Redefining Treatment at First Relapse in RRMM: Exploring BCMA-Targeted Therapies

Section 1: Overview
Advancements in therapeutic options for multiple myeloma (MM) have led to notable improvements in progression-free and overall survival, providing meaningful benefits to patients. However, MM treatments are not curative, and relapse is a common occurrence in the course of the disease for most patients. Additionally, some patients may become refractory to existing treatment options. In the first-line treatment setting with subsequent relapse for patients receiving therapy containing immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), and CD38-targeted therapies, there is a growing need for novel agents to improve outcomes as patients develop refractory disease to these classes (Bhatt et al, 2023). To address these challenges, novel therapies, such as those targeting B-cell maturation antigen (BCMA), have been developed to improve outcomes in this specific patient population, with the goal of overcoming relapsed/refractory MM (RRMM) (Ahmed et al, 2023).

Here, we review the management of early relapse with a particular focus on BCMA-targeted agents and how they may fit into the treatment paradigm. To start, let’s examine the definition and principles of relapsed disease (Figure 1).

It’s important to understand that there are some differences in biology that may define how long a patient was in first remission. Patients who remain in remission after first-line treatment for less than 3 years are considered functional high-risk myeloma. In many of those patients, we know that a more aggressive treatment approach for early relapse is standard therapy, because these patients see shorter remission durations than those whose first remissions last longer than 3 years. Other factors to consider include: What treatment(s) are the patient refractory to? Are they lenalidomide refractory? Are they daratumumab refractory? Are they triple class refractory (i.e. proteasome inhibitor [bortezomib, carfilzomib, ixazomib], daratumumab, and lenalidomide refractory)? These and other important questions need to be answered as we're parsing through what therapies to off in the management of early relapse. Finally, consider previous treatment-related toxicities, and use this knowledge to tailor management of future treatments for early relapse.

“Now, one big difference that I think is important to recognize as well is that patients with first or second relapse myeloma can, in many cases, with our new drugs, have remissions longer than perhaps their first remission. So, the idea of, ‘Well, they've relapsed, and now we don't have other really good options,’ that is no longer the case. And so, I like to think about ‘early relapse’ as being the new ‘newly diagnosed’ where we really try and achieve maximum depth of response, particularly targeting MRD negativity, and more importantly, that we expect and anticipate really long remissions for patients in that context as well.” – Sagar Lonial MD, FACP

Now, let's turn to the definitions of relapsed and refractory myeloma (Kumar et al, 2016; Figure 2).

We know that, according to the IMWG, primary refractory myeloma means disease progression on first-line therapy. Relapsed myeloma means the patient’s disease has met the IMWG definition for progression but does not fit in the diagnosis of relapsed/refractory or primary refractory. The criteria for IMWG progression involves not just a greater than 25% increase from the lowest serum or urine M-component recorded, but differences between involved and uninvolved free light chain levels, bone marrow plasma cell percentages, and other relevant criteria such as the presence or absence of new bone lesions.

“This is something that I think is really critically important, if I'm going to watch a patient with biochemical relapse, I will often do a PET/CT, just to make sure that I'm not missing anything in terms of bone lesions that may not have shown up as symptomatic myeloma, when it comes to laboratory testing alone.” – Sagar Lonial MD, FACP

Approach to First Relapse
When thinking about how to manage patients in the early-relapse setting, there are a lot of data from randomized phase 3 trials that we can draw from (Figure 3).

The left side of Figure 3 summarize data regarding patients who are not refractory to lenalidomide at first relapse. As important as those trials were at the time they were published, they are now irrelevant in 2024 because almost every patient is progressing on lenalidomide maintenance in one form or another. So, in that context, focusing on the right side of this figure that addresses patients who are refractory to lenalidomide at first relapse gives you the landscape of what treatment approaches might be most important for early-relapsed multiple myeloma.

There are 4 trials that use either carfilzomib or pomalidomide in combination with an anti-CD38 antibody, either daratumumab or isatuximab, that we’ll review here in this setting: CANDOR, IKEMA, APOLLO, and ICARIA-MM.

