General MM

ASH 2017 | BCMA as a target for MM

The MM Hub team were pleased to attend the 59th American Society of Hematology (ASH) Annual Meeting and Exposition, from 9-12 December 2017 in Atlanta, GA. This article collates some of the key abstracts from ASH where B cell maturation antigen (BCMA) is targeted, which was a key theme emerging from ASH, as mentioned in the video summary given by our co-chair Sagar Lonial, which you can listen to here

On Monday 11 December, an oral abstract session was held entitled: Session: 653. Myeloma: Therapy, excluding Transplantation I. The first talk from this session is summarized here. Three talks from this session shared the common theme of using BCMA as a target for MM and are summarized below. Data in this article are based on the presentation at ASH and may, therefore, differ from the pre-published abstract.

Abstract 740: Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-Bcma CAR T Cell Therapy.

The second talk in the series was presented by Jesus G. Berdeja from the Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, US, with work carried out along with James N. Kochenderfer, from the National Cancer Institute, National Institutes of Health Clinical Center, Bethesda, MD, US. We previously reported the initial results from this trial presented in ASCO 2017 – see previous MM Hub article. BCMA is a good candidate target molecule in Multiple Myeloma (MM) as it is expressed almost universally on MM cells, and its expression is restricted to plasma cells and some mature B cells.

The bb2121 construct is a second generation CAR, consisting of a lentiviral vector encoding anti-BCMA scFv, a 4-1BB co-stimulatory motif and a CD3zeta T cell activation domain. It was validated in pre-clinical studies showing high levels of efficacy in clearing MM in mouse models. This talk presents the data from the phase I open-label trial CRD-401, which aimed to determine the safety and efficacy recommended for phase II dosing. In this phase, 21 patients received bb2121 in a standard 3 + 3 dose escalation and expansion cohort and were evaluable.

Key Findings:

  • Patients (pts) were eligible for dose escalation if they had RRMM with ≥ 3 lines of therapy (including PI and IMiD), had measurable disease and ≥ 50% BCMA expression
  • For expansion study (initiated August 2017) no BCMA expression was required, pts must have received daratumumab and been refractory to the last line of therapy
  • Additional pts (n = 12) added to expansion cohort in November 2017
  • Median follow-up = 35 weeks
  • Median age = 58 (range 37-74)
  • All pts had received prior ASCT
  • Prior exposure/refractory: bortezomib = 100%/67%, carfilzomib = 91%/57%, lenalidomide = 100%/86%, pomalidomide = 91%/71%, daratumumab = 71%/48%
  • Adverse Events (AEs): Cytokine release syndrome (CRS) = 71%, neurotoxicity = 24%, neutropenia = 86%, thrombocytopenia = 52%, anemia = 67%
  • Deaths: due to disease progression = 3, cardiac arrest = 1, MDS following discontinuation = 1
  • Serious AEs = 14 pts; CRS = 4, pyrexia = 2
  • CRS was resolved rapidly within 24 hrs; 4 pts received tocilizumab and 1 steroids
  • Pts with grade 3 CRS had highest cytokine elevation
  • Bb2121 was administered at active doses of 150-800 x 106 CAR T-cells
  • ORR = 94%, VGPR or better = 89%, CR or better = 56%
  • Median PFS (40-week follow-up) = not reached; 4 pts progressed
  • Progression appears to be independent of: tumor burden, bb2121 dose, CRS and bb2121 persistence; pts are therefore eligible for re-treatment
  • MRD negativity = 90% of evaluable samples
  • Safety profile is manageable at doses as high as 800 x 106 CAR T-cells
  • Two cases of CRS were resolved within 24 hours
  • One case of delayed onset, reversible grade 4 neurotoxicity with tumor lysis syndrome and CRS (although this occurred in the pt with highest tumor burden and the pt had a VGPR despite BCMA expression on only 1% of cells)
  • Global trial (KarMMa) is now open for enrollment: bb2121 dose: 150-300 x 106 CAR T cells

In conclusion, bb2121 demonstrates deepening and durable responses of over a year with improvements still observed even at month 15 and had a manageable safety profile. On the basis of this study, b2121 CAR T-cells were recently granted both breakthrough therapy designation and PRIME statues by the FDA and EMA, respectively – see previous MM Hub article.

