Evaluating The Potential Impact Of Anti-BCMA Therapies In The Multiple Myeloma Space

By Snigdha Gupta, Ph.D., and Sorcha Cassidy, Ph.D., Decision Resources Group (DRG), part of Clarivate

The multiple myeloma treatment landscape is undergoing rapid transformation with the arrival of novel therapies and label expansions of key regimens. Despite the flurry of new drug approvals, a high unmet need persists to improve patient survival and for therapies to combat relapsed or refractory (R/R) disease. The plethora of available efficacious antimyeloma agents has set a high bar for emerging therapies seeking entry into this competitive space. Nevertheless, opportunity remains for novel therapies to improve clinical efficacy over standard of care treatment options and enhance patient quality of life.  

To harness this opportunity, many drug developers are pursuing a key drug target, namely the cell-surface B-cell maturation antigen (BCMA), an antigen that is highly expressed on myeloma tumor cells. There are more than 70 ongoing clinical trials in development investigating over 30 BCMA-targeting agents¹, each utilizing innovative technologies and strategies such as antibody-drug conjugates (ADCs), bispecific antibodies, and CAR T cell therapies. In August 2020, GSK’s first-in-class anti-BCMA ADC Blenrep (belantamab-mafodotin-blmf) was granted accelerated and conditional FDA and EC approval, respectively, for patients with R/R multiple myeloma, generating considerable excitement in the field. We review three key anti-BCMA therapies in late-phase clinical development that are likely to impact multiple myeloma treatment and discuss some of the clinical and commercial differentiators that may influence adoption of these therapies going forward.

First-in-class Blenrep Inches Ahead Of Its Competitors

Blenrep is an off-the-shelf ADC that targets BCMA on myeloma cells and is linked to the antitubulin agent monomethyl auristatin F (active drug component). ADCs target tumor cells delivering a cytotoxic payload and have revolutionized treatment for other oncology indications such as Hodgkin’s lymphoma (e.g., Adcetris), diffuse large B-cell lymphoma (e.g., Polivy), and HER2+ breast cancer (e.g., Enhertu, Kadcyla). Blenrep was granted FDA and EC approval for R/R multiple myeloma patients who have received at least four prior therapies, including a proteasome inhibitor (PI), an immunomodulator (IMiD), and a CD38-targeting antibody.^2,3 Regulatory approval by both agencies was supported by positive data from the pivotal DREAMM-2 study (Table 1).   

In addition to Blenrep, two autologous anti-BCMA CAR T cell therapies, Bristol Myers Squibb/bluebird bio’s idecabtagene vicleucel (ide-cel; bb2121) and Janssen/Legend Biotech’s JNJ-69284528 (LCAR-B38M), are in the late-phase pipeline for R/R patients. Earlier in 2020, ide-cel had been the front-runner in terms of development in the Phase 2 KarMMa study; however, in an unprecedented turn of events, in May 2020, the FDA requested the company to submit additional data in order to review the BLA (biological license application) submitted in March 2020.^4,5 Ide-cel’s BLA was resubmitted in July 2020 with supplemental information on the validation and control processes used in lentiviral vector and drug product manufacturing, as demanded by the FDA.⁶ Further intensifying competition in the anti-BCMA space is J&J’s dual BCMA domain targeting CAR-T cell therapy, JNJ-69284528, which was previously granted FDA  breakthrough designation in December 2019 based on its impressive efficacy noted in the Phase 1b/2 CARTITUDE-1 study for the same R/R patient population (Table 1).⁷