The first of these trials is the phase 3 CANDOR trial which compared dara-Kd (daratumumab, carfilzomib, and dexamethasone) with Kd (carfilzomib and dexamethasone) in patients with RRMM with at least a partial response to between 1 and 3 previous therapies (Usmani et al, 2022). Results show a significant improvement in progression-free survival, favoring the triplet over the doublet therapy. The median progression-free survival was 28.6 months in the dara-Kd group and 15.2 months in the Kd group (HR 0.59). 

Looking at the CANDOR trial in contrast with the phase 3 IKEMA trial, which compared isa-Kd (isatuximab, carfilzomib, and dexamethasone) with Kd in relapsed MM, the median progression-free survival is very similar to what we see in the CANDOR trial with a significant benefit in favor of the anti-CD38 antibody. The median PFS was 35.7 months vs 19.2 months, respectively (HR 0.58; Moreau et al, 2022).

The data from the phase 3 APOLLO trial of pomalidomide and dexamethasone alone vs daratumumab plus pomalidomide and dexamethasone in RRMM showed a substantial improvement in PFS with the addition of daratumumab. The median PFS was 12.4 months vs 6.9 months (HR 0.63; Dimopoulos et al, 2021).

The phase 3 ICARIA-MM trial of isatuximab, pomalidomide, and dexamethasone versus pomalidomide and dexamethasone in RRMM also showed significant improvement in progression-free survival (Attal et al, 2019). The median PFS was 11.5 months in the isatuximab, pomalidomide, and dexamethasone group versus 6.5 months in the pomalidomide and dexamethasone group (HR 0.596).

“What I think is important is that with this PI/CD38 combination using carfilzomib, PFS really looks so long, because a majority of patients in both trials [CANDOR and IKEMA] were in first relapse. And I think that that's an important distinction, because when we begin to look at pomalidomide in combination with an anti-CD38 antibody [APOLLO and ICARIA-MM], it looks as though the progression-free survival is shorter. But in reality, the pomalidomide combinations are at least one line later in those trials, because the label for pomalidomide is beyond second relapse. And so, I think that accounts for the difference, not that the carfilzomib/CD38 combination is really superior to the pomalidomide/CD38 combination across the board...But we certainly, at our center, have data with pom/dara in first relapse, showing that if patients have a remission, first remission of greater than 3 years, the median is close to 4 years for the pom/dara approach, even in patients who are lenalidomide resistant. So, I think there's a lot of variables that make it look like one combination is better than the other. I'm not sure that that pans out. And the same really applies for the ICARIA trial. And this also suffers from the same challenge that I think we see with the APOLLO trial, which is, on average, this was one line later than the carfilzomib combination trials. But these really represent, in the modern era of myeloma therapy, what are the 4 sort of highest top of mind, if you will, options for patients to think about, or for docs and patients to think about, in the context of early relapse, particularly for a patient who's progressing on either lenalidomide alone or potentially lenalidomide plus bortezomib, for the high-risk cohort of patients.” – Sagar Lonial MD, FACP

Minimal Residual Disease (MRD) Status in Multiple Myeloma
Minimal residual disease (MRD) status is an important predictor of survival outcomes in both the newly diagnosed and relapsed/refractory settings of MM and has helped to guide treatment (de-)escalation and duration of maintenance therapy. MRD assessment in MM is an important tool in evaluating depth of remission, understanding disease risk, predicting outcomes, and potentially guiding therapy. In fact, the U.S. Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) very recently supported the use of MRD-negative complete response (CR) as an early endpoint for accelerated drug approval in MM (ODAC, 2024). This is based on a number of different analyses that suggest that MRD negativity is a good surrogate for PFS, as it is associated with prolonged PFS and OS. MRD assessment was incorporated into International Myeloma Working Group (IMWG) uniform response criteria for MM in 2016 after multiple prospective clinical trials established the power of next-generation flow cytometry (NGF) and next-generation sequencing (NGS) as effective techniques to measure depth of remission. The IMWG defines MRD negativity as the absence of clonal plasma cells on bone marrow aspirate with a minimum test sensitivity to detect 1 in 10⁵ nucleated cells (10⁻⁵ threshold; Kumar et al, 2016).

