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At the 2021 American Society of Hematology (ASH) Annual Meeting, new clinical trial data in multiple myeloma (MM) were reported, including studies on triplet vs quadruplet therapy and BCMA-targeted therapy for newly diagnosed disease, updated data on novel maintenance approaches after autologous stem cell transplants (ASCT), and novel treatment approaches for patients with relapsed/refractory (R/R) MM.
In this module, Shaji K. Kumar, MD, and Sagar Lonial, MD, review and discuss the clinical implications of key studies in MM that were presented at the annual American Society of Hematology meeting.
Please note that the slide thumbnails in this activity link to brief PowerPoint slidesets that can also be found here, each focused on the specific study or topic of interest. These slidesets also may be downloaded by clicking on any of the thumbnails within the activity.
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Before continuing with this educational activity, please take a moment to answer the following questions.
Shaji Kumar, MD:
The treatment of newly diagnosed MM continues to evolve with the introduction of new therapies. There have been several trials looking at the role of 4‑drug combinations as initial therapy in this setting. For example, GRIFFIN explored the addition of daratumumab to VRd,1,2 and CASSIOPEIA added daratumumab to bortezomib, thalidomide, and dexamethasone (VTd).3,4 Both trials demonstrated improvements in depth of response and PFS. Isatuximab is another CD38-targeted monoclonal antibody that is being investigated in combination with VRd in the GMMG-HD7 study and in combination with carfilzomib, lenalidomide, and dexamethasone in the GMMG-CONCEPT trial.5,6
Shaji Kumar, MD:
The randomized phase III GMMG-HD7 trial enrolled 662 patients who were eligible for high-dose chemotherapy and autologous stem cell transplant (ASCT).5 Patients were randomized to either VRd alone or VRd with isatuximab. Induction treatment was administered for three 6‑week cycles followed by a single ASCT. Afterward, patients were randomized a second time to receive either lenalidomide maintenance or isatuximab with lenalidomide maintenance for up to 3 years.
The primary endpoint for the study was measurable residual disease (MRD) negativity at the end of induction therapy. The secondary endpoints were safety and depth of response with CR, as well as MRD negativity at selected times during the study.
Shaji Kumar, MD:
Patients in both treatment arms were very similar in their underlying disease characteristics (including WHO performance status, renal impairment lactate dehydrogenase level, and International Staging System [ISS] stage) and particularly regarding the high‑risk cytogenetics and the Revised-ISS (R‑ISS) stages.
Shaji Kumar, MD:
The rate of MRD negativity by next-generation flow cytometry (10-5) was significantly better for patients who received VRd with isatuximab (50.1%) compared with those who received VRd alone (35.6%), with an odds ratio (OR) of 1.83 (95% CI: 1.34-2.51) and P value <.001. An analysis of the depth of response showed a statistically significant improvement in the proportion of patients achieving VGPR or better with the addition of isatuximab to VRd vs VRd alone (77.3% vs 60.5%, P <.001) and with partial response or better (90% vs 83.6%, P = .02).
Shaji Kumar, MD:
The improvement in the rate of MRD negativity with the addition of isatuximab was seen in all subgroups in this study. However, less benefit was seen in patients with R‑ISS stage III disease, perhaps due to the small number of patients (n = 54) randomized to the 2 arms.
Shaji Kumar, MD:
The rate and severity of AEs and the discontinuation rates in both arms were similar to each other and to what we have seen with the other 4‑drug combinations involving anti‑CD38 monoclonal antibodies. Grade ≥3 AEs were reported in 64% of patients who received isatuximab plus VRd and in 61% with VRd arm. Rates of serious AEs (any grade) were also similar with isatuximab plus VRd at 34.8%, and with VRd at 36.3%.
Infections were seen in 13% of patients who received isatuximab plus VRd and in 10% of patients who received VRd. Cytopenias were along the lines of what were expected, with 26% of patients who received isatuximab plus VRd reporting leukocytopenia/neutropenia vs 9% of patients who received VRd.
