The treatment patients diagnosed with relapsed or relapsed/refractory multiple myeloma (RRMM), those who have relapsed or who are refractory to at least 1 line of approved therapy, requires a careful evaluation of the results of previous treatments, including a understanding of treatment associated toxicities as well as proper assessment of prognostic factors. [1]

The majority of patients with relapsed/refractory multiple myeloma have received prior treatment with drug combinations. Hence, the complex task of the treating physician is to select the best time to start a new therapy, which is generally based on a number of factors, including previous treatment and prior responsiveness as well as adverse events, the condition of the patient and expected effectiveness and tolerability of the new therapy. [1]

Multiple myeloma is the second most common blood cancer in the US and is generally considered treatable, but not curable. [2][3]

In the US, more than 32,000 people are estimated to be diagnosed with multiple myeloma this year and nearly 13,000 people will die from the disease. [4] Research into new therapies is needed as multiple myeloma commonly becomes refractory to available treatments. [5]

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Updates from the DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) clinical trial program evaluating belantamab mafodotin (Blenrep®; GlaxoSmithKline/GSK), a B-cell maturation antigen (BCMA)-directed antibody and microtubule inhibitor conjugate used  in combination with both standard of care and investigational agents in earlier lines of therapy, were presented during the annual meeting of the American Society of Clinical Oncology (ASCO), held June 3 – 7, 2022 in Chicago, Il.

Antibody-drug Conjugate
Belantamab mafodotin is an antibody-drug conjugate or ADC with 3 components, including  an afucosylated, humanized immunoglobulin G1 monoclonal antibody covalently linked to  monomethyl auristatin F (MMAF), a potent microtubule polymerization inhibitor, via a protease-resistant maleimidocaproyl linker.

The antibody is produced in a mammalian cell line (Chinese Hamster Ovary) using recombinant DNA technology and the microtubule inhibitor and linker are produced by chemical synthesis. Approximately 4 molecules of mafodotin are attached to each antibody molecule. The molecular weight of belantamab mafodotin-blmf is approximately 152 kDa.

Attaya Suvannasankham MD, and her colleagues from Indiana University Health shared their expertise on safety and clinical activity of belantamab mafodotin with pembrolizumab in patients with relapsed/refractory multiple myeloma. Photo courtesy: © 2022 IU Simon Comprehensive Cancer Center. Used with permission.

DREAMM-4
Results from the DREAMM-4 study were included in a poster by Attaya Suvannasankha, MD, an oncologist at Indiana University Health/Simon Comprehensive Cancer Center and her team.[6]

The phase I/II, single-arm, open-label study of adults with RRMM after ≥3 lines of therapy, including anti-CD38 monoclonal antibody, proteasome inhibitor, and immunomodulator, showed a favorable Overall Response Rate (ORR) compared with single-agent belantamab mafodotin in heavily pre-treated RRMM. [6]

The two-part study was assigned to assess the safety, tolerability and clinical activity of belantamab mafodotin in combination with a programmed cell death-1 (PD-1) inhibitor pembrolizumab (Keytruda®; Merck & Co).

In the first part of the study researchers established the dose of belantamab mafodotin 2.5 mg/kg with pembrolizumab 200 mg, both IV Q3W up to 35 cycles, for the second phase of the study, the expansion part.

Primary efficacy endpoint was investigator-assessed Overall Response Rate (ORR, ≥partial response [PR] per IMWG criteria by investigator). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), adverse events per NCI-CTCAE v4.03, and pharmacokinetics (PK).

This primary analysis  included included 34 patients  (Part 1 n = 6; Part 2 n = 28). In both parts, the median prior lines of therapy was 5 (range 3–13). Ten (10) patients (29%) had high-risk cytogenetics and 9 (26%) had extramedullary disease.

The Overall Response Rate was 47%, with most responses (10/16 patients) ≥ very good PR (VGPR). Median follow-up was 14.7 months. The median (95% CI) DoR was 8.0 (2.1–not reached) months and the median Progression Free Survival (PFS) was 3.4 (1.4–5.6) months. [6]

Adverse events
Most patients had ≥1 adverse event (any grade: 97%; grade ≥3: 74%) and treatment-related adverse events (TRAE, any grade: 97%; grade ≥3: 65%). The most common (≥35%) adverse events included keratopathy (any grade: 76%; grade ≥3: 38%), vision blurred (any grade: 38%; Gr ≥3: 0%), and thrombocytopenia (any grade: 35%; grade ≥3: 29%). Overall, the Adverse Events frequency and severity were similar to single-agent belantamab mafodotin.  The researchers did not observe new TRAEs

The observed adverse events led to dose delays in 65% cases and to dose reductions in 32% of incidents/. However, the adverse events did not result in discontinuation of treatment. Nine patients had a serious adverse events (SAE). Among those, 4 patients had ≥1 SAE related to the study treatment and 2 patents who had immune-related adverse events of grade 1, incluiding gout and autoimmune hypothyroidism.