“I think that that is a reasonable endpoint from the perspective of clinical trial endpoints. If I'm talking about curative therapy or what gives us the longest progression-free survival, I'm still personally looking at 10^-6 as the right endpoint there. But again, what they're looking at is MRD testing at fixed timepoints, and the timepoint that they recommended is either 9 months or 12 months after the initiation of therapy, not whenever a patient becomes MRD negative.” – Sagar Lonial MD, FACP

The most common techniques that are used in the assessment of MRD testing are multiparameter flow cytometry (MFC) and NGS (Table 1).

NGF, which can be done in very specialized centers, is used to assess MRD negativity by flow at a level of 10^-6. And then finally, there are attempts to use MALDI-TOF or mass spectrometry to assess for MRD negativity. These techniques are being compared in real time with MRD by NGS, which remains the gold standard, or NGF by flow, which is what most European centers use because they have the expertise to do that on a routine basis.

MRD Criteria and Guidelines
Sagar Lonial MD, FACP: When we talk about the use of MRD testing, certainly in the context of NCCN Guidelines^®, I think looking at MRD testing for patients in the posttransplant period makes a lot of sense, and looking at it at defined periods of time. So, the first benchmark that at least for now I think is important, is that a patient be in complete remission when we do MRD testing. That is part of the IMWG definition of what it means to be MRD negative, that they’re already in complete remission. If not, then technically they're not eligible for an MRD-driven endpoint by the current response criteria. Now, we are reviewing the response criteria in November of this year [2024], and this may change, so hold on to your algorithms, if you will. But at least for now, the current recommendation is that a patient be in complete remission before you do MRD testing. I think given the FDA’s approach to really looking very closely at 9-month and 12-month endpoints, this makes good sense to me. And typically, we look at the 1-year and 2-year timepoint to assess MRD testing and what it can potentially mean for a patient overall.

Section 2: Prior Evidence with BCMA-Directed Therapies Driving Current Guideline Recommendations in First Relapse
Now that we’ve reviewed conventional agents (proteasome inhibitors, anti-CD38 antibodies, and second-generation IMiDs like pomalidomide), let’s focus on targeting BCMA, particularly in the context of CAR T cells (ciltacabtagene autoleucel [cilta-cel] and idecabtagene vicleucel [ide-cel]), as well as potentially using antibody-drug conjugates (belantamab mafodotin) and/or bispecifics. At this time there are no bispecifics approved for early relapse, so we focus here on ide-cel and cilta-cel as well as belantamab mafodotin based on recent trials.

B-cell maturation antigen (BCMA) is highly expressed in malignant plasma cells and is a novel treatment target for MM (Yu et al, 2020). BCMA is an important signaling factor in survival of transformed plasma cells. Its natural ligands in the blood are APRIL and BAFF (Figure 4).

In myeloma, these are responsible for drug resistance, plasma cell proliferation, and particularly for plasma cell binding to the microenvironment. There are a number of trials investigating soluble BCMA in the blood as a surrogate marker for tumor burden, and it appears that high-soluble BCMA is associated with poorer outcomes. But most importantly, BCMA expression is also upregulated as you go from MGUS to smoldering to symptomatic myeloma. So, it represents a highly important target in general.

“There are multiple agents that target BCMA, including bispecific antibodies, bispecific T cell engagers, CAR T-cells, and antibody-drug conjugates, that each work to use BCMA to their optimal advantage and to “teach” myeloma cells that the more you express BCMA, the more we're going to come after you with something that's an important target. “And this is in fact, incredibly important, because BCMA-directed therapy has, I think, really revolutionized myeloma, particularly in the context of triple-class–refractory multiple myeloma, where patients had very few, if any, potential treatment options available at that timepoint.” – Sagar Lonial MD, FACP

