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“Taken together with results from the [previous] DREAMM-7 trial, these data highlight the potential of belantamab mafodotin-containing triplets to address an unmet need for novel regimens to treat patients with multiple myeloma at the first relapse,” senior author Suzanne Trudel, MD, of the department of medical oncology and hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada, said in presenting the late-breaking findings in a press briefing at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago.
The results, published concurrently in The New England Journal of Medicine, are from an interim analysis of the ongoing phase 3, global open-label DREAMM-8 trial, involving 302 patients with lenalidomide-refractory multiple myeloma who were randomized to treatment with either belantamab mafodotin (n = 155) or bortezomib (n=147), each in addition to the pom-dex combination.
The study met its primary endpoint of PFS at a median follow-up of 21.8 months, with the median PFS in the belantamab mafodotin group not met, and the rate 12.7 months for bortezomib (HR 0.52; P < .001).
The 12-month rate of PFS was significantly higher with belantamab mafodotin compared with the bortezomib group (71% versus 51%).
The overall response rates between the 2 groups were similar (77% versus 72%), however, the belantamab mafodotin group had an improved rate of complete response of 40% versus 16% in the bortezomib group.
The median duration of response was not reached with belantamab mafodotin versus 17.5 months with bortezomib.
While a positive trend for median overall survival favored belantamab mafodotin for median overall survival (HR .77), the authors note that survival data still need to mature.
Further analyses showed early and sustained separation in favor of belantamab mafodotin for PFS in all prespecified subgroups, including those with high-risk cytogenetics, and those refractory to lenalidomide and anti-CD38s.
In terms of safety, grade 3 or higher adverse events (AEs) occurred among 91% of those in the belantamab mafodotin group compared with 73% in the bortezomib group, however, when the researchers adjusted for time on treatment, the belantamab mafodotin group had similar or lower rates of AEs.
Discontinuation rates for fatal or AEs of any cause were similar in both arms.
The most prominent side effects of belantamab mafodotin are the ocular AEs that affect the majority of patients. In the DREAMM-8 study, the ocular events affected 89% of patients, with events that were grade 3 or higher occurring among 43% (grade 3, 42%; grade 4, 1%).
The ocular events, which included blurred vision, dry eye, and a foreign body sensation in the eyes, were generally reversible and managed with treatment delays and dose modifications.
As of the time of the analysis, the first occurrence of the ocular events had improved in 92% of patients and resolved in 85%, with a median time to resolution of 57 days.
The AEs resulted in treatment discontinuation for 9% of patients.
The ocular events were managed with a protocol-recommended modification of the belantamab mafodotin dose, which included dose delays until the KVA grade improved to 1 or lower, as well as reductions in the frequency of administration from every 4 weeks to every 8 weeks.
“Ocular AEs are seen in the majority of patients, and the best strategies to mitigate things at this time that we know of are dose holds for grade 2 ocular events, which allow for full recovery and minimize cumulative toxicity, and then prolonging dosing intervals for subsequent doses,” Dr. Trudel said in an interview.
Previous FDA Approval Withdrawn
Of note, belantamab mafodotin previously generated high interest for relapsed/refractory multiple melanoma, with early clinical results earning the therapy accelerated approval from the US Food and Drug Administration (FDA).
However, the FDA approval was subsequently revoked when the DREAMM-3 trial filed to achieve its primary outcome of superior PFS.
Dr. Trudel explained in an interview that since then, key changes have included combinations to improve responses, “overcome early progression and allow patients to benefit from the long duration of response that is achieved with belantamab mafodotin once they respond.”
While the ocular toxicities are common, Dr. Trudel underscored that they are “reversible and manageable.”
Antibody-Drug Conjugates: Less is More?
The ocular AEs observed with belantamab mafodotin are among the variety of unique side effects that are reported with the emerging antibody-drug conjugates, which, with precision targeting, deliver highly potent cytotoxic ‘payloads’ that bind to cells, earning the drugs nicknames such as “smart bombs” and “biologic missiles.”
