Monthly educational theme | CAR T in multiple myeloma

Throughout January and February, the Multiple Myeloma (MM) Hub will be focusing on a new educational topic of chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapy involves removing a patient’s T cells by apheresis, modifying them ex vivo to express a CAR construct that specifically targets an antigen on the target cell surface, and subsequently re-infusing them into the patient. Most CAR T therapies for MM target B-cell maturation antigen (BCMA), which is expressed on the surface of plasma cells and B cells, though other potential targets include CD19 and CD38. Currently, most clinical trials of CAR T therapy in MM are undertaken in patients with relapsed/refractory (RR) disease.¹

Current status of CAR T therapy in MM

During the 61^st American Society of Hematology (ASH) Meeting & Exposition, Orlando, US, the MM Hub spoke to Steering Committee member Miles Prince about new data presented for patients with RRMM. One of the main topics that Miles Prince discusses in the video below is the data coming from CAR T trials.

Miles Prince | Two major highlights from ASH for patients with relapsed/refractory multiple myeloma

The MM Hub were also pleased to speak to Nina Shah at the 61^st ASH meeting about the most promising CAR T therapies in development for the treatment of MM.

Nina Shah | What are the most promising CAR T therapies in development for multiple myeloma?

Other summaries of CAR T in MM were provided in January 2019, during the 1^st European CAR T Cell Meeting, Paris, FR. One such presentation was given by Alfred Garfall, during which he summarized the latest clinical data from CAR T trials including CAR T-cell therapies; bb2121, CAR-BCMA and P-BCMA-101. Another presentation, delivered by Hermann Einsele, discussed when CAR T should be used in the treatment pathway for MM.

In this introductory article, we have focused on the latest developments in CAR T from recent congresses, why CAR T is such a hot topic currently, and looked at the unanswered questions surrounding CAR T in MM.

Latest CAR T developments in MM

LEGEND-2 (LCAR-B38M) and CARTITUDE-1 (JNJ 4528)

Some of the most promising data in CAR T therapy for MM comes from the LEGEND-2 and CARTITUDE-1 trials. LEGEND-2 is a phase I, first-in-human study in China using CAR T-cell product LCAR-B38M. The initial results from LEGEND-2 were published in December 2018 and summarized by the MM Hub here. The CARTITUDE-1 trial is a phase Ib/II study investigating a CAR T-cell product identical to LCAR-B38M termed JNJ-4528 in the United States (US).

At the recent 61^st ASH meeting, long-term follow-up from LEGEND-2 was presented by Bai-Yan Wang, and the phase Ib results from CARTITUDE-1 were presented by Deepu Madduri. Read a summary of both of these presentations here. The CARTITUDE-1 trial provided an overall response rate (ORR) of 100% in 29 patients with RRMM, with 66% stringent complete responses (sCR).² The MM Hub were pleased to speak to Deepu Madduri about the CARTITUDE-1 study during the ASH meeting (video below).

In December 2019, the U.S. Food & Drug Administration (FDA) announced that JNJ-4528 had been granted breakthrough therapy designation. This followed previous announcements by the FDA and European Medicines Agency (EMA) that JNJ-4528 had been granted orphan drug designation, and Priority Medicines (PRIME) designation, respectively, for the treatment of RRMM.^3-4

Deepu Madduri | CARTITUDE-1 trial: Is JNJ-4528 safe and efficacious for patients with RRMM?

There are several ongoing studies using this CAR T-cell product including:^5-7

• CARTIFAN-1: a phase II study in China to confirm the efficacy and safety of LCAR-B38M in patients with RRMM. The primary outcome is ORR⁵
• CARTITUDE-2: a phase II multicohort study in the US to evaluate JNJ-4528 in various patient populations⁶
• CARTITUDE-4: a phase III study comparing pomalidomide + bortezomib + dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) to one or two cycles of PVd or DPd followed by JNJ-4528⁷

CRB-401 and KarMMA (bb2121) and CRB-402 (bb21217)

Other promising CAR T-cell therapies in development for patients with RRMM are bb2121 and bb21217. The CRB 401 trial (NCT02658929), a dose escalation and expansion trial of bb2121 in patients with RRMM, reported an ORR (partial response [PR] or better) of 85% with 9% of patients achieving a CR and 36% achieving a sCR.⁸ Based on these promising results, the phase II KarMMA study (NCT03361748) was initiated. In December 2019, it was announced that the study met its primary endpoint of ORR and the key secondary endpoint of CR rate.⁹

The MM Hub spoke to Jesus Berdeja at the European Hematology Association (EHA) meeting in 2018 about the phase I CRB-401 study of bb2121.