Therapies Present Impressive Efficacies, Different Safety Barriers

Although cross-trial comparison must be undertaken with caution, we weighed available clinical trial data reported for the key anti-BCMA therapies (Blenrep, ide-cel, and JNJ-69284528). The pivotal DREAMM-2 and KarMMa studies are investigating Blenrep and ide-cel, respectively, in heavily pretreated multiple myeloma patients. Broadly, the design of both studies is similar to that of the Phase 2 SIRIUS trial, which led to the accelerated approval of Darzalex monotherapy in the United States and Europe, and to that of the Phase 2 study, which led to the U.S. approval of Kyprolis monotherapy. In the DREAMM-2 study (Table 1), Blenrep demonstrated more modest response rates and progression-free survival (PFS) than reported previously in the Phase 1 DREAMM-1 study (DREAMM-1 reported 60% overall response rate (ORR) and median PFS of 12 months in heavily pretreated patients).^8,9 In contrast, despite being assessed in a similar heavily pretreated population (median seven prior lines of treatment), ide-cel demonstrated markedly higher response rates and improved PFS and overall survival (OS) in the Phase 2 KarMMa study. Previously, in the Phase 1 DREAMM-1 and CRB-401 studies investigating Blenrep and ide-cel, respectively, the two therapies demonstrated a comparable PFS benefit (12- and 11.8-months median PFS, respectively).^9,10 Ide-cel has maintained its clinical efficacy in the KarMMa study with an estimated median OS of 19.4 months (Table 1).¹¹ 

Janssen’s ongoing Phase 1b/2 CARTITUDE-1 study is also assessing the anti-BCMA CAR T cell therapy JNJ-68284528 in patients with heavily pretreated R/R multiple myeloma. Data from this study boasts an outstanding ORR of 100%, albeit in a small patient population (29 evaluable patients), of which 10 patients were minimum residual disease (MRD)-negative post-CAR T-cell infusion with responses independent of baseline BCMA expression.¹² Additionally, the responses were durable, with 76% of patients achieving stringent complete response (sCR) at a median follow-up of nine months.¹³  Notably, the randomized Phase 3 CARTITUDE-4 trial¹⁴ is also assessing JNJ-68284528 head-to-head with key regimens DPd (Darzalex-Pomalyst-dexamethasone) or PBd (Pomalyst-Velcade-dexamethasone) in R/R multiple myeloma patients who have received one to three prior line(s) of therapy. The interim data from CARTITUDE-1 may indicate JNJ-68284528’s potential to achieve a comparable outcome in delaying disease progression in the CARTITUDE-4 study.  

In terms of safety, unique issues are associated with both Blenrep and the CAR T cell therapy approaches. Blenrep is available through a Risk Evaluation and Mitigation Strategy (REMS) program in the United States. In the DREAMM-2 study, keratopathy/microcyst-like epithelial changes (71% of patients) and ocular adverse reactions were reported (e.g., changes in visual acuity [55% of patients], blurred vision [25% of patients], and dry eye [19% of patients]). Keratopathy leading to treatment discontinuation was reported in 2.1% of patients, conferring an ocular toxicity warning to Blenrep’s FDA label.¹⁵ While cytokine release syndrome (CRS) and neurotoxicity have plagued other anti-CD19 CAR T cell therapies in non-Hodgkin’s lymphoma (NHL) and acute lymphoblastic leukemia, ide-cel and JNJ-68284528 appear to be relatively well tolerated and have lower rates of severe CRS and neurotoxicity (although both have high rates of grade ≥3 neutropenia) compared with the currently marketed anti-CD19 CAR T cell therapies, Yescarta and Kymriah, that are also only available in specialized facilities that meet REMS requirements.

Table 1: Key Efficacy and Safety Outcomes of Key Anti-BCMA Therapies in R/R Multiple Myeloma

Key Efficacy / Safety outcome	Blenrep	Ide-cel / bb2121	JNJ-68284528
Highest Phase of Development	Marketed (U.S.)	Phase 3	Phase 3
Pivotal trial results	DREAMM-2/Phase 2 (NCT03361748)             (2.5 mg/kg cohort;  N = 97)	KarMMA/Phase 2 (NCT03361748)      (N = 128)	CARTITUDE-1/Phase 1/2 (NCT03548207)     (N = 29)
Median duration of follow-up	13 months	11.3 months	9 months
ORR	32%	73%	100%
CR / sCR	1%	31%	sCR: 76%
Median DOR	11 months	10.7 months	-
Median PFS	2.8 months	8.8 months	(six-month PFS rate 93%)
Median OS	13.7 months	19.4 months (estimated)	-
Grade ≥3 Neutropenia	11%	89%	100%
Grade ≥3 Keratopathy	29%	-	-
Grade ≥3 CRS	-	5%	7%
Grade ≥3 Neurological events	-	3%	3%
Abbreviations: CR = complete response; CRS = cytokine release syndrome; DOR = duration of response; NR = not reached; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; sCR = stringent complete response