Abstract 741: Deep and Durable Responses in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (MM) Treated with Monotherapy GSK2857916, an Antibody Drug Conjugate Against B-Cell Maturation Antigen (BCMA): Preliminary Results from Part 2 of Study BMA117159

The third talk in this session was given by Suzanne Trudel from the University of Toronto, Princess Margaret Cancer Centre, Toronto, Canada, in which she provided an update for the part 2 expansion of the Phase I DREAMM-1 of GSK2857916 in heavily pre-treated RRMM patients.

GSK2857916 is a humanized IgG1 anti-BCMA antibody conjugated to the microtubule disrupting agent monoethyl auristatin-F and was recently granted breakthrough therapy designation by the FDA – see previous MM Hub article. In this study, GSK2857916 is dosed once every 3 weeks as a 1-hr intravenous infusion, without required prophylaxis for infusion-related reactions (IRR), for up to 16 cycles. Part 1 results (N=38) were previously published but no maximum tolerated dose was identified and the RP2D was determined to be 3.4 mg/kg.

Demographics:

  • N = 35 MM pts were enrolled and treated at 3.4 mg/kg
  • Median age: 60 (46-75) years; 51% were female
  • ≥5 prior lines of therapy (range 1- >10) = 57% of pts
  • Previous ASCT = 89%
  • All pts were treated with IMiDs:
    • Lenalidomide = 94%
    • Pomalidomide = 60%
    • Thalidomide = 34%
  • Pts were refractory to IMiD = 91%
Key Findings:
  • ORR: 60% (95% CI, 42.1-76.1)
  • Prior daratumumab = 43%
  • Refractory to both IMiD and PI = 58%
  • Refractory to IMiD, PI and prior daratumumab = 42%
  • Median duration of response = not reached
  • Median PFS = 7.9 months (95% Cl, 3.1, not reached)
  • Median duration of follow up = 6.6 months
  • All pts had at least 1 AE: corneal events = 63%, decrease in thrombocytopenia/platelet count = 57%, blurred vision = 46%, anemia = 29%, increase in AST = 29%, cough = 26%, nausea = 23%
  • Serious AEs = 40% of pts
  • Most frequent ≥Grade 3 AEs: Thrombocytopenia = 34%; Anemia = 14%

Dr Trudel concluded that GSK2857916 resulted in an ORR of 60% in heavily pre-treated pts with no selection for BCMA expression, with 51% of pts responding with a VGPR or better. The median PFS was 7.9 months and GSK2857916 was well tolerated with manageable side effects. Dr Trudel highlighted that GSK2857916 distinguishes itself from currently approved drugs in MM by its target and therapeutic mechanisms of action and explained that the DREAMM-1 trial is ongoing with additional monotherapy and combination studies scheduled.

Abstract 742: Development and Evaluation of a Human Single Chain Variable Fragment (scFv) Derived Bcma Targeted CAR T Cell Vector Leads to a High Objective Response Rate in Patients with Advanced MM

The third talk was presented by Eric Smith from Department of Medicine, Myeloma Service, Memorial Sloan-Kettering Cancer Center/New York Presbyterian, New York, and described the development and evaluation of human anti-BCMA CAR T cell therapy in patients with relapsed/refractory MM (RRMM). The initial stage of this study involved the screening of a human cell-derived scFv phage display library containing 6x1010 scFvs with BCMA expressing NIH 3T3 cells. This led to the identification of 57 unique and diverse BCMA specific scFvs. Pre-clinical evaluation of efficacy and safety led to a stringent selection of scFv/CAR construct for clinical translation. Extensive pre-clinical experiments were carried out in which 17 scFvs were identified and cloned into CAR vectors for testing both in vitro and in vivo, with three retroviral constructs of EGFRt/hBCMA-41BBz selected for clinical use and denoted: MCARH171, JCARH125, and FCARH143.

