Multiple Myeloma:The Next Frontier for Cell Therapy
The development of chimeric antigen receptor T-cell therapies for multiple myeloma was one of the hottest topics at ASH Annual Meeting and Exposition.
The hype surrounding new CAR T-cell therapies for this indication began to build well before data were presented in Orlando, and a survey conducted by InCrowd revealed that one-fifth of ASH 2019 attendees considered multiple myeloma the tumor type with the most interesting data.
Cell Therapy Next provides the following overview of key studies for CAR-T in myeloma, along with perspective from experts in the field who offered insights into the potential implications of the findings.
CRISPR-edited T Cells
Immune cells genetically edited with CRISPR/Cas9 technology and infused back into patients with multiple myeloma and sarcoma appeared to be safe and represent a feasible therapeutic approach, according to results of a prospective phase 1 study.
“CRISPR technology allows us to edit genes in cells. The question is how to best use that technology to treat cancer,” study co-author Edward A. Stadtmauer, MD, section chief of hematologic malignancies at University of Pennsylvania, told Cell Therapy Next. “The approach we have been undertaking is to first remove the most immunologically active cells against cancer from the patient’s blood and engineer them to be even better cancer fighters, and then reinfuse these now-energized cells back into the patients.”
Stadtmauer and colleagues obtained T cells from the blood of three patients — two of whom had multiple myeloma — and used CRISPR/Cas9 technology to remove three genes from the cells, including two T-cell receptors and PD-1. They then used a lentivirus to insert an affinity-enhanced T-cell receptor directing the edited cells to target the NY-ESO-1 antigen. The patients received the edited cells in a single infusion following a short chemotherapy course.
An analysis of blood samples showed the CRISPR-edited cells expanded and survived in all three patients. No serious treatment-related adverse events occurred.
“Despite successes and high response rates [with current technology], we still have patients treated with CAR T cells who relapse or do not respond,” Stadtmauer said. “CRISPR editing is an attempt to further enhance the activity of these cells.
“In addition to inserting the gene, we also used CRISPR to remove three other genes, two of which coded for the inherent T-cell receptor that’s on every T cell,” he added. “The idea is that this will allow these cells to better target tumors, because there is no competition. It also removes the PD-1 gene, so these cells do not have any check on their proliferation and activity.”
The study is preliminary and only included a handful of patients, but the methodology behind it is promising, according to Paul G. Richardson, MD, director of clinical research at Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute.
“The idea behind this study is particularly imaginative and could be transformative in the long run, but these data remain early,” Richardson, who was not involved in the investigation, told Cell Therapy Next.
More than 90% of patients with relapsed or refractory multiple myeloma responded to a bispecific CAR T-cell therapy that targets both the CD38 protein and B-cell maturation antigen, according to results of a phase 1 dose-escalation trial.
“Although anti-BCMA CAR T cells have shown promising results in relapsed or refractory multiple myeloma, short-term relapse due to low expression of BCMA is a major problem that needs to be solved,” researcher Yu Hu, MD, professor of hematology at Tongji Medical College at Huazhong University of Science and Technology in China, told Cell Therapy Next.
“CD38 is also expressed on suppressor cells,” he said. “BM38 CAR T cells have the potential to overcome an immunosuppressive microenvironment, thus enhancing the effect in patients with extramedullary tumors.”
Hu said his team’s CAR construct is unique compared with current commercially available therapies because BM38 CAR T cells are the first dual-target CAR T cells that contain anti-BCMA and anti-CD38 in tandem and the 4-1BB costimulatory domain for the treatment of multiple myeloma.
“Our product can bind to both BCMA and CD38 antigens on myeloma cell membranes simultaneously or individually, thus reducing the off-target effect,” Hu said.
Researchers enrolled 22 patients (median age, 59 years; range, 49-72; 50% men) with relapsed or refractory multiple myeloma. Nine patients (41%) had extramedullary disease.
At median follow-up of 68 weeks, 20 patients achieved response, equating to an overall response rate of 90.9%. These included 12 (54.5%) serum complete responses, two (9%) very good partial responses and five (22.7%) partial responses. Eighteen patients (81.8%) achieved bone marrow minimal residual disease (MRD)-negative status.