Preliminary PK and soluble BCMA data were consistent with single-agent belantamab mafodotin therapy.[6]

DREAMM-5
DREAMM-5 is a phase 1/2, open-label, randomized, platform study designed to evaluate the effects of belantamab mafodotin in combination with other anti-cancer drugs in participating patients diagnosed with relapsed/refractory multiple myeloma.

Data from the ongoing DREAMM-5 sub-study 3 of low-dose belantamab mafodotin in combination with nirogacestatan, an investigational gamma secretase inhibitor, has been shown to increase target density and reduce levels of soluble BCMA, and, as such the potential to enhance the activity of BCMA-targeted therapies like belantamab mafodotin is under investigation. [7][8]

The combination was designed to determine if the combination can result in similar efficacy and an improved ocular safety profile compared to the currently approved treatment schedule for belantamab mafodotin (single agent dose 2.5 mg/kg Q3W) in patients with RRMM which showed a 31% Overall Response Rate (ORR) and 44.5% Gr3/4 keratopathy.

The study has a sequential dose-exploration phase evaluating 0.95 mg/kg Q3W belantamab mafodotin with 100 mg BID nirogacestat continuously, followed by a randomized cohort expansion comparing the combination to a belantamab mafodotin 2.5 mg/kg Q3W arm.

The preliminary results from 10 patients in the dose-exploration cohort of the study, showed that patients had a median (range) of 4.5 (3–10) prior lines of therapy.

At time of data cut-off in November 2021, all participating patients received a median range of 7 cycles (1–26). The ORR was 60% (n = 6/10) and 20% (n = 2) achieved a very good partial response. The study investigators noted that a key emergent adverse events included ocular events (n = 7 [70%]; ≥ grade 3, n = 2 [20%] of which grade 3 keratopathy was reported in 1 patient [10%]), diarrhea (n = 7 [70%]; grade 3, n = 1 [10%]) and hypophosphatemia (n = 7 [70%]; grade 3, n = 1, [10%]).[7]

The investigators also reported 2 grade 5 adverse events, neither of which were related to study treatment. The study was not permanently discontinued due to treatment related adverse events.

Overall, the investigators concluded that the clinical activity and a manageable safety profile is observed with this sub-study of low dose belamaf (0.95 mg/kg Q3W) + nirogacestat (100 mg BID continuously) in patients with relapsed/refractory Multiple Myeloma is encouraging.[8]

Hang Quach, MD, FRACP FRCPA, MBBS(Hons) SpecCertOC, is a consultant clinical and laboratory hematologist based at St. Vincent’s Hospital and Epworth Hospital in Melbourne, Australia. She is a professor of hematology at the University of Melbourne and is the Departmental Head of Clinical Hematology and Clinical Hematology Research at St. Vincent’s Hospital. Her clinical area of expertise is hematological malignancy, in particular multiple myeloma, lymphoma and myeloid disorders. Quach and her team presented a poster with interim outcomes from the DREAMM-6 study. Photo courtesy: © 2020 – 2022 Epworth Foundation

DREAMM-6
Results from preclinical studies have demonstrate synergy between belantamab mafodotin and lenalidomide (Revlimid®; Celgene/Bristol Meyers Squibb). This outcome suggest the possibility of an added benefit when combining belantamab mafodotin with approved standard of care such as lenalidomide + dexamethasone. [8]

This hypotheses is being investigated in the ongoing, two part, two arm DREAMM-6 study which evaluates belantamab mafodotin in combination with lenalidomide + dexamethasone  (Arm A) or bortezomib (Velcade®; Takeda) + dexamethasone (Arm B) in participants with RRMM. The primary objectives of the study were safety (including treatment-related adverse events related to the combination belantamab mafodotin n combination with lenalidomide + dexamethasone, tolerability, and efficacy (including overall response rate [ORR] defined as ≥partial response).

During the annual meeting interim outcomes from the DREAMM-6 study from several dose cohorts of belantamab mafodotin in combination with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma who have received one or more prior lines of treatment were presented [8]

Participating patients received 4 belantamab mafodotin doses/schedules (1.9 mg/kg Q8W or Q4W; 2.5 mg/kg Q4W or Q4W SPLIT dose [50% on Days (D)1, 8] IV) in combination with lenalidomide (20 mg PO D1–21) and dexamethasone (20 mg PO/IV D1, 8, 15, 22).

The results of the interim analysis showed that 45 participating patients received ≥1 dose (12 at 1.9 mg/kg Q8W; 4 at 1.9 mg/kg Q4W; 16 at 2.5 mg/kg Q4W; 13 at 2.5 mg/kg Q4W SPLIT). Across cohorts, the median age was 68 y (range: 36–80). Thirteen patients (29%) had high-risk cytogenetics and 6 (13%) had extramedullary disease.

The median prior line of therapy was 3 (range: 1–11) and 26 (58%) had received prior treatment with lenalidomide. In study’s investigators reported that the median duration of follow-up and ORR ranged across cohorts. The median duration of response was only reached in the 1.9 mg/kg Q4W cohort (11.1 mo [95% CI: 3.7–not reached [NR]).

