Multiple myeloma is the second most common hematological malignancy in the United States and is generally considered treatable, but not curable. [2] Multiple myeloma is a relatively uncommon cancer with a lifetime risk of getting the disease estimated at 1 in 132 (0.76%). According to the American Cancer Society, an estimated 32,270 people (17,530 in men and 14,740 in women) are will be diagnosed with multiple myeloma this year, and about 12,830 deaths are expected to occur (7,190 in men and 5,640 in women)[3]

Multiple myeloma affects plasma cells. The disease develops in the bone marrow crowding out the normal, healthy, plasma cells that help fight infection. In multiple myeloma, malignant plasma cells produce an abnormal antibody called M protein, which may cause tumors, kidney damage, bone destruction, and impaired immune function. With the growth of the malignant cells, there is less space for the healthy cells, which, in time, results in a decreased number of red blood cells, white blood cells, and platelets, causing anemia, excessive bleeding, and decreased ability to fight infection.

Furthermore, the buildup of M protein in the blood and urine can damage the kidneys and other organs. Bone damage can cause bone pain and osteolytic lesions, which increases the risk of fractures.

Depending on the classification of a patient’s disease management may include, treatment with proteasome inhibitors, immunomodulatory drugs (IMiDs), steroids, histone deacetylase (HDAC) inhibitors, antibodies, or chemotherapy.

Major improvements
Although the treatment of multiple myeloma has dramatically improved due to the availability of immunotherapies. More research into new therapies is needed as multiple myeloma commonly becomes refractory to available treatments. [4]

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During the American Society of Hematology (ASH) Annual Meeting and Exposition, hosted virtually from 5-8 December 2020 results from multiple studies discussing novel treatment options will be presented.

Belantamab mafodotin
Among the presentations is new data from studies demonstrating the potential of belantamab mafodotin (GSK2857916; belantamab mafodotin-blmf; Blenrep®; GlaxoSmithKline/GSK), a first-in-class anti-BCMA (B-cell maturation antigen) in combination with standard therapies in earlier treatment settings.

Belantamab mafodotin is an antibody-drug conjugate or ADC, a highly targeted biopharmaceutical drug that combines monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker. In belantamab mafodotin, the potent anti-cancer drug is monomethyl auristatin-F(MMAF). a member of the dolastatin family of microtubule inhibitors, potent anti-tumor agents that can lead to immunogenic cell death (ICD), a type of cell death that stimulates host immune responses.

With nine approved drugs on the market, ADCs have become a powerful class of therapeutic agents in oncology and hematology.

Function of BCMA
The normal function of BCMA is to promote plasma cell survival by transduction of signals from two known ligands, BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand). This pathway has been shown to be important for myeloma cell growth and survival.

BCMA expression is limited to B cells at later stages of development. BCMA is expressed at varying levels in myeloma patients and BCMA membrane expression is universally detected in myeloma cell lines.[5][1]

DREAMM
‘The presentations planned during the American Society of Hematology (ASH) Annual Meeting and Exposition include data from the extensive DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) clinical trial program, which is evaluating belantamab mafodotin in different lines of therapy, and in combination with standard of care and novel therapies.

“Belantamab mafodotin is a significant advance for patients with relapsed or refractory multiple myeloma who previously had limited treatment options available. We believe that via our ongoing research […] in combination with other agents, and in earlier lines of treatment, we have the potential to continue to address the unmet needs of multiple myeloma patients and redefine the way this cancer is treated,” noted Axel Hoos, M.D., Ph.D., Senior Vice President and Head of Oncology R&D, GSK.

Key studies being presented at ASH will demonstrate the potential of belantamab mafodotin in combination with standard therapies in earlier lines of treatment and include:

  • The DREAMM-6 analysis (poster #1419) will report outcomes from the combination of belantamab mafodotin with bortezomib and dexamethasone in patients whose disease has become refractory or relapsed after one or more prior lines of treatment.
  • ALGONQUIN (presentation #725), a supported collaborative study being led by the Canadian Myeloma Research Group, is evaluating the combination of belantamab mafodotin with pomalidomide and dexamethasone in relapsed or refractory patients who were previously treated with two or more prior lines of treatment that must have included lenalidomide and a proteasome inhibitor.

Analysis
The analysis of the DREAMM studies confirms that single-agent belantamab mafodotin demonstrated deep and durable responses with a manageable safety profile in patients with heavily pretreated refractory or relapsed multiple myeloma (median 7 lines of prior therapy) treated with an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and and/or intolerant to an anti-CD38 monoclonal antibody in the pivotal Phase II DREAMM-2 study (NCT03525678). In addition, data from a 13-month follow-up further demonstrated that single-agent belantamab mafodotin was well-tolerated with clinically meaningful responses which were sustained despite dose modifications with longer follow-up. The results showed an overall response rate (ORR) was 32% and the median duration of response (DoR) was 11.0 months in the belantamab mafodotin 2.5 mg/kg arm. [5][6]

Combination
The multimodal mechanism of action, efficacy, and safety profile of belantamab mafodotin, as well as preclinical data, suggest possible synergy with the standard of care agents and a potential benefit in combination with IMiDs and PIs. The ability of IMiDS to enhance immune responses including antibody-dependent cellular cytotoxic (ADCC) forms, for example, the basis for combining belantamab mafodotin with pomalidomide.

The results from one study demonstrated belantamab mafodotin to have clinically meaningful activity and a manageable safety profile in patients with refractory or relapsed multiple myeloma.