Median PFS had not been reached, but researchers reported a 78.9% PFS rate at 9 months. Results at 68 weeks also showed that extramedullary lesions were eliminated among eight of nine patients after BM38 CAR T-cell therapy.
Twenty patients (90.9%) had cytokine release syndrome (CRS) after BM38 CAR T-cell infusion. This included five cases (23%) of grade 3 or higher CRS. The researchers reported no cases of treatment-related neurotoxicity; however, nearly all patients had some form of hematologic toxicity.
“Our ORR of 90.9% and stringent complete response rate of 54.5% is higher than any other current CAR T-cell therapy used to treat myeloma,” Hu said. “More encouragingly, extramedullary lesions were partially or completely eliminated in eight of nine patients, which is the best result yet seen for extramedullary myeloma. Our humanized dual-target BM38 CAR T cells provide hope for patients with relapsed or refractory multiple myeloma with low expression of BCMA or single-target disease recurrence and extramedullary lesions.”
It’s too early to conclude whether the second-generation dual-target CAR used by Hu and colleagues will lead to improved survival, “but the 50% serum complete response rate is on target with previous studies,” Ruben Niesvizky, MD, director of the Multiple Myeloma Center at NewYork-Presbyterian/Weill Cornell Medicine, told Cell Therapy Next.
Niesvizky, who was not involved with the study, said these data were “very promising” and show improvement for treating this population with advanced multiple myeloma.
BCMA and CD38 are two of the more attractive targets for multiple myeloma treatment, Richardson said.
“BCMA is an important target for myeloma broadly,” he told Cell Therapy Next. “As exciting as the CAR-T results were at ASH, I was also struck by the success of the [bispecific T-cell engager] technology,” he added.
As for the study by Hu and colleagues, Richardson agreed the strategy to target both BCMA and CD38 yielded encouraging results.
“The science underlying this study is particularly strong and the overall response rate of 91% is promising,” he said.
JNJ-4528 (Janssen Pharmaceuticals) — an investigational CAR T-cell therapy that targets BCMA — induced a response in 100% of patients with relapsed or refractory multiple myeloma, according to results of the phase 1b/phase 2 CARTITUDE-1 trial.
More than two-thirds of patients in the open-label, multicenter study achieved complete response.
“These patients are heavily pretreated and are usually running out of options,” researcher Deepu Madduri, MD, assistant director of the cellular therapy service within Center of Excellence for Multiple Myeloma at Tisch Cancer Institute and Icahn School of Medicine at Mount Sinai, told Cell Therapy Next. “Median OS in this group is less than a year for heavily refractory patients, so we need to come up with new therapies that provide sustained and deep responses.”
LCAR-B38M contains a 4-1BB costimulatory domain and two BCMA-targeting single domain antibodies. It is identical to the CAR used in the LEGEND-2 trial, a phase 1 investigator-initiated study of 74 patients conducted in China that demonstrated the safety and feasibility of the investigational CAR T-cell therapy (see box). Phase 2 of CARTITUDE evaluated efficacy of JNJ-4528 for patients with heavily pretreated multiple myeloma.
The study included 29 adults (mean age, 60 years; range, 50-75) diagnosed with multiple myeloma per International Myeloma Working Group criteria who had measurable disease. All patients had received at least three previous lines of therapy (median, 5; range, 3-18), and 25 (86%) were triple-refractory to a proteasome inhibitor, immunomodulatory drug and an anti-CD38 antibody. Twenty-five patients (86%) had undergone autologous stem cell transplant.
All patients achieved response as assessed by independent committee review, and 69% achieved complete response. An additional 17% of patients achieved very good partial responses and 14% achieved partial responses.
Twenty-seven patients (93.1%) developed CRS; however, all but two cases were grade 1 or grade 2. One patient who had prolonged grade 4 CRS died of treatment-related complications at day 99 after CAR T-cell infusion. Three patients experienced immune effector cell-associated neurotoxicity syndrome; only one case was grade 3 or higher.