They also reported that at the time of data cut, median progression-free survival was not reached in the 1.9 mg/kg Q8W or 2.5 mg/kg Q4W cohorts. Grade ≥3 TRAEs occurred in 42–85%.  The investigators reported that grade ≥3 keratopathy did not occur in patients receiving 1.9 mg/kg Q8W, but was observed in 1 patients (25%) in 1.9 mg/kg Q4W, 8 patients (50%) in 2.5 mg/kg Q4W, and 6 patients (46%) in 2.5 mg/kg Q4W SPLIT cohorts.

Overall, belantamab mafodotin in combination with lenalidomide and dexamethasone had demonstrated encouraging clinical activity and a tolerable safety profile, without new safety signals identified in participating patients. The investigators reported that the adverse events, including keratopathy, were common but manageable with dose modifications. [9]

Clinical trails
Study Evaluating Safety, Tolerability and Clinical Activity of GSK2857916 in Combination With Pembrolizumab in Subjects With Relapsed/Refractory Multiple Myeloma (RRMM) (DREAMM 4) – NCT03848845
Platform Study of Belantamab Mafodotin as Monotherapy and in Combination With Anti-cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (DREAMM 5) – NCT04126200
To Evaluate Safety, Tolerability, and Clinical Activity of the Antibody-drug Conjugate, GSK2857916 Administered in Combination With Lenalidomide Plus Dexamethasone (Arm A), or in Combination With Bortezomib Plus Dexamethasone (Arm B) in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (DREAMM 6) – NCT03544281

Highlights of prescribing information
Belantamab mafodotin (Blenrep®; GlaxoSmithKline/GSK)[Prescribing Information]
Pembrolizumab (Keytruda®; Merck & Co)[Prescribing Information]
Lenalidomide (Revlimid®; Celgene/Bristol Meyers Squibb) [Prescribing Information]
Dexamethasone (Decadron®) [Prescribing Information]
Bortezomib (Velcade®; Takeda) [Prescribing Information]

Reference
[1] Sonneveld P, Broijl A. Treatment of relapsed and refractory multiple myeloma. Haematologica. 2016 Apr;101(4):396-406. doi: 10.3324/haematol.2015.129189. Erratum in: Haematologica. 2016 Aug;101(8):995. PMID: 27033237; PMCID: PMC5004403.
[2] CA: A Cancer Journal for Clinicians, Vol. 70, Issue 1, Han/Feb 2020 Pages 7-30.
[3] Kazandjian D. Multiple myeloma epidemiology and survival: A unique malignancy. Semin Oncol. 2016;43(6):676–681. doi:10.1053/j.seminoncol.2016.11.004.
[4] SEER Cancer Facts & Figures 2019. Available at: https://seer.cancer.gov/statfacts/html/mulmy.html. Accessed October 2021.
[5] Nooka AK, Kastritis E, Dimopoulos MA. Treatment options for relapsed and refractory multiple myeloma. Blood. 2015;125(20)
[6] Suvannasankha S, Bahlis NJ, Trudel S, Weisel K, Koenecke C, Rocafiguera AO,  Voorhees PM, et al. Safety and Clinical Activity of Belantamab Mafodotin with Pembrolizumab in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): DREAMM-4 Study J Clin Oncol 40, 2022 (suppl 16; abstr 8018) | DOI 10.1200/JCO.2022.40.16_suppl.8018
[7] Eastman S, Shelton C, Gupta I, Krueger J, Blackwell C, Bojczuk P. Synergistic Activity of Belantamab Mafodotin (anti-BCMA immuno-conjugate) with PF-03084014 (gamma-secretase inhibitor) in BCMA-Expressing Cancer Cell Lines. Blood. 2019;134(supplement_1):4401. doi:10.1182/blood-2019-123705.
[8] Lonial S, Grosicki S, Hus M, Song KW, Facon T, Callander NS, Ribrag V, et al. Synergistic effects of low-dose belantamab mafodotin in combination with a gamma-secretase inhibitor (nirogacestat) in patients with relapsed/refractory multiple myeloma (RRMM): DREAMM-5 study. J Clin Oncol 40, 2022 (suppl 16; abstr 8019) | DOI
10.1200/JCO.2022.40.16_suppl.8019
[9] Quach H, Gironella M, Lee C, Popat R, Cannell P, Kasinathan R, Chopra B, et al. Safety and Clinical Activity of Belantamab Mafodotin with Lenalidomide Plus Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): DREAMM-6 Arm-A Interim Analysis. J Clin Oncol 40, 2022 (suppl 16; abstr 8017) | DOI
J Clin Oncol 40, 2022 (suppl 16; abstr 8017) | DOI 10.1200/JCO.2022.40.16_suppl.8017.

Featured image: 58th ASCO Annual Meeting – Physicians, researchers, and health care professionals from over 100 countries are attending the ASCO Annual Meeting. Photo courtesey: © 2022 ASCO/Zach Boyden-Holmes. Used with permission.

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