Key findings from the clinical study using vector MCARH171:

  • Treatment scheme:
    • Dose level 1 (DL1): 3 pts received cyclophosphamide conditioning (3g/m2 x1) and 72x106 mean CAR+ T cells
    • Dose level 2 (DL2) = 3 pts
    • Cyclophosphamide/fludarabine (300/30 mg/m2 x3) and 137x106 mean CAR+ T cells
    • All pts screened for BCMA expression by IHC were eligible
  • Patient Characteristics:
    • Median age = 55.5 years (43-66)
    • High risk cytogenetics = 4/6 pts
    • Median prior lines of therapy = 7
    • All pts had IMiD, PI, high dose melphalan, and CD38 directed therapies
  • Objective responses at:
    • DL1: VGPR = 1 pt; SD = 1 pt; 1 pt could not be assessed by IMWG criteria
    • DL2: PR = 1 pt; VGPR = 1 pt
  • AEs: grade 1 CRS: 2 pts; grade 2 CRS = 1 pt (2 pts received IL6R directed Tocilizumab -Toci- with near immediate resolution)
Conclusion:

The speaker concluded that human B cell scFv library screening enabled the identification of multiple anti-BCMA ‘hits’ for direct evaluation in CAR vectors. In addition to this, in vitro proliferation after repeat antigen stimulation was found to be an effective surrogate for in vivo studies to screen large numbers of CAR T-cell vectors. The construct MCARH171 displayed a favorable safety profile with no dose-limiting toxicities (DLTs) and manageable CRS in dose levels 1-2. No severe AEs were observed in this study. Finally, future developments are set to include a dose escalation study and the investigation of MM TME/CAR T-cell interactions.

On Sunday 10 December an oral abstract session as held entitled: Session 653. Myeloma: Therapy, excluding Transplantation: Immunotherapy in Myeloma and Amyloid. Two talks from this session also focused on targeting of BCMA, and are summarized below.

Abstract 505: Safety and Efficacy of B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells (CART-BCMA) with Cyclophosphamide Conditioning for Refractory Multiple Myeloma (MM)

The second talk in this session was given by Adam D. Cohen from the Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, US, who presented extended data from a study to examine the safety and efficacy of a BCMA CAR T-cell construct. This construct consists of a fully humanized anti-BCMA ScFv engineered into a lentiviral vector, with CD3ζ and 4-1BB signaling domains. Data was presented from three cohorts of patients:  1) 1-5 x 108 CART cells alone (9 pts); 2) Cy 1.5 g/m2+ 1-5 x 107 CART cells (5 pts); and 3) Cy 1.5 g/m2 + 1-5 x 108 CART cells (11 pts).

CART-BCMA cells were administered as split-dose infusions: 10% on day 0, 30% on day 1, and 60% on day 2, with Cyclophosphamide (Cy) given on day 3. BCMA expression was assessed but was not a pre-requisite for inclusion.

Key Data (across three cohorts):
  • N = 24 patients (pts)
  • ORR (≥PR) = 11/24 (46%); ORR (≥PR) @ 108 = 10/19 (53%)
  • ≥MR = 16/24 (67%)
  • Median DOR = 4 months
  • CRS = 33%; Neurotoxicity = 22%
  • No interference by soluble BCMA
  • Cytoxan lymphodepletion allowed improved expansion
  • High-risk cytogenetics = 95%, (67% del17p or TP53 mutation; 29% extramedullary disease); 47% of pts with PR were high-risk

In conclusion, high efficacy was observed with an early follow-up of a BCMA-CAR T infusion in a heavily pre-treated cohort of 24 patients with highly advanced disease. Improved efficacy was observed with the higher dose of 108 CAR T-cells in cohort 3, and consequently, more patients are currently being recruited to this group.  