Jesus Berdeja | EHA 2018 | The CRB-401 phase I bb2121 CAR T-cell study

Additionally, during the 60^th ASH meeting in San Diego, US, Nina Shah presented results from the non-randomized, phase I trial (CRB-402) of bb21217 in patients with RRMM. These results showed bb21217, at a dose of 150 x 10⁶ CAR T cells, was efficacious, with a safety profile consistent with known toxicities of CAR T-cell products. The ORR was 83%, with results from a longer follow-up expected in due course.¹⁰

How can we improve the efficacy of CAR T therapy?

Currently, most CAR T therapies for MM target BCMA. Earlier this year, the MM Hub interviewed James Kochenderfer about the status of anti-BCMA CAR T therapy in MM, with Dr Kochenderfer remarking that “We should be very optimistic with the amazing response rates which we are seeing with anti-BCMA CAR-T cell therapy in patients with 7–9 prior lines of therapy.”

Dual targeting approaches

Dual targeting of CAR T cells is another approach being investigated to improve efficacy. During the 45^th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), Xiaolan Shi presented the results from the SZ-CART-MM02 study (NCT03455972). This study investigated tandem autologous stem cell transplant (ASCT) with dual targeting CAR T cells (anti-BCMA and anti-CD19) in patients with high-risk newly diagnosed MM.

ChengCheng Fu | EBMT 19 | CAR T-cell therapy in the front-line treatment of patients with high-risk multiple myeloma

Allogeneic CAR T

One alternative to patient-derived CAR T therapy is allogeneic CAR T therapy. Allogeneic CAR T cells may be; from healthy donors (with edited genes), mismatched non-gene edited CAR T cells or be derived from a stem cell transplant donor that are human leukocyte antigen (HLA) matched.¹¹ To read a summary of the advantages and limitations of manufacturing and using allogeneic versus patient-derived CAR T products, click here.

What else do we need to consider?

Patient quality-of-life (QoL) and cost implications

An important consideration with CAR T-cell therapy is patient QoL. The MM Hub were pleased to speak to Steering Committee member, Morie Gertz, about patient QoL with CAR T compared to stem cell transplant.

Morie Gertz | Is patient quality of life superior with CAR T or stem cell transplant?

Furthermore, it is important to consider the cost implications of CAR T therapy since it is a novel, personalized therapy with a high cost compared to existing standard of care (SOC) treatments e.g. transplant. However, it was recently announced that Medicare would cover the cost of CAR T therapy in the US Click here to read more.

Unanswered questions surrounding the use of CAR T in patients with myeloma

Should we use CAR T in first relapse?

CAR T remains a topic of some discussion within the field of MM, with several unanswered questions. At the 5^th World Congress on Controversies in Multiple Myeloma (COMy) meeting in Paris, FR, Andrew Yee and Sagar Lonial debated the topic of whether we should use CAR T therapy at first relapse. Andrew Yee argued that in a heavily pretreated population, CAR T achieves impressive ORRs, and therefore we should use these therapies earlier in the treatment pathway in order to optimize the survival rates. However, Sagar Lonial argued that there are no data to support the use of CAR T in first relapse and until such data are available comparing CAR T to current SOC, there is no valid argument to support this.¹²

Can CAR T replace transplant?

There is also a question of whether CAR T has the potential to replace transplantation in MM. We spoke to MM Hub Co-Chair, Sagar Lonial, about this topic at the European School of Haematology (ESH) MM meeting in Berlin, DE earlier this year.

Sagar Lonial | ESH MM 2019 | The potential of CAR T therapy to replace autologous stem cell transplantation

Conclusion

The field of CAR T therapy is rapidly progressing, with initial trials in patients with RRMM demonstrating impressive efficacy and manageable safety. Whilst many of these approaches are yielding promising results, several questions remain. The advent of bispecific antibodies has put the role of CAR T within the myeloma treatment pathway into question, and with no published data comparing CAR T to SOC therapies such as transplant in MM, it remains unknown what role CAR T will play in the MM treatment pathway.

Ongoing trials will seek to understand whether CAR T therapy may be more efficacious in earlier lines of therapy and whether CAR T can provide an additional benefit to, or instead of, SOC treatments.

In many hematological malignancies, there is a trend towards personalized medicine, based on patient-specific disease characteristics. CAR T has the potential to offer a one-time personalized treatment, ultimately providing another option to heavily pretreated patients, and potentially in earlier lines of therapy. Throughout January and February, the MM Hub will be exploring these themes, and bringing you coverage of the latest data and expert opinions on the subject.