ASH also featured an accompanying oral presentation of translational data from the CARTITUDE-1 study. The analysis indicated that the CAR-T memory phenotype may be associated with an agent’s clinical activity.
“It appears that the JNJ-4528 BCMA CAR-T has a preferential and consistent in vivo expansion of CAR CD8 T cells with a central memory phenotype,” study co-author Saad Z. Usmani, MD, FACP, chief of plasma cell disorders and director of clinical research in hematologic malignancies at Levine Cancer Institute at Atrium Health, told Cell Therapy Next. “I would be very interested in seeing data from other BCMA CAR-T products in this regard.”
The advances reported at ASH contribute to the momentum of cellular therapy for multiple myeloma treatment.
“There are a lot of CAR-Ts in the multiple myeloma space right now, and it’s just a matter of timing before they become approved therapies,” Madduri said.
“We initially hoped that CAR-Ts would cure everything, but we have found that a true cure may still be way down the line,” Madduri said. “However, if we can provide patients with a one-time treatment that provides deep, sustained and durable response, then patients won’t have to come into the clinic once a week and can actually live their lives.”
Richardson said the results of the CARTITUDE study presented at ASH were reassuring.
“They were consistent with the earlier encouraging LEGEND experience and supportive of the original study,” he said.
However, Richardson expressed caution about the safety results from CARTITUDE.
“We have to be thoughtful in evaluating the side-effect profile because the study has reported treatment-related mortality, emphasizing the importance of safety with these approaches,” he added.
Because this was one of the most potent myeloma/CAR T-cell-related studies presented at ASH, treatment-related mortality was more of a potential concern, Richardson said.
The investigational agent used by Madduri and colleagues in CARTITUDE had an acceptable safety profile, according to Niesvizky.
“There are no curative therapies for multiple myeloma, but the closest point we can get to achieving a cure first comes through achieving a complete response — a complete response that is sustained and MRD-negative,” he told Cell Therapy Next.
The patients in this study who had complete responses could be cured, but the results are still too early to make this determination, Niesvizky added.
“The hope is that, if this product is offered in an earlier stage of the disease, it could offer a cure,” he said. “Nevertheless, this is still a breakthrough drug in this area.”
Fully Human BCMA CAR-T
CT103A (IASO BIO, Innovent), a novel CAR T-cell treatment derived from human components, induced 100% overall response and demonstrated enduring activity in a small study presented by Jue Wang, MD, of the department of hematology at Tongji Hospital of Tongji Medical College in China.
CT103A is a second-generation CAR design with a unique fully human single-chain variable fragment (scFv) sequence and a 4-1BB costimulatory and CD3-zeta domain encoded within the lentiviral vector. Wang presented data on 18 study participants who underwent a three-plus-three dose-escalation treatment regimen.
All 18 patients responded to CT103A, with 88.2% achieving very good partial response or better, and 70% achieving stringent complete response or complete response. Of the four who previously underwent CAR T-cell therapy, three achieved stringent complete response and one achieved very good partial response.
All evaluated patients tested negative for MRD at some point within 100 days after infusion and a third had stringent complete response within 2 weeks, Wang said.
“Results of CT103A are very promising,” Wang told Cell Therapy Next. “It is a safe and highly effective therapy for heavily pretreated [patients with] refractory or relapsed multiple myeloma.”
He added that the toxicity profile was manageable; 94% of patients had some form of CRS, with no observed cases of treatment-related neurotoxicity.
“BCMA is an ideal target for multiple myeloma. However, even with the encouraging results and high response rates of previous anti-BCMA CAR-T trials, more than half of the patients treated with this therapy will have their disease come back within a year,” Wang said. “This raises the big question: What are the mechanisms of relapse and how can we overcome this? There may be several answers to that question, but we chose to focus on the topic of host anti-CAR immunity because there are lines of evidence that nonhuman scFvs may induce cellular and humoral immune responses, which may result in the inability of certain CAR T cells to survive in vivo. Utilizing a fully human BCMA CAR-T may be the correct answer.”
The data from this study are also promising, Richardson said. However, he noted this was a relatively small study of 18 patients and requires further investigation.
