Cell therapy for multiple myeloma: "what is now" and "what is next"

Although treatment of multiple myeloma (MM) has improved significantly in recent years, cure remains elusive, and patients who fail proteasome inhibitors, immunomodulatory drugs, and CD38 monoclonal antibody therapy remain challenging
due to lack of standard therapy and low survival rates.

The development of T cell redirection, including bispecific T-cell engagers and CAR T-cell therapies, has greatly improved outcomes
in patients with relapsed and refractory MM (RRMM).
BCMA has proven to be an important target for MM, and BCMA-targeted CAR T-cell therapy has shown unparalleled efficacy and long response times in RRMM patients, resulting in the approval of two different BCMA CAR T cell products
.

However, the current cell therapy still has huge room for improvement, and the survival curve of the treated patients has not improved, and there is still a risk of
recurrence.
Therefore, there is still room
for significant improvement.
Early patient use, as well as optimized designs on next-generation CAR, may further improve the efficiency of
these CAR T therapies.
This article briefly introduces
the current application of BCMA-targeted CAR T cell therapy in RRMM, as well as the progress of optimizing patient care and the design of novel CAR in MM.

BCMA CAR T-cell therapy approved: "what is now"

CAR T-cell therapy has shown excellent response rates in RRMM patients, resulting in the approval of two BCMA-targeted CAR T-cell products (ABECMA™ and CARVIKTI™) for the treatment of RRMM patients
who have received at least 4 prior treatments.

Idecabagene vicleucel (Ide-cel, bb2121, ABECMA™) is the first CAR-T cell therapy
approved for the treatment of RRMM patients.
Ide-cel, a second-generation CAR-T cell therapy with a 4-1BB co-stimulatory domain, was accelerated approval
based on Phase II single-arm pivotal KarMMa trial data.
In the study, 128 patients received CAR T-cell infusion therapy with Ide-cel doses ranging from 150-460 x^10E6.

The data showed that the median follow-up was more than 2 years (24.
8 months), and among 128 patients, the median overall survival (OS) was 24.
8 months, the overall response rate (ORR) was 73%, and the response was durable
.
Overall, the safety profile was acceptable, with 84% of patients reporting cytokine release syndrome (CRS) with a predominantly grade 1 or 2 degree, and less than 6% of patients with CRS above or equal to grade 3, with a median time of onset of 1 day
.
In 18% of patients, there were fewer neurological symptoms, mainly grade
1 to 2.
On the other hand, the incidence of cytopenia is dose-independent, and the median recovery time from grade 3 or higher neutropenia and thrombosis is 2 and 3 months
, respectively.

CARVIKTI™ is the first CAR-T therapy
targeting BCMA developed by Chinese company Nanjing Legend Biologics approved by the FDA in February 2022.
The approval is based primarily on the results of CARTITUDE-1 Phase Ib/II studies
.
Overall, the 97 patients enrolled in the clinical trial were patients with advanced RRMM who no longer had better treatment options in the clinic, and experienced deep and durable remission
after receiving CARVIKTI™.
THE TOTAL ORR WAS AS HIGH AS 98%, AND SURPRISINGLY, 78% OF PATIENTS ACHIEVED CR, WHICH MEANS THAT NEARLY 80% OF ADVANCED PATIENTS, EVEN IN ADVANCED PATIENTS, COMPLETELY DISAPPEARED AFTER RECEIVING CARVIKTI™
.
In addition, the 12-month progression-free survival (PFS) rate was 77% and the overall survival (OS) rate was 89%.

In terms of safety, erythrocytopenia and CRS were the most common treatment-related adverse events
reported.
Neutropenia
occurs in 96% of patients.
The incidence of CRS is 95%, mostly grade 1~2, and the median time of onset is 7 days
.
Neurotoxicity
was reported in 20 patients.
Of these, 16 presented with immunocytotoxic syndrome (ICNS) and 12 with other neurotoxic reactions
.
Five of the patients developed motor and neurocognitive impairment with a median time of onset of 27 days
.

Other BCMA-targeted CAR T therapies are still in development, and the progress of the research is summarized in the table below, not in detail
.

Table 1.
Major clinical studies of BCMA-targeted CAR T cell therapy in RRMM

"What is next", how to further improve the therapeutic effect of cell therapy

Despite the impressive clinical results achieved by cell therapy, no changes have been seen in the survival curve, and relapses occur
frequently.
Therefore, further improvements are needed to improve the efficiency
of these CAR T therapies.

• Improve patient choice

Patient selection is a key aspect of
CAR T-cell therapy.
Although both approved CAR T achieved a high and durable response, it remained
in the high-risk population compared to standard-risk patients.
In the KarMMa trial, patients with extramedullary lesions, high-risk CAs, and R-ISS 3 showed lower rates of CR and shorter PFS
compared to patients without high-risk disease.
Similarly, in the CARTITUDE-1 trial, patients with high-risk CAs, R-ISS 3, and plasma cell tumors showed lower PFS over 2 years, suggesting that further improvements are needed to stop adverse outcomes
in patients with high-risk characteristics.

