Page 323 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR
Belantamab mafodotin: an important treatment option for vulnerable patients with triple class exposed relapsed and/or refractory multiple myeloma
We, as leaders in the European myeloma clinical research community and from nine countries across the European Union, are writing in response to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommendation to not renew the conditional marketing authorization of belantamab mafodotin issued on September 15, 2023.
Multiple myeloma (MM) is the second most frequent he- matological cancer with four to five new cases per 100,000 inhabitants/year and although remarkable progress has occurred in the last years, it does remain for most patients an incurable disease.1
There are three main drug classes used for the treatment of MM: proteasome inhibitors, immunomodulatory drugs and CD38 monoclonal antibodies, all of which are now part of the standard of care for patients with MM in early lines of therapy. However, when patients become triple class exposed and/or refractory to these treatments, they typically have poor outcomes,2 thus representing an unmet medical need with a lack of new standards of care options in this population.
New targets and new approaches have emerged to address this unmet need including new targets, like BCMA3,4 or GPRC5D5 and new modalities, like chimeric antigen receptor T-cell (CAR T) therapies or bispecific monoclonal antibodies and all of them have shown to be effective in the triple class refractory population resulting in their approval. However, despite their proven benefit, safety concerns such as risk of serious infections and burden of administration often makes these agents less suitable for elderly patients or those with other comorbidities. Additionally, accessibility represents a significant hurdle for most patients in Europe, leaving many patients without viable options and without proven effective therapies.
Belantamab mafodotin is a BCMA-targeted therapy in the modality of an antibody drug conjugate and it was the first drug, in this category, approved for the treatment of triple class refractory MM patients. Although belantamab mafodotin is a BCMA-targeted therapy, its mechanism of action is different6-8 and makes it suitable for some MM patients not eligible for either CAR T cells or bispecific an- tibodies. The rationale for the approval was the significant clinical benefit observed for those patients included in the DREAMM-29 clinical trial (overall response rate [ORR], 32%) and especially those who experienced a partial response or better with a durability of response of 12.5 months (median duration of responses [DoR], 95% confidence interval [CI]:
4.2-19.3 months), and a tolerable safety profile.
We acknowledge that the phase III DREAMM-3 study10 failed to meet its primary endpoint, but it is important to note that belantamab mafodotin is not indicated to replace pomalidomide in this current label but is a useful addition to the therapeutic armamentarium for patients with pomalidomide failure. Indeed, it has been shown to be effective in the pomalidomide-exposed patients as was demonstrated in the DREAMM-2 trial. Other trials assessing new agents such as venetoclax (CANOVA trial11) and melflufen (OCEAN trial)12 have shown the challenges of doublet comparisons in the relapsed/refractory setting. However, the unmet medical need in specific sub-types of patients and especially in those who are not candidates for the currently approved therapies justify the possibility of having beneficial alternatives available to them, such as belantamab mafodotin and targeting BCMA as an anti- body drug conjugate. Indeed, melflufen as a peptide drug conjugate, is currently fully approved in Europe given the results of the HORIZON study with the supportive results of OCEAN and based upon a similar premise.13 Moreover, as with belantamab mafodotin both venetoclax and melflufen have been shown to be effective in pomalidomide-exposed patients and to be especially active in combination. Despite not meeting its primary endpoint in the DREAMM-3 trial,10 belantamab mafodotin demonstrated numerical im- provement with a median progression-free survival (mPFS) of 11.2 months versus pomalidomide-dexamethasone at 7 months, and an improved hazard ratio (HR) of 0.90 after 10 months more of follow-up. Overall response rate (41%, 95% CI: 34.2-47.7 vs. 36%, 95% CI: 26.5-45.4), depth of re- sponse as measured by VGPR or better (25% vs. 8%) and DoR (25.6 months, 95% CI: 20.7-not reached [NR] vs. 10.4 months, 95% CI: 7.6-21.1) were markedly superior in the belantamab mafodotin arm versus pomalidomide-dexa- methasone, supporting a meaningful treatment effect and potential clinical benefit.10
As investigators and physicians managing MM patients, we believe belantamab mafodotin provides an important treat- ment option for an important subgroup of patients, such as the elderly and/or frail patients who may not tolerate the rigors of intensive therapies, as well as for individuals with renal impairment where other more intensive treat- ments targeting BCMA can be especially challenging, not least as this is a frequent complication of advanced MM. Moreover, patients who are unable to adhere to the de- manding administration of bispecific antibodies and wish
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