In the case of belantamab mafodotin, the target is the protein B-cell maturation antigen (BCMA).
In a commentary on the DREAMM-8 study presented at the meeting, Sagar Lonial, MD, chair of the department of hematology and medical oncology at the Winship Cancer Institute of Emory University in Atlanta, noted the importance of BCMA: “In describing it to fellows, I explain that everything bad that a myeloma cell wants to do is mediated through BCMA.”
He underscored, however, the need to consider strategic dosing reductions, evoking iconic architect Ludwig Mies van der Rohe’s adage “less is more.”
“These results show belantamab mafodotin is clearly effective, but the question is how do we most effectively deliver it,” he said. “The idea that more is better is not necessarily the case when we’re talking about antibody drug conjugates,” he said.
“We need to use less [drug], less frequently, and do it in a way that preserves patient function,” Dr. Lonial said. “Missed doses may actually result in better safety profiles and maintain the efficacy of the treatment,” he said.
That being said, Dr. Lonial emphasized that the DREAMM-8 study is important, showing “the longest PFS in a pom-dex combination that we’ve seen in multiple myeloma.”
And “less ocular toxicity with similar efficacy are big wins,” he added.
“Future studies should take less frequent dosing into account as they are planned and as they’re executed.”
Other Therapies
In addition to the bortezomib, pom-dex regimen, other currently approved triplet regimens used at the first relapse in multiple myeloma include selinexor-bortezomib-dexamethasone, however that regimen is associated with adverse events that can pose challenges.
Furthermore, two chimeric antigen receptor (CAR) T-cell therapies — ciltacabtagene autoleucel and idecabtagene vicleucel, have emerged and been approved for multiple myeloma patients who have received at least one and at least two previous lines of therapy, respectively.
While those CAR T-cell therapies show important improvements in PFS benefit and quality of life compared with standard triplet regimens, access is a significant stumbling block, and safety issues, including the potential for cytokine release syndrome and neurotoxic effects are also a concern.
“Each regimen for myeloma comes with unique toxicities. Thus, it is beneficial for physicians and patients to have access to multiple treatment regimens to individualize to the patient, based on patient characteristics [and] drug related factors,” Dr. Trudel said.
The current DREAMM-8 regimen represents a convenient, “off-the-shelf option that can be given in the community,” she added.
The trial was sponsored by GSK. Dr. Trudel disclosed relationships with Amgen, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Jansen Biotech, Pfizer, Roche, and Sanofi. Dr. Lonial reported ties with Takeda, Amgen, Novartis, BMS, GSK, ABBVIE, Genentech, Pfizer, Regeneron, Janssen, and TG Therapeutics.
“Taken together with results from the [previous] DREAMM-7 trial, these data highlight the potential of belantamab mafodotin-containing triplets to address an unmet need for novel regimens to treat patients with multiple myeloma at the first relapse,” senior author Suzanne Trudel, MD, of the department of medical oncology and hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada, said in presenting the late-breaking findings in a press briefing at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago.
The results, published concurrently in The New England Journal of Medicine, are from an interim analysis of the ongoing phase 3, global open-label DREAMM-8 trial, involving 302 patients with lenalidomide-refractory multiple myeloma who were randomized to treatment with either belantamab mafodotin (n = 155) or bortezomib (n=147), each in addition to the pom-dex combination.
The study met its primary endpoint of PFS at a median follow-up of 21.8 months, with the median PFS in the belantamab mafodotin group not met, and the rate 12.7 months for bortezomib (HR 0.52; P < .001).
The 12-month rate of PFS was significantly higher with belantamab mafodotin compared with the bortezomib group (71% versus 51%).
The overall response rates between the 2 groups were similar (77% versus 72%), however, the belantamab mafodotin group had an improved rate of complete response of 40% versus 16% in the bortezomib group.
The median duration of response was not reached with belantamab mafodotin versus 17.5 months with bortezomib.
While a positive trend for median overall survival favored belantamab mafodotin for median overall survival (HR .77), the authors note that survival data still need to mature.