The KarMMa-3 study moved CAR T cells for targeting BCMA from late-line therapy (4 or more prior lines of therapy) into earlier-line therapy. This was a randomized, phase 3 trial of ide-cel versus standard therapy in heavily pretreated triple-class–exposed RRMM (Rodríguez-Otero et al, 2023). The standard therapy arms include combinations such as daratumumab, pomalidomide, dexamethasone (DPd); daratumumab, bortezomib, dexamethasone (DVd); ixazomib, lenalidomide, dexamethasone (IRd); carfilzomib, dexamethasone (Kd); or elotuzumab, pomalidomide, dexamethasone (EPd). Randomization was 2:1, and patients were allowed crossover if they progressed on the standard arm. Baseline characteristics were balanced between the two treatment arms, including patients who were daratumuab refractory, 95% (ide-cel) and 93% (standard regimens) in both arms; triple-class refractory, 65% and 67%; and median duration of response to prior therapy, 7.1 months and 6.9 months. Results show a substantial difference in PFS favoring ide-cel at 18 months, with 41% of patients still in remission with ide-cel, compared to only 19% in the standard of care arm (Figure 5).

Median PFS was 13.8 months with ide-cel compared to 4.4 months in the control arm (HR 0.49).

The other CAR T-cell trial that led to the approval of cilta-cel for patients having received one prior line of therapy was the CARTITUDE-4 trial. This randomized phase 3 trial compared cilta-cel versus physician’s choice of pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd) for patients with lenalidomide-refractory MM after 1-3 prior lines of treatment (San-Miguel et al, 2023). Patients at baseline in this trial were not as resistant as in the KarMMa-3 trial since many were enrolled after fewer relapses. However, roughly 25% of patients in both arms were triple-class exposed, 6.7% (cilta-cel) and 4.7% (standard of care) were penta-class refractory, 100% of patients in both arms were lenalidomide refractory, and 14.4% (cilta-cel) and 15.6% (standard of care) were triple-class refractory. The primary endpoint of PFS was not reached in the cilta-cel arm, whereas median PFS was 11.8 months in the standard of care arm (HR 0.26; Figure 6).

The 12-month PFS rate was 76% for the cilta-cel arm, compared to 49% for the standard of care arm. When looking further at MRD or depth of response, the overall response rate was 84.6% versus 67.3% in the standard of care arm, MRD at 10^-5 was 61% in the cilta-cel arm versus only 16% in the standard of care arm, and 12-month duration of response was 84.7% for cilta-cel versus only 63% for the standard of care arm.

CAR-T FDA Approvals
Ciltacabtagene autoleucel [cilta-cel] is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T-cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and who are refractory to lenalidomide (Carvykti prescribing information, 2024).

Idecabtagene vicleucel [ide-cel] is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody (Abecma prescribing information, 2024).

ASCO 2024
Data from the CARTITUDE-4 trial was updated at ASCO this year (2024), with a focus on the high-risk subset of patients who received cilta-cel vs standard of care as second-line therapy (Costa et al, 2024). Median PFS was longer among patients who received cilta-cel vs standard of care, including the subset who had functional high-risk MM. The 12-month PFS rate was 78% for cilta-cel versus 59% for the standard of care arm. When looking at the functional high-risk group, at 1 year 77% of patients are still in remission with cilta-cel versus only 49% in the standard of care arm.

“This certainly does represent, in my mind, a substantial benefit in an unmet medical need, and those are patients with functional high-risk myeloma relapsing within 3 years of diagnosis. And so, by definition, they are in fact high risk. This is part of the story of introducing BCMA into an earlier line of therapy using a CAR T-cells in this context.” – Sagar Lonial MD, FACP

Section 3: Latest Evidence From Clinical Trials Exploring BCMA-Directed ADCs for First Relapse
Belantamab mafodotin is a BCMA-targeted ADC that has previously demonstrated clinical activity in combination with standard-of-care (SOC) therapies in RRMM. The randomized, phase 3 DREAMM-7 trial evaluated belantamab mafodotin + bortezomib + dexamethasone (BVd) vs SOC daratumumab + bortezomib + dexamethasone (DVd) in RRMM with at least 1 prior line of therapy (Figure 7;

Mateos et al, 2024; Hungria et al, 2024). Belantamab mafodotin was dosed at 2.5 mg/kg intravenously every three weeks.

