet regimen in elderly and transplant ineligible patients with multiple myeloma.

According to results from SWOG S0777, the triplet regimen bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (RVD) was better than the previous standard of care, lenalidomide with dexamethasone (RD). Both the overall survival and progression-free survival were improved with RVD, Madduri says.

The triplet regimen is now used at a lower dose, according to Madduri. Bortezomib is administered once weekly rather than twice a week on a 35-day cycle versus the previous 28-day cycle. Lenalidomide has also been reduced to 15 mg from the previous standard of 25 mg. 

Deepu Madduri, MD