Further analyses showed early and sustained separation in favor of belantamab mafodotin for PFS in all prespecified subgroups, including those with high-risk cytogenetics, and those refractory to lenalidomide and anti-CD38s.
In terms of safety, grade 3 or higher adverse events (AEs) occurred among 91% of those in the belantamab mafodotin group compared with 73% in the bortezomib group, however, when the researchers adjusted for time on treatment, the belantamab mafodotin group had similar or lower rates of AEs.
Discontinuation rates for fatal or AEs of any cause were similar in both arms.
The most prominent side effects of belantamab mafodotin are the ocular AEs that affect the majority of patients. In the DREAMM-8 study, the ocular events affected 89% of patients, with events that were grade 3 or higher occurring among 43% (grade 3, 42%; grade 4, 1%).
The ocular events, which included blurred vision, dry eye, and a foreign body sensation in the eyes, were generally reversible and managed with treatment delays and dose modifications.
As of the time of the analysis, the first occurrence of the ocular events had improved in 92% of patients and resolved in 85%, with a median time to resolution of 57 days.
The AEs resulted in treatment discontinuation for 9% of patients.
The ocular events were managed with a protocol-recommended modification of the belantamab mafodotin dose, which included dose delays until the KVA grade improved to 1 or lower, as well as reductions in the frequency of administration from every 4 weeks to every 8 weeks.
“Ocular AEs are seen in the majority of patients, and the best strategies to mitigate things at this time that we know of are dose holds for grade 2 ocular events, which allow for full recovery and minimize cumulative toxicity, and then prolonging dosing intervals for subsequent doses,” Dr. Trudel said in an interview.
Previous FDA Approval Withdrawn
Of note, belantamab mafodotin previously generated high interest for relapsed/refractory multiple melanoma, with early clinical results earning the therapy accelerated approval from the US Food and Drug Administration (FDA).
However, the FDA approval was subsequently revoked when the DREAMM-3 trial filed to achieve its primary outcome of superior PFS.
Dr. Trudel explained in an interview that since then, key changes have included combinations to improve responses, “overcome early progression and allow patients to benefit from the long duration of response that is achieved with belantamab mafodotin once they respond.”
While the ocular toxicities are common, Dr. Trudel underscored that they are “reversible and manageable.”
Antibody-Drug Conjugates: Less is More?
The ocular AEs observed with belantamab mafodotin are among the variety of unique side effects that are reported with the emerging antibody-drug conjugates, which, with precision targeting, deliver highly potent cytotoxic ‘payloads’ that bind to cells, earning the drugs nicknames such as “smart bombs” and “biologic missiles.”
In the case of belantamab mafodotin, the target is the protein B-cell maturation antigen (BCMA).
In a commentary on the DREAMM-8 study presented at the meeting, Sagar Lonial, MD, chair of the department of hematology and medical oncology at the Winship Cancer Institute of Emory University in Atlanta, noted the importance of BCMA: “In describing it to fellows, I explain that everything bad that a myeloma cell wants to do is mediated through BCMA.”
He underscored, however, the need to consider strategic dosing reductions, evoking iconic architect Ludwig Mies van der Rohe’s adage “less is more.”
“These results show belantamab mafodotin is clearly effective, but the question is how do we most effectively deliver it,” he said. “The idea that more is better is not necessarily the case when we’re talking about antibody drug conjugates,” he said.
“We need to use less [drug], less frequently, and do it in a way that preserves patient function,” Dr. Lonial said. “Missed doses may actually result in better safety profiles and maintain the efficacy of the treatment,” he said.
That being said, Dr. Lonial emphasized that the DREAMM-8 study is important, showing “the longest PFS in a pom-dex combination that we’ve seen in multiple myeloma.”
And “less ocular toxicity with similar efficacy are big wins,” he added.
“Future studies should take less frequent dosing into account as they are planned and as they’re executed.”