 

Future Outlook For Anti-BCMA Therapies

Future prescribing and adoption of novel anti-BCMA therapies for multiple myeloma will be dependent on many factors, including but not limited to clinical efficacy and safety, logistics of manufacturing/administration, cost of therapy/reimbursement, and patient accessibility. The novel anti-BCMA therapies will help to address an important unmet need for patients who have received at least three or four prior lines of therapy with limited therapeutic options remaining (particularly patients who are relapsed or refractory to Darzalex); however, prescribing of these novel approaches may be subjected to unique clinical and commercial barriers.

Despite Blenrep’s modest efficacy, the ADC holds distinct advantages as an off-the-shelf therapy in a disease that impacts a predominantly older patient population. Indeed, Blenrep bypasses the complex manufacturing process that is involved with production and administration of autologous CAR T cell therapy products. Despite the impressive efficacy and safety of the anti-BCMA CAR T cell therapies, drug developers continue to face significant hurdles in bringing their CAR T cell therapies to market. Given the highly personalized nature of the treatment, accessibility, especially for patients visiting rural/community hospitals, may be problematic, with larger academic hospitals more likely to have the capabilities and access to such treatments. Furthermore, the costs of ide-cel and JNJ-68284528 are likely to be a significant factor that could cause substantial burden to healthcare systems and hospitals, especially considering the heavily pretreated multiple myeloma setting for which these therapies are being developed (i.e., patients will already have accumulated large costs for their myeloma treatment).

Overall cost of treatment and frequency of administration may influence future use of the anti-BCMA therapies. CAR T cell therapy would entail a one-time (single infusion) treatment cost, whereas Blenrep is administered once every three weeks (until disease progression or unacceptable toxicity); therefore, the cumulative treatment cost and the impact on a patient’s quality of life would need to be weighed when selecting the appropriate treatment modality in the long term. Lastly, safety and toxicity concerns will likely remain at the forefront of physicians’ minds in this older patient population, with Blenrep’s ocular toxicities and CAR T cell-associated severe CRS and neutropenia important considerations when deciding on a treatment.

Despite demonstrating impressive efficacy, anti-BCMA therapies will face future hurdles given existing physician comfort and familiarity with well-established drug options for this disease particularly in earlier lines of treatment. Indeed, studies are ongoing seeking to expand the key anti-BCMA therapies to earlier lines of treatment either alone or combined with standard of care regimens. The Phase 1 DREAMM-9 study¹⁶ is evaluating Blenrep in combination with the Velcade-Revlimid-dexamethasone (VRd) regimen in newly diagnosed patients, while JNJ-68284528 in combination with Revlimid or DVRd (Darzalex-Velcade-Revlimid-dexamethasone) is being investigated as a first-line treatment in the Phase 2 CARTITUDE-2 trial.¹⁷ Similarly, the Phase 1 KarMMa-4 study is assessing ide-cel in newly diagnosed high-risk patients who have received induction therapy before undergoing stem cell transplantation.¹⁸ The anti-BCMA approaches will further diversify options for newly diagnosed patients in the earlier lines of therapy. In addition to the anti-BCMA therapies, J&J’s anti-CD38 monoclonal antibody Darzalex is now available as a subcutaneous infusion that may influence the choice of the combination regimens prescribed in this disease.

With the plethora of approved multi-drug regimens in the R/R multiple myeloma landscape, the key challenge remains optimal positioning of the novel anti-BCMA therapies in the treatment algorithm.  Ultimately, convenience of administration, safety, cost, and reliable manufacturing/production processes will help to differentiate the prescription, positioning, and sequencing of this novel drug class in the multiple myeloma treatment algorithm.

References:

1.Information extracted from http://www.clinicaltrials.gov (accessed September 2020).