At a median follow-up of 28.2 months, median PFS was 36.6 months in the BVd group compared to 13.4 months in the DVd group, a 59% reduction in the risk of disease progression or death (HR 0.41; Figure 8).

A strong and clinically meaningful overall survival (OS) trend favoring the BVd arm was observed at the interim analysis, with a 43% reduction in the risk of death (HR 0.57), which has not yet reached the interim criteria for statistical significance of OS. OS follow-up continues and further analyses are planned. Overall survival at 18 months was 84% in the BVd group and 73% in the DVd group. There was also better depth of response with belantamab mafodotin, including overall response rate (83% versus 71%), with 35% of the patients in the BVd group achieving a CR or better compared with 17% of the patients in the DVd group. BVd also demonstrated a greater rate of MRD negativity (39% versus 17%) compared with DVd (Table 2).

A CR or better plus MRD-negative status occurred in 25% of the patients in the BVd group versus 10% in the DVd group. The median response duration was 35.6 months in the BVd group and 17.8 months in the DVd group. The belantamab mafodotin combination resulted in clinically meaningful improvements in all secondary efficacy endpoints including a doubling of the CR rate (stringent complete response plus complete response), MRD negativity rate and median duration of response (DOR). So, there is a substantial benefit for a triplet therapy that uses an off-the-shelf ADC targeting BCMA with belantamab mafodotin. When looking at the prespecified subgroup analysis of PFS, even cytogenetic high-risk patients seem to gain benefit from belantamab mafodotin, as well as patients who were refractory to lenalidomide. This is compelling data for treating some of the more challenging patients.

“These results from DREAMM-7 show how belantamab mafodotin in combination with BorDex represents a significant improvement over the daratumumab-based regimen in a second-line multiple myeloma treatment setting. Anti-BCMA therapies are helping to improve outcomes for patients with multiple myeloma, and having an off-the-shelf option, like belantamab mafodotin, that can be administered in a community oncology treatment center where the majority of patients are treated has the potential to transform the way we treat myeloma at or after first relapse.” – María-Victoria Mateos, MD, PhD, Head of Myeloma and Clinical Trials Unit, Haematology Department and Professor of Medicine at the University of Salamanca, Spain (quoted in GSK, 2024)

The randomized, phase 3 DREAMM-8 also evaluated patients in first or second relapse. In this trial, belantamab mafodotin was given in combination with pomalidomide and dexamethasone (BPd) versus bortezomib in combination with pomalidomide and dexamethasone (PVd) in RRMM patients who received ≥1 prior line of therapy, including lenalidomide (Trudel et al, 2024; Figure 9).

In DREAMM-8, the belantamab mafodotin dose was 2.5 mg/kg IV for the first cycle and 1.9 mg/kg IV thereafter, every 4 weeks.

BPd led to a statistically significant and clinically meaningful reduction in risk of disease progression or death vs PVd (HR 0.52; Trudel et al, 2024; Dimopoulos et al, 2024). At 12 months, 71% of patients were still in remission (12-month PFS), compared to 51% for the PVd arm (Figure 10).

The estimated PFS is well over 3 years for belantamab mafodotin in combination with pomalidomide and dexamethasone and median PFS was not yet reached at 21.8 months follow-up versus 12.7 months with the bortezomib combination. A positive OS trend was observed but this was not statistically significant (HR 0.77) at the interim analysis. Similar to the DREAMM-7 trial, there is a benefit for patients with high-risk cytogenetics, for older patients (age >65 years), and for patients who relapse within 12 months of their first line of salvage therapy.

“So these, I think, are really important benchmarks, and suggest that the ADC may have significant activity and potency, particularly in the context of high-risk disease.” – Sagar Lonial MD, FACP

The overall response rate was 77% for BPd versus 72% for PVd. CR or better plus MRD-negative status was achieved in 24% of the patients in the BPd group compared to 5% of those in the PVd group (Table 2).