“The science behind this is important because it incorporates a number of immunological approaches,” he said.
This multipronged strategy is potentially key to eliciting sustained responses, Richardson added.
A Matter of Timing
Hundreds of clinical trials around the world are examining the effectiveness of CAR T-cell therapies against a range of diseases. Because no curative therapies are available for multiple myeloma, it has become a target of some of the world’s most dedicated and gifted researchers as they look to improve on previous generations of the technology.
When asked about its prospects, experts in the field agree: It’s just a matter of time before the FDA begins approving CAR T-cell therapies for multiple myeloma.
That approval may come for bb2121 (Bluebird Bio), an investigational CAR T-cell therapy for which limited phase 1 data on a subset of six patients were presented at ASH.
The FDA granted breakthrough therapy designation to bb2121 for treatment of multiple myeloma in November 2017.
Subsequent study results published in The New England Journal of Medicine showed bb2121 to be safe and effective for patients with relapsed or refractory multiple myeloma, including an 85% response rate, as well as a 45% complete response rate among the first 33 patients treated. Median PFS was 11.8 months.
The results presented in this review reflect early data, Usmani said. It is not hard to imagine multiple targets for CAR T-cell therapies in multiple myeloma that go beyond BCMA and CD38, he added. These could include the SLAMF7 and GPRC5D target antigens.
“What will eventually distinguish one BCMA CAR-T therapy from another is the time from apheresis to CAR-T delivery, CRS grading and pattern, depth and durability of response, and possibly the development of memory T cells that keep the disease under check,” he said.
Richardson said he is impressed by ongoing efforts to develop effective CAR T-cell therapies for the disease and hopes future efforts will focus on achieving sustainable and durable responses.
“The strategies presented at ASH were encouraging in my view and reflect determined efforts on the part of investigators to improve on the current CAR-T platform,” he concluded. – by Drew Amorosi
Healio staff writers John DeRosier, Alaina Tedesco and Katrina Altersitz contributed to this report.
- Raje N, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1817226.
- The following were presented at ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando:
- Li C, et al. Abstract 930.
- Madduri D, et al. Abstract 577.
- Stadtmauer EA, et al. Abstract 49.
- Wang BY, et al. Abstract 579.
- Wang J, et al. Abstract 582.
- Zudaire E, et al. Abstract 928.
- For more information:
- Yu Hu, MD, can be reached at firstname.lastname@example.org.
- Deepu Madduri, MD, can be reached at email@example.com.
- Ruben Niesvizky, MD, can be reached at firstname.lastname@example.org.
- Paul G. Richardson, MD, can be reached at email@example.com.
- Edward A. Stadtmauer, MD, can be reached at firstname.lastname@example.org.
- Saad Z. Usmani, MD, FACP, can be reached at email@example.com.
- Jue Wang, MD, can be reached at firstname.lastname@example.org.
Disclosures: Madduri reports consultant roles with AbbVie, Celgene, Foundation Medicine, Janssen Pharmaceuticals and Takeda. Niesvizky reports consultant fees with Amgen, Bristol-Myers Squibb, Celgene, Janssen Pharmaceuticals and Takeda. Richardson reports research grants from Bristol-Myers Squibb, Celgene, Oncopeptides and Takeda, and advisory roles with Celgene, Janssen, Karyopharm Therapeutics, Oncopeptides, Sanofi and Takeda. Stadtmauer reports consultant/advisory roles with Amgen, Celgene, Janssen Pharmaceuticals and Novartis, and research funding from AbbVie, Novartis and Tmunity Therapeutics. Usmani reports consultant fees from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, EdoPharma, GlaxoSmithKline, Janssen Pharmaceuticals, Merck, Sanofi, Seattle Genetics, Skyline Dx, Takeda and TeneoBio, as well as research funding from Amgen, Array BioPharma, Bristol-Myers Squibb, Celgene, Janssen Pharmaceuticals, Merck, Pharmacyclics, Prothena, Sanofi, Seattle Genetics, Skyline Dx and Takeda. Hu, Bai-Yan Wang and Jue Wang report no relevant financial disclosures.