COMy 2019 | DEBATE: CAR T-cell therapy in first relapse

A debate at the 5^th World Congress on Controversies in Multiple Myeloma (COMy), saw Doctor Andrew Yee, Massachusetts General Hospital, Boston, MA, argue that we should use CAR T-cell therapy (CAR T) in first relapse in multiple myeloma (MM), countered by our Co-Chair Professor Sagar Lonial, Winship Cancer Institute of Emory University, Atlanta, GA.¹

FOR

Dr Yee began the debate by presenting evidence for using CAR T in first relapse. Using the example of the CAR T product bb2121 predominately, Dr. Yee argued:^1,2

• bb2121 is an anti-B-cell maturation antigen (BCMA) CAR T product
  • BCMA is highly expressed on MM cells and normal plasma cells but is not expressed in other tissues making it an ideal target
  • Other targets for such therapies include CD38 and SLAMF7
  • bb2121 uses a 4-1BB costimulatory domain to reduce toxicity and ensure a more durable persistence in vivo
• Other drugs also target BCMA, including: antibody-drug conjugates (e.g. GSK28578916), bispecific T-cell engagers (e.g. AMG 420), and other anti-BCMA CAR T products (e.g. P-BCMA-101, JCARH125, bb21217)
• Phase I trial data with bb2121 (n= 33, median 7 lines of previous treatment) shows:
  • Minimal residual disease (MRD) negativity in 100% of evaluable patients (10^-4 by next generation sequencing)
  • A very good partial response (VGPR) or better in 80% of patients
  • A complete response (CR) or better in 50% of patients
  • Cytokine release syndrome (CRS) grade 3–4: 6%
  • Neurotoxicity grade 3–4 in bb2121: 3%
  • Median PFS: 11.8 months

Dr Yee stated the patient experience is also an important consideration in determining the best course of treatment. The current model for treating MM is to treat until disease progression, however, since CAR T is a one-time treatment, followed by observation, this may reduce the number of hospital visits and improve the patient’s quality of life whilst retaining efficacy.

Providing additional evidence for his point, Dr Yee described how response to treatment decreases over time, as patients experience more side effects from prior treatments, develop more comorbidities and die. This means few patients survive to receive the later lines of therapies. Therefore, in order to optimize the response to treatment, he suggested that it is better to administer the most effective therapies as early as possible in the treatment pathway.

Dr Yee added that in early relapse, there is a higher chance of CAR T response due to:

• Less clonal heterogeneity, i.e. less resistant clones
• Lower tumor burden
• Higher function status
• Less comorbidity
• Better renal function
• CAR T cells produced earlier, may be more efficient than using treatment exhausted T-cells

Current CAR T trials are largely in a heavily pretreated population and use in early relapse is under researched. A new phase II trial of bb2121 (KarMMa-2, NCT03601078) will be treating patients with R-ISS stage III disease who relapse early (<18 months) after first therapy which may provide data to support this argument. Dr Yee emphasized the importance of CAR T trials in early relapse as studies show patients who progress early have poorer outcomes.

Dr. Yee concluded his argument by stating that in a heavily pretreated population, CAR T such as bb2121 is able to achieve an overall response rate of over 90%, and we should use these therapies earlier in the treatment pathway in order to optimize the survival rates.

AGAINST

Prof. Lonial began his argument against the use of CAR T in first relapse by describing his rebuttal to the main arguments for this intervention.

Firstly, Prof. Lonial addressed the concept that CAR T will work better in earlier lines of therapy.

• Extrapolation from use in later lines is unrealistic
  • No data to show that response rates are improved when a drug is moved into earlier lines of therapy, particularly in single agents
• A patient’s death at first relapse due to CAR T toxicity will have cost them years of life compared to using traditional therapies, which have proven life-prolonging abilities

The second argument Prof. Lonial presented, was that patients who are less immunosuppressed will have a longer PFS.

• Since using CAR T requires the use of fludarabine/cyclophosphamide for approximately 6 months post-treatment, patients are not less immunocompromised

Prof. Lonial then moved on to the notion that early CAR T-cells will be of higher quality compared to those derived further down the treatment pathway.

• Prior daratumumab and dexamethasone exposure could impact the collection, even at an early stage

Prof. Lonial questioned the theory that the toxicity of CAR T would be better tolerated in earlier therapy lines.

• Though this may be true for CAR T, this is also true for other therapies
• Main question to address is whether CAR T can show continuous efficacy

Finally, the triplet of pomalidomide + daratumumab + dexamethasone in first relapse, was compared to the bb2121 trial presented by Dr Yee.

• At a follow-up of 41 months, median PFS and OS had not been reached³
• Current estimates for PFS and OS that are four times the 11.8 month PFS seen for bb2121³

Concluding his speech, Prof. Lonial’s stated 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 standard-of-care, there is no valid argument to support this.

The Multiple Myeloma Hub Twitter poll, conducted shortly after the debate, which reached a consensus that CAR T should not be used in first relapse (69%).