BPd was associated with greater depth of response, including undetectable measurable residual disease and durability. Undetectable MRD at 10^-5 in patients with a very good partial response or better was 32% in the BPd group versus 5% in the PVd group. Similar to the results seen of the DREAMM-7 trial, in DREAMM-8 the belantamab mafodotin combination also resulted in clinically meaningful improvements consistently across secondary efficacy endpoints, including rate of CR or better (more than twofold improvement), MRD negativity rate (nearly fivefold improvement), and duration of response (median not yet reached with the belantamab mafodotin combination versus 17.5 months with the bortezomib combination).

“The profound progression-free survival benefit seen in DREAMM-8 highlights the potential for belantamab mafodotin, when used with pomalidomide and dexamethasone, to improve outcomes for patients with relapsed/refractory multiple myeloma. This combination may have potential to redefine treatment of multiple myeloma at or after first relapse, a setting where patients may benefit from novel therapies.” – Suzanne Trudel, MD, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada (quoted in GSK, 2024)

DREAMM-7 and DREAMM-8 Trials Summary
The DREAMM-7 and DREAMM-8 phase III trials of belantamab mafodotin combinations both met their primary endpoints showing statistically significant and clinically meaningful improvements in PFS compared to standard of care combinations in RRMM. Additionally, a positive OS trend was observed in both trials, although at the time of interim analysis, this was not statistically significant. Clinically meaningful improvements across all other secondary efficacy endpoints were also reported, including deeper and more durable responses compared to the respective standard of care combinations.

“Taken together with the results of phase III DREAMM-7, these results suggest that belantamab mafodotin combinations can be new standards of care at first relapse or later due to their robust efficacy, manageable safety, and ease of administration.” – Suzanne Trudel, MD, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada (quoted in ASCO Post, 2024) 

Section 4: Approach to Treatment in First Relapse
As we begin to consider differences between these approaches, there are some real-world considerations to take into account when we think about managing patients in early relapse (Figure 11).

When focusing on antibody-drug conjugates versus CAR T cells, there are pros and cons to each. The upside of CAR T is that it can be considered a ‘one-and-done’ therapy, whereas ADCs do require continuous therapy. There's no hospitalization required for ADCs. Particularly for CAR T cells, there is a risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), requiring patients to be closer to a major myeloma treatment center for safety as well as for effective delivery. For belantamab mafodotin, regular visits to an ophthalmologist are needed, but this could become less frequent when less frequent dosing is delivered.

In addition, patients with MM are often elderly, with advanced disease stages, comorbidities, and frailty, which can increase the risk of therapy-related toxicities and limit the number of viable treatment options. When considering treatment options for patients with MM, it is important to consider potential side effects and expected toxicities associated with different therapies, as well as practical aspects such as the availability, costs, and logistical differences of treatment administration. Access to CAR T-cell therapies faces significant barriers, primarily due to high costs and serious adverse effects, such as CRS. In comparison to CAR T-cell therapies, ADCs offer certain advantages, as they are more cost-effective and simpler to manufacture and administer. These characteristics make ADCs a more convenient and potentially safer treatment option for certain patients.

“Belantamab mafodotin is off-the-shelf, easily available, practically speaking, likely dosing every 8 to 12 weeks. We have to see what the FDA label looks like if and when belamaf comes back, but certainly very patient friendly and easy to administer.” – Sagar Lonial MD, FACP

“If these belantamab mafodotin combinations get regulatory approval, they will be very good options for colleagues in the community. There are big chunks of the population in the US that do have access to CAR-T cell therapies or bispecific antibodies, and I think this will be a very good off-the-shelf option for those patients.” – Saad Usmani, MD, MBA, FACP, FASCO

“What I really want to leave you as take-home messages are that ‘early relapse’ really is the new ‘newly diagnosed’ in terms of outcomes for patients with myeloma. The benefit for phase 3 trials of standard agents like PIs, IMiDs, and anti-CD38s may be less in the era of quads, and that really begins to move BCMA-directed therapies earlier and earlier in the paradigm for that very reason. If patients are getting daratumumab up front or they're getting a CD38 as part of maintenance, using CD38 as first salvage likely doesn't make a lot of sense. I agree that transplant does remain a standard of care for induction, so use it less in the context of early relapse. The timing of CAR T-cell early versus late really represents an important discussion to have with patients. And particularly as the bispecifics come earlier and earlier in therapy, these are conversations we're going to have to have with our patients about whether to choose an antibody-drug conjugate, a bispecific, or a CAR T cell as their first shot at BCMA-directed therapy. And these are very challenging and long discussions as there is no right answer, but hopefully we'll have answers to these questions in the near future.” – Sagar Lonial MD, FACP