A phase I, 2-part multicenter, dose-escalation study evaluated the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, tolerability, and efficacy of belantamab mafodotin in combination with pomalidomide, an immunomodulatory drug that auguments T-cell and natural killer cell-mediated immunity, and dexamethasone in patients with refractory or relapsed multiple myeloma.

In this study, eligible patients had received > 2 prior lines of treatment, were exposed to lenalidomide and a proteasome inhibitor, and were refractory to their last line of therapy. Pomalidomide was administered at 4 mg days 1-21, dexamethasone 40 mg (20 mg age > 75 years) weekly in conjunction with IV belantamab mafodotin SINGLE (1.95 or 2.5 mg/kg, day 1) or belantamab mafodotin SPLIT (2.5 or 3.4 mg/kg, split equally on days 1 and 8) Q4W. based on the results of the study a maximum tolerated dose was established as 2.5 mg/kg SINGLE and 2.5 mg/kg SPLIT in combination with standard dosing of pomalidomide and dexamethasone. At the time of the median follow-up of 6 months, 29 patients were evaluable for response. Across all cohorts, the ORR was 86.2% (6 Partial Response/PR, 15 very good partial response/VGPR and 4 stringent complete response/sCR). The median number of cycles administered was 6 (range 1-20). A total of 8 patients discontinued treatment due to progressive disease (PD) (n=5), patient decision (n=2), and adverse events of Grade 4 decreased VA (n=1); 27 patients are ongoing. The median Progression-Free Survival (mPFS) has not been reached in any of the treatment groups.

These results show promising efficacy. The treatment-emergent Adverse Events (AE) were considered acceptable and consistent with the known safety profiles for belantamab mafodotin and pomalidomide. The study authors note that the high rate of dose holds at the 2.5 mg/kg dose has prompted exploration of alternative dosing schedules.

Approval
Belantamab mafodotin was approved earlier this year in the United States and in the European Union for the treatment of patients with relapsed and/or refractory multiple myeloma who have received at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

During the annual meeting of the American Society of Hematology (ASH) Annual Meeting and Exposition, GlaxoSmithKline/GSK-sponsored presentations include:

DREAMM Studies

Abstract NamePresenterPresentation
DREAMM-2: Single-Agent Belantamab Mafodotin (Belamaf) in Patients With Relapsed/Refractory Multiple Myeloma (RRMM) – 1-Year Outcomes by Prior TherapiesLonial S.#1417
Exposure–Response (E-R) for Ocular Safety Endpoints for Belantamab Mafodotin (Belamaf), a B-Cell Maturation Antigen (BCMA)-Targeting Agent, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) in the DREAMM-2 StudyFerron-Brady G.#1420
DREAMM-2: Single-Agent Belantamab Mafodotin (Belamaf) Effects on Patient-Reported Outcome (PRO) Measures in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)Popat R.#2278
Infusion-Related Reactions (IRRs) in the DREAMM-2 Study of Single-Agent Belantamab Mafodotin (Belamaf) in Patients With Relapsed/Refractory Multiple Myeloma (RRMM)Nooka A.#3221
Recovery of Ocular Events with Longer-term Follow-up in the DREAMM-2 Study of Single-Agent Belantamab Mafodotin (Belamaf) in Patients with Relapsed or Refractory Multiple Myeloma (RRMM)Lonial S.#3224
Patient-Reported Experiences During and Following Treatment with Belantamab Mafodotin (Belamaf) for Relapsed/Refractory Multiple Myeloma (RRMM) in the DREAMM-2 StudyEliason L.#3248
DREAMM-5 Platform Trial: Belantamab Mafodotin (Belamaf) in Combination With 4 Different Novel Agents in Patients With Relapsed/Refractory Multiple Myeloma (RRMM)Richardson P.#2299
DREAMM-7: A Phase III Study of the Efficacy and Safety of Belantamab Mafodotin (Belamaf) with Bortezomib, and Dexamethasone (B-Vd) in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)R. Rifkin#3247
DREAMM-8: A Phase III Study of the Efficacy and Safety of Belantamab Mafodotin (Belamaf) with Pomalidomide and Dexamethasone (B-Pd) in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)Trudel S.#2302

 

Real-World Multiple Myeloma Data

AbstractPresenterPresentation
Population-level Projections for Multiple Myeloma Patients by Line of Therapy in the USAKanas G.#2300

 

Clinical trials
A Study to Investigate the Efficacy and Safety of Two Doses of GSK2857916 in Participants With Multiple Myeloma Who Have Failed Prior Treatment With an Anti-CD38 Antibody – NCT03525678
Multi-Center Study of GSK2857916 in Combination With Pomalidomide and Dex – NCT03715478

Reference
[1] NCI Drug Dictionary – Anti-BCMA Antibody-Drug Conjugate GSK2857916. National Cancer Institute. Online Last accessed on December 4, 2020.
[2] 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.
[3] SEER Cancer Facts & Figures 2019. Online. Last accessed on December 4, 2020.
[4] Nooka AK, Kastritis E, Dimopoulos MA. Treatment options for relapsed and refractory multiple myeloma. Blood. 2015;125(20)
[5] Lonial, S, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020; 21(2):207–21.
[6] Lonial S, Lee HC, Badros A, Trudel S, Nooka AK, Chari A, Abdallah AA. 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 38: 2020 (suppl; abstr 8536) 10.1200/JCO.2020.38.15_suppl.8536.

Featured image: Scientist at GlaxoSmithKline/GSK. Photo courtesy: © 2016 – 2020 GlaxoSmithKline/GSK. Used with permission.

This article was first published in ADC Review | Journal of Antibody-drug Conjugates on December 5, 2020.

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