Recent analysis of the KarMMa trial showed that high tumor burden (soluble BCMA) and high inflammation (D-dimer, ferritin) and myeloma subtypes were inversely correlated
with CR realization.
High copy number in drug production was positively correlated
with CR rate.
These factors suggest that optimal and timely patient selection is necessary as CAR is not an off-the-shelf treatment, and that aging may be difficult for patients with high-risk features or slow progression of limited bridging options due to manufacturing time constraints
.
In fact, 10%~20% of patients are unable to carry out drug
infusion due to complications or inconvenience in the manufacturing process in different cases.

Therefore, in the manufacturing process, choosing the right bridging treatment is essential
to maintain the patient's health.
Whenever possible, drugs that the patient has not pre-used should be given priority
.
In this sense, BCMA-targeted drugs may not be the best option
during the bridging phase.
Recent evidence from Cohort C of the CARTITUDE-2 trial shows that the response of patients previously treated with BCMA-ADC and BCMA-BsAb suggests that the response to cedarchicel is inferior to the CATTUTION-1 trial (ORR: 62% in the BCMA-ADC group and 57% in the BCMA-BsAb group
).
This suggests that previous BCMA treatments have a potentially negative impact
on outcomes of CAR T-cell therapy.

In addition, strategies to shorten vein-to-vein time are being developed, such as platforms for rapid manufacturing of CAR T cells or allogeneic universal CAR T platforms
.
Allo-715 is an allogeneic CAR T
targeted by the allogeneic BCMA.
It is manufactured by knocking out the constant region α T cell receptor and CD52 to minimize the risk of secondary host disease after transplantation and to allow the use of anti-CD52 antibodies to facilitate the implantation
of CAR T cells.
Phase I clinical studies are being evaluated
.

• Optimize the design of CAT and improve the manufacturing process of T cells

Studies of different CAR T cell products have shown a positive correlation
between the deep lasting response of CAR T cell therapy and the degree of expansion of DoR and CAR T cells.
Therefore, efforts have been made to optimize the final CART cell product
.
An important aspect to consider is immunogenicity
.
In the KarMMa trial, the number of patients with antibiotic antibodies (ADAs) increased over time, from 21% at month 3 (21 of 102) to 65% (34 of 52)
at 12.
9 months.
Although these ADAs do not appear to affect CAR concentration or response, only ADA-negative patients respond to CAR T cell reinfusion, suggesting that these ADAs have a potential role
in CAR T cell activity.
Humanized or fully human structures may be a way
to overcome the negative effects of immunogenicity in CART cells.
Preliminary data from several phases I and II show that humanized or fully human structural CAR T has high clinical efficacy, high ORR, and deep and long-lasting
response.
In addition, in clinical study I, humanized BCMA CAR T ARI-002 was found to be suitable for re-infusion in patients who had a sustained response and no significant toxicity to the first infusion
.
Sixteen of the 30 patients received a secondary infusion, and 5 patients responded better
.

Higher levels of memory T cells are associated with better clinical outcomes, and several strategies, such as 1:1 CD4/CD8, may produce a higher proportion of memory T cells
in the final product.
Another interesting approach
was evaluated in the phase I CRB-402 study.
In this experiment, ide-cel and PI3K inhibitor (bb007) were cultured together to produce a different CAR T cell product (bb21217) that is rich in memory T cell phenotype and has a higher adoptive transfer capacity
.
Of the 72 patients who received a median of 6 lines of therapy, the ORR was 69% and 36% achieved CR.

The median DoR was 23.
8 months
.
What's more, CAR T cells stay longer, with up to 24 months detectable in some patients
.

One limitation of targeted immunotherapy is the heterogeneity of tumor antigen expression and the loss or downregulation
of antigen expression after drug treatment.
Simultaneously targeting different antigens can overcome this obstacle, and this possibility
is being evaluated.
In vitro and in vitro studies have confirmed that dual- or triple-target CAR-T cell therapy can provide CAR-T anti-tumor effects and reduce immune escape
.
For example, approximately 87% of RRMM patients receiving CD38/BCMA CAR-T cells achieved ORR, and 52% achieved a rigorous CR
at a median follow-up of 9.
0 months.

Summary

BCMA-targeted CAR-T cell therapy has achieved good clinical results in RRMM, resulting in the approval of two BCMA-targeted CAR T therapies
.
New designs and strategies are being developed to overcome some of the limitations of current CAR T-cell therapies and aim to further improve prognosis, shorten the time to vein-to-vein, and reduce toxicity
.
It is hoped that through continuous optimization, a cure
for MM can be found in the near future.

References

1.
Cellular ther apy for mul ti ple mye loma: what ’ s  now and what ’ s next.