Section 5: Optimizing the Course of Treatment in First Relapse Via Multidisciplinary Safety Management
Implementing a coordinated and multidisciplinary approach from the time of diagnosis is of utmost importance in effectively addressing the diverse needs of patients with MM. This approach recognizes the significance of collaboration and emphasizes the early integration of different specialties (Sorensen et al, 2022). It is widely recognized that a collaborative effort involving various healthcare disciplines is essential for achieving favorable outcomes in cancer patients with complex needs. The adoption of a multidisciplinary approach in cancer care is now considered essential and is supported by a growing body of evidence and clinical consensus. However, the timely integration of different disciplines poses challenges. Barriers to effective integration include organizational structures, limited resources and funding, and a lack of education and training. Overcoming these barriers is imperative to ensure optimal care for patients with MM and to harness the benefits multidisciplinary care affords. Multidisciplinary teams (MDTs) involved in MM care have the potential to enhance patient outcomes through various strategies (Selby et al, 2019). MDTs should be well-organized and efficient. Timely and accurate information exchange within the team and with patients is crucial. Patients involved in decision-making require comprehensive and well-prepared information, and patient engagement and empowerment within MDTs enhance satisfaction and outcomes. By implementing these strategies, MDTs can continue to advance MM care and improve patient outcomes.

While CAR T-cell therapy has revolutionized the treatment of RRMM, this therapy has certain limitations, such as life-threatening toxicities, including CRS and ICANS (Karmali, 2021). In addition to CRS and ICANS, side effects associated with CAR T-cell therapy include prolonged and recurrent cytopenias with increased risk of infection, secondary hematological malignancies, Parkinsonism, Guillain-Barré syndrome, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). These therapies are only available through restricted programs under a Risk Evaluation and Mitigation Strategy (REMS; Carvykti prescribing information; Abecma prescribing information). Despite the high prevalence of CRS and ICANS associated with CAR T-cell therapies, effective management strategies are available, such as the use of tocilizumab, corticosteroids, and anti-seizure medicines.

The most significant adverse event associated with the ADC belantamab mafodotin is ocular toxicity, resulting in changes in visual acuity as well as itchy, scratchy, or dry eyes. This includes keratopathy, characterized by corneal epithelial changes known as microcyst-like epithelial changes (MECs), as well as reductions in best corrected visual activity (BCVA) and other ocular symptoms such as blurred vision, dry eye, and corneal ulceration (More et al, 2023). Adverse events observed with ADCs like belantamab mafodotin can be attributed to on-target or off-target mechanisms. In the case of ocular events, since the proteins targeted by these agents are typically not expressed in the cornea (such as BCMA), ocular toxicity may represent a specific off-target mechanism. The cytotoxic component of belantamab mafodotin, monomethyl auristatin F (MMAF), is proposed as a causative factor for ocular toxicity, and causes the formation of cysts that can lead to (a largely reversible) loss of visual acuity.

In the DREAMM-7 study patients underwent regular ocular assessments due to belantamab mafodotin’s known toxic effects. Ocular adverse events were more common in the BVd group than in the DVd group (any grade, 79% vs. 29%; grade 3 or 4, 34% vs. 3%). However, ocular side effects were managed with dose modifications, including delays and reductions (Hungria et al, 2024). It was planned that belantamab mafodotin would be given every 3 weeks. However, a majority of patients were ultimately dosed every 12 or every 8 weeks. The efficacy of BVd was maintained even with dose delays and reductions, and most patients who developed worsening visual acuity recovered. The most common grade 3 or 4 ocular adverse events with BVd were blurred vision, dry eyes, and cataracts, whereas cataracts were more common with DVd. In DREAMM-8, ocular events, primarily blurred vision and dry eye, occurred in 89% of the patients who received BPd (grade 3 or 4 in 43%) versus 30% of those who received PVd (grade 3 or 4 in 2%) and were managed with dose modification (Dimopoulous et al, 2024). Ocular events leading to dose interruptions or delays occurred in 83%, and 59% required dose reductions primarily in the form of increasing the dosing interval. Ocular events led to treatment discontinuation in 9% of the patients in the BPd group and in no patients in the PVd group. In the DREAMM trials, ocular side effects were managed with dose delays and/or reductions; however, it may be possible to reduce toxicity and retain the efficacy of belantamab mafodotin. 