Other Therapies
In addition to the bortezomib, pom-dex regimen, other currently approved triplet regimens used at the first relapse in multiple myeloma include selinexor-bortezomib-dexamethasone, however that regimen is associated with adverse events that can pose challenges.
Furthermore, two chimeric antigen receptor (CAR) T-cell therapies — ciltacabtagene autoleucel and idecabtagene vicleucel, have emerged and been approved for multiple myeloma patients who have received at least one and at least two previous lines of therapy, respectively.
While those CAR T-cell therapies show important improvements in PFS benefit and quality of life compared with standard triplet regimens, access is a significant stumbling block, and safety issues, including the potential for cytokine release syndrome and neurotoxic effects are also a concern.
“Each regimen for myeloma comes with unique toxicities. Thus, it is beneficial for physicians and patients to have access to multiple treatment regimens to individualize to the patient, based on patient characteristics [and] drug related factors,” Dr. Trudel said.
The current DREAMM-8 regimen represents a convenient, “off-the-shelf option that can be given in the community,” she added.
The trial was sponsored by GSK. Dr. Trudel disclosed relationships with Amgen, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Jansen Biotech, Pfizer, Roche, and Sanofi. Dr. Lonial reported ties with Takeda, Amgen, Novartis, BMS, GSK, ABBVIE, Genentech, Pfizer, Regeneron, Janssen, and TG Therapeutics.
“Taken together with results from the [previous] DREAMM-7 trial, these data highlight the potential of belantamab mafodotin-containing triplets to address an unmet need for novel regimens to treat patients with multiple myeloma at the first relapse,” senior author Suzanne Trudel, MD, of the department of medical oncology and hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada, said in presenting the late-breaking findings in a press briefing at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago.
The results, published concurrently in The New England Journal of Medicine, are from an interim analysis of the ongoing phase 3, global open-label DREAMM-8 trial, involving 302 patients with lenalidomide-refractory multiple myeloma who were randomized to treatment with either belantamab mafodotin (n = 155) or bortezomib (n=147), each in addition to the pom-dex combination.
The study met its primary endpoint of PFS at a median follow-up of 21.8 months, with the median PFS in the belantamab mafodotin group not met, and the rate 12.7 months for bortezomib (HR 0.52; P < .001).
The 12-month rate of PFS was significantly higher with belantamab mafodotin compared with the bortezomib group (71% versus 51%).
The overall response rates between the 2 groups were similar (77% versus 72%), however, the belantamab mafodotin group had an improved rate of complete response of 40% versus 16% in the bortezomib group.
The median duration of response was not reached with belantamab mafodotin versus 17.5 months with bortezomib.
While a positive trend for median overall survival favored belantamab mafodotin for median overall survival (HR .77), the authors note that survival data still need to mature.
Further analyses showed early and sustained separation in favor of belantamab mafodotin for PFS in all prespecified subgroups, including those with high-risk cytogenetics, and those refractory to lenalidomide and anti-CD38s.
In terms of safety, grade 3 or higher adverse events (AEs) occurred among 91% of those in the belantamab mafodotin group compared with 73% in the bortezomib group, however, when the researchers adjusted for time on treatment, the belantamab mafodotin group had similar or lower rates of AEs.
Discontinuation rates for fatal or AEs of any cause were similar in both arms.
The most prominent side effects of belantamab mafodotin are the ocular AEs that affect the majority of patients. In the DREAMM-8 study, the ocular events affected 89% of patients, with events that were grade 3 or higher occurring among 43% (grade 3, 42%; grade 4, 1%).
The ocular events, which included blurred vision, dry eye, and a foreign body sensation in the eyes, were generally reversible and managed with treatment delays and dose modifications.
As of the time of the analysis, the first occurrence of the ocular events had improved in 92% of patients and resolved in 85%, with a median time to resolution of 57 days.
The AEs resulted in treatment discontinuation for 9% of patients.
The ocular events were managed with a protocol-recommended modification of the belantamab mafodotin dose, which included dose delays until the KVA grade improved to 1 or lower, as well as reductions in the frequency of administration from every 4 weeks to every 8 weeks.