2.FDA approves GSK’s Blenrep (belantamab mafodotin-blmf) for the treatment of patients with relapsed or refractory multiple myeloma. Published September 6, 2020 (accessed September 2020). Link: https://www.gsk.com/en-gb/media/press-releases/fda-approves-gsk-s-Blenrep-belantamab-mafodotin-blmf-for-the-treatment-of-patients-with-relapsed-or-refractory-multiple-myeloma/

3.European Commission approves Blenrep (belantamab mafodotin) for the treatment of patients with relapsed and refractory multiple myeloma. Published September 26, 2020 (accessed September 2020). Link: https://www.gsk.com/en-gb/media/press-releases/european-commission-approves-Blenrep-belantamab-mafodotin-for-the-treatment-of-patients-with-relapsed-and-refractory-multiple-myeloma/

4.Bristol Myers Squibb and bluebird bio Announce Submission of Biologics License Application (BLA) for Anti-BCMA CAR T Cell Therapy Idecabtagene Vicleucel (Ide-cel, bb2121) to FDA. Published March 31, 2020 (accessed September 2020). Link: https://news.bms.com/press-release/celltherapy/bristol-myers-squibb-and-bluebird-bio-announce-submission-biologics-license

5.Bristol Myers Squibb and bluebird bio Provide Regulatory Update on Idecabtagene Vicleucel (ide-cel, bb2121) for the Treatment of Patients with Multiple Myeloma. Published May 13, 2020 (accessed September 2020). Link: https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-and-bluebird-bio-provide-regulatory-update

6. Bristol Myers Squibb and bluebird bio Announce Submission of Biologics License Application (BLA) to FDA for Idecabtagene Vicleucel (Ide-cel, bb2121) for Adults with Relapsed and Refractory Multiple Myeloma. Published July 29, 2020 (accessed September 2020). Link: https://www.businesswire.com/news/home/20200729005776/en/Bristol-Myers-Squibb-bluebird-bio-Announce-Submission
7. Janssen Announces BCMA CAR-T Therapy JNJ-4528 Granted U.S. FDA Breakthrough Therapy Designation for the Treatment of Relapsed or Refractory Multiple Myeloma. Published December 6, 2019 (accessed September 2020). Link: https://www.jnj.com/janssen-announces-bcma-car-t-therapy-jnj-4528-granted-u-s-fda-breakthrough-therapy-designation-for-the-treatment-of-relapsed-or-refractory-multiple-myeloma
8. Lonial S, et al. Pivotal DREAMM-2 study: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) refractory to proteasome inhibitors (PIs), immunomodulatory agents, and refractory and/or intolerant to anti-CD38 monoclonal antibodies (mAbs). J Clin Oncol. May 2020. 38: suppl; abstr 8536.
9. Trudel S, 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. Blood. 2017. 130:741.
10. Raje NS, et al. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2019; 380(18):1726-1737.
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12. Madduri D, et al. Results from CARTITUDE-1: A Phase 1b/2 Study of JNJ-4528, a CAR-T Cell Therapy Directed Against B-Cell Maturation Antigen (BCMA), in Patients with Relapsed and/or Refractory Multiple Myeloma (R/R MM). 61st Annual Meeting of Hematology. 7-10th December, 2019. Abstract 577.
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About The Authors:

Snigdha Gupta, Ph.D., is a principal analyst on the Oncology team at DRG, part of Clarivate. She has worked on multiple oncology indications including multiple myeloma, non-small cell lung cancer, gastroesophageal, prostate, and colorectal cancer. Gupta holds a Ph.D. in infectious diseases from the Indian Institute of Chemical Biology at Jadavpur University in Kolkata. She pursued a postdoctoral fellowship at the Mucosal Immunology Lab of the National Institute of Immunology in New Delhi and has published in several peer-reviewed journals.

Sorcha Cassidy, Ph.D., leads primary and secondary market research on oncology indications across the major pharmaceutical markets as associate director of the Oncology team for DRG, part of Clarivate. She is passionate about hematological cancer research and has covered many indications in this space including, but not limited to NHL, CLL, and AML. Cassidy has in-depth expertise in competitive intelligence, market research, and delivering strategic insights that address key client business questions. She holds an M.Res. and Ph.D. in immunology from Imperial College London, where she investigated the role of killer immunoglobulin-like receptors (KIR) on natural killer (NK) cells in various diseases.