Abstract 506: Combined Infusion of CD19 and Bcma-Specific Chimeric Antigen Receptor T Cells for RRMM: Initial Safety and Efficacy Report from a Clinical Pilot Study

The first talk in this session was presented by Fu Cheng Cheng, from the First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, China, in which a study investigating the safety and efficacy of combined infusion of CD19 and BCMA-Specific CART Cells for RRMM was outlined.

Pre-clinical trials using chimeric antigen receptor (CAR) T cells targeting B-Cell Maturation Antigen (BCMA) have shown encouraging anti-tumor activity. Despite the rarity for CD19 expression on MM plasma cells (PC), rare CD19+B cells can be identified in MM patients and appear to be clonally related to the MM PC. Those cells exhibit properties of cancer stem cells, hence making CD19 a potential therapeutic target, in conjunction with other therapies that target MM PC. This study included a small cohort of 8 patients, who received 3 doses of 300mg/m2 of cyclophosphamide and 3 doses of 30mg/m2 of IV Fludarabine qd×3 days on day -5, -4 and -3, followed by administration of CART-19 (1×107/kg on day 0) and CART-BCMA cells as split-dose infusions (40% on day 1 and 60% on day 2).

Responses were assessed by IMWG criteria with a median follow-up of 5 weeks (range 2-20). All 8 patients had acute CRS; high-grade CRS was associated with elevated levels of IL-6, IFNγ and IL-10. A significant increase in IL-6 observed for 2 patients (one with grade 2 CRS and one with grade 3 CRS due to abnormal renal and blood coagulation function). Both patients were treated with tocilizumab (4mg/kg) leading to a full recovery within a week. Five patients were monitored for more than 4 weeks with 4 out of 5 showing a partial response (PR). Three patients were followed up for less than 4 weeks and were asymptomatic.

This study demonstrates the promising in vivo expansion and clinical activity of combining CART-19 and CART-BCMA cells into MM patients. No treatment-related mortality (TRM) was observed and any toxicities identified were controlled and reversed. Ongoing data are being generated from this study as new patients are being recruited.

Conclusion:

Together these five abstracts show extremely positive data for the targeting of BCMA to treat MM, and will undoubtedly be followed by more extensive studies with greater patient numbers. In particular, it was interesting to see the data for combined infusion of two CAR T-cells, with a similarly manageable safety profile to the use of a single agent. This bodes well for combined use in order to target two different molecules with potential to enhance precision and duration of response. In addition, the success in terms of response and management of infusion reactions with a BCMA-antibody drug conjugate also opens up the opportunity for trialing different drug attachments and combining with other regimens. As increased efficacy and safety is confirmed for these agents, we will no doubt also see BCMA being targeted in the frontline setting.

 

References
  1. Jesus G. Berdeja et al. Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-Bcma CAR T Cell Therapy. #Abstract 740. 59th ASH Annual Meeting and Exposition 2017, Atlanta, GA.
  2. Suzanne Trudel et al. Deep and Durable Responses in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (MM) Treated with Monotherapy GSK2857916, an Antibody Drug Conjugate Against B-Cell Maturation Antigen (BCMA): Preliminary Results from Part 2 of Study BMA117159. #Abstract 741. 59th ASH Annual Meeting and Exposition 2017, Atlanta, GA.
  3. Eric Smith et al. Development and Evaluation of a Human Single Chain Variable Fragment (scFv) Derived Bcma Targeted CAR T Cell Vector Leads to a High Objective Response Rate in Patients with Advanced MM. #Abstract 742. 59th ASH Annual Meeting and Exposition 2017, Atlanta, GA.
  4. A.D. Cohen et al. Safety and Efficacy of B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells (CART-BCMA) with Cyclophosphamide Conditioning for Refractory Multiple Myeloma (MM). #Abstract 505. 59th ASH Annual Meeting and Exposition 2017, Atlanta, GA
  5. L. Yan et al. Combined Infusion of CD19 and Bcma-Specific Chimeric Antigen Receptor T Cells for RRMM: Initial Safety and Efficacy Report from a Clinical Pilot Study. #Abstract 506. 59th ASH Annual Meeting and Exposition 2017, Atlanta, GA.