“Patients and physicians worry that missed doses may impact progression-free survival. We now have evidence that this is not true. Missed doses may actually result in better safety profiles and maintain the efficacy of the treatment. This is a unique target and payload, and the efficacy may be superior with less toxicity….I would argue that the current dosing schedule of this highly effective regimen is too much. We need to use less, less frequently, and do it in a way that preserves patient function….I think really the key here is going to a different dose and schedule. Every 8 to 12 weeks probably represents the optimal interval for dosing” – Sagar Lonial MD, FACP

“Obviously, the ocular toxicity is an issue. We recognize that. But the good news is that it is reversible and manageable. The great news is the way around it is by using combinations and less frequent dosing.” – Paul Richardson, MD, Harvard Medical School, Clinical director of the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute, Boston, Massachusetts

Surveillance and Management of Ocular Toxicity
To ensure patient safety during treatment, the FDA requested a REMS in response to the ocular adverse events associated with belantamab mafodotin. As part of this strategy, a keratopathy visual acuity (KVA) scale was developed, which assesses ocular toxicity through slit lamp examination and changes in best corrected visual acuity (BCVA) (Leong et al, 2023). Dose interruption is required if patients experience a grade 3 or higher ocular adverse event in either visual acuity or corneal changes, or a grade 2 in both modalities. Once corneal changes or visual acuity recover to grade 1, treatment may be resumed at a lower dose. A baseline eye examination within 3 weeks prior to the first dose of belantamab mafodotin is recommended, with differing follow-up examination recommendations based on regional requirements. In the US, eye examinations are needed before each dose, while in the EU, they are required before the first 3 treatment cycles. Additional eye examinations should be conducted promptly when ocular symptoms worsen, and follow-up examinations can occur at least 1 week after the previous dose and within 2 weeks before the next dose. These regular examinations are advised even during dose delays, whether caused by ocular or non-ocular events, to ensure patient safety and monitoring (Lonial et al, 2021). The guidelines below are recommended for the assessment and management of belamaf-associated ocular events to help mitigate ocular risk and enable patients to continue to experience a clinical benefit with belamaf:

• Close collaboration among hematologist/oncologists and eye care professionals is needed, in part, to provide optimal care in relation to the belamaf benefit-risk profile
• Patients receiving belamaf should undergo eye examinations before and during every treatment cycle and promptly upon worsening of symptoms
• Severity of corneal events should be determined based on corneal examination findings and changes in best corrected visual acuity
• Treatment decisions, including dose modifications, should be based on the most severe finding present

Effective management of belantamab mafodotin-related corneal events necessitates close collaboration and clear communication among hematologist/oncologists, the RRMM patient care team (including oncology nurses, nurse practitioners, physician assistants, and hem/onc pharmacists), and eye care professionals (Figure 12).

Proactive, timely, and appropriate multidisciplinary management of treatment-related toxicities is another core component of ADC treatment optimization. A clear understanding of the toxicity profile associated with ADCs can help address the challenge of managing ADC-associated adverse events in routine clinical practice (Tarantino et al, 2022). A simulation framework integrating efficacy, ocular safety, and pharmacokinetic data predicted that modifying certain parameters of belantamab mafodotin treatment, such as lower doses, longer intervals between doses, or implementing a different dose-modification algorithm, could potentially enhance the benefit-to-risk profile compared to the currently approved regimen (Collins et al, 2023). This simulation framework offers insights into potential strategies for optimizing the use of belantamab mafodotin in clinical practice.

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