“Ocular AEs are seen in the majority of patients, and the best strategies to mitigate things at this time that we know of are dose holds for grade 2 ocular events, which allow for full recovery and minimize cumulative toxicity, and then prolonging dosing intervals for subsequent doses,” Dr. Trudel said in an interview.
Previous FDA Approval Withdrawn
Of note, belantamab mafodotin previously generated high interest for relapsed/refractory multiple melanoma, with early clinical results earning the therapy accelerated approval from the US Food and Drug Administration (FDA).
However, the FDA approval was subsequently revoked when the DREAMM-3 trial filed to achieve its primary outcome of superior PFS.
Dr. Trudel explained in an interview that since then, key changes have included combinations to improve responses, “overcome early progression and allow patients to benefit from the long duration of response that is achieved with belantamab mafodotin once they respond.”
While the ocular toxicities are common, Dr. Trudel underscored that they are “reversible and manageable.”
Antibody-Drug Conjugates: Less is More?
The ocular AEs observed with belantamab mafodotin are among the variety of unique side effects that are reported with the emerging antibody-drug conjugates, which, with precision targeting, deliver highly potent cytotoxic ‘payloads’ that bind to cells, earning the drugs nicknames such as “smart bombs” and “biologic missiles.”
In the case of belantamab mafodotin, the target is the protein B-cell maturation antigen (BCMA).
In a commentary on the DREAMM-8 study presented at the meeting, Sagar Lonial, MD, chair of the department of hematology and medical oncology at the Winship Cancer Institute of Emory University in Atlanta, noted the importance of BCMA: “In describing it to fellows, I explain that everything bad that a myeloma cell wants to do is mediated through BCMA.”
He underscored, however, the need to consider strategic dosing reductions, evoking iconic architect Ludwig Mies van der Rohe’s adage “less is more.”
“These results show belantamab mafodotin is clearly effective, but the question is how do we most effectively deliver it,” he said. “The idea that more is better is not necessarily the case when we’re talking about antibody drug conjugates,” he said.
“We need to use less [drug], less frequently, and do it in a way that preserves patient function,” Dr. Lonial said. “Missed doses may actually result in better safety profiles and maintain the efficacy of the treatment,” he said.
That being said, Dr. Lonial emphasized that the DREAMM-8 study is important, showing “the longest PFS in a pom-dex combination that we’ve seen in multiple myeloma.”
And “less ocular toxicity with similar efficacy are big wins,” he added.
“Future studies should take less frequent dosing into account as they are planned and as they’re executed.”
Other Therapies
In addition to the bortezomib, pom-dex regimen, other currently approved triplet regimens used at the first relapse in multiple myeloma include selinexor-bortezomib-dexamethasone, however that regimen is associated with adverse events that can pose challenges.
Furthermore, two chimeric antigen receptor (CAR) T-cell therapies — ciltacabtagene autoleucel and idecabtagene vicleucel, have emerged and been approved for multiple myeloma patients who have received at least one and at least two previous lines of therapy, respectively.
While those CAR T-cell therapies show important improvements in PFS benefit and quality of life compared with standard triplet regimens, access is a significant stumbling block, and safety issues, including the potential for cytokine release syndrome and neurotoxic effects are also a concern.
“Each regimen for myeloma comes with unique toxicities. Thus, it is beneficial for physicians and patients to have access to multiple treatment regimens to individualize to the patient, based on patient characteristics [and] drug related factors,” Dr. Trudel said.
The current DREAMM-8 regimen represents a convenient, “off-the-shelf option that can be given in the community,” she added.
The trial was sponsored by GSK. Dr. Trudel disclosed relationships with Amgen, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Jansen Biotech, Pfizer, Roche, and Sanofi. Dr. Lonial reported ties with Takeda, Amgen, Novartis, BMS, GSK, ABBVIE, Genentech, Pfizer, Regeneron, Janssen, and TG Therapeutics.
FROM ASCO 2024