Shaji Kumar, MD:
The ability to tolerate and maintain dose intensity was similar in both arms, with the median relative dose intensity for the 4-drug regimen reported at 98% to 100% vs 97% to 100% with VRd. Few patients discontinued therapy with isatuximab (1.8%), and similar rates of patients discontinued lenalidomide (30.9% vs 29.9%), bortezomib (27.0% vs 29.6%), and dexamethasone (15.5% vs 14.3%).
Shaji Kumar, MD:
So, the GMMG-HD7 trial clearly showed that adding isatuximab to standard VRd induction therapy resulted in deep responses, confirming that addition of a CD38 antibody to VRd could be considered for patients with newly diagnosed MM.
The MRD negativity rates from this trial should not be compared with 4‑drug regimens from other trials because of differences in study design and patient populations; however, it is clear that isatuximab and VRd are an effective combination. We also need to wait for longer‑term results, particularly for the OS and PFS data, as we are starting to see with other phase III trials.
I think the field remains split on whether everybody needs a 4‑drug regimen as initial therapy or whether we can use the 4‑drug combination based on the disease characteristics of patients (eg, high‑risk disease, failure to experience deep responses, and other factors that evolve during therapy). In our clinic, we consider 4-drug regimens selectively for patients with high-risk disease characteristics.
Sagar Lonial, MD:
In our clinic, we do the opposite: We often use daratumumab plus VRd in standard risk patients, and we use carfilzomib, lenalidomide, and dexamethasone (KRd) in high-risk patients.
Overall, GMMG-HD7 is an interesting study. In many ways, it is the isatuximab version of the GRIFFIN study with daratumumab,2 but with a larger number of patients. At ASH 2021, people were comparing the depth of response at the end of induction in the GMMG-HD7 study to either the CASSIOPEIA4 or GRIFFIN trials, but as Dr. Kumar mentioned, we must recognize that there are subtle differences in trial design and patient population among these trials. So, comparing these 3 trials side by side may misrepresent some of the absolute benefit of isatuximab.
I agree that we need longer follow-up to truly understand the PFS and OS data for GMMG-HD7. As we saw from GRIFFIN, the median PFS likely will belong with both isatuximab plus VRd and VRd alone.2 Expecting a difference in the 2‑year rate of PFS is probably not reasonable, given the success of the VRd/ASCT/maintenance regimen.
Shaji Kumar, MD:
It is also important to note that in this study, the MRD negativity data were based on assessment of bone marrow at a sensitivity of 10-5 at the end of induction. These MRD negativity rates are lower at this point in the course of therapy, and as more patients achieve a CR with additional therapy, the rates of MRD negativity may increase. This can make it even harder to compare the true rate of MRD negativity early on.
Sagar Lonial, MD:
I agree, but at the end of induction, there was clearly a difference in depth of response between the patients who received VRd alone or VRd plus isatuximab. I think that is an important corroboration of existing data, suggesting that the addition of an anti-CD38 antibody to VRd can be a reasonable approach for patients with newly diagnosed MM.
Sagar Lonial, MD:
The next study to discuss is DREAMM‑9. It is a randomized phase I study evaluating the dose and scheduling of belantamab mafodotin combined with VRd in transplant-ineligible, newly diagnosed patients with MM (N = 144).7
At ASH 2021, investigators reported early results from 5 of the 8 cohorts representing different dosing schedules. Doses of belantamab mafodotin were 1.0 mg/kg (cohort 4), 1.4 mg/kg (cohorts 2 and 5), and 1.9 mg/kg (cohorts 1 and 3). In cohorts 1, 4, and 5, patients received belantamab mafodotin with VRd on the first day of every 21-day cycle for 8 cycles, followed by belantamab mafodotin being administered with lenalidomide and dexamethasone (Rd) every first day of 28-day cycles from cycle 9 and beyond (Q3/4W). Patients in cohorts 2 and 3 received that combination on the first day of every other 21-day cycle for 8 cycles, followed by belantamab mafodotin being administered with Rd every other cycle for 28-day cycles from cycle 9 and beyond (Q6/8W).
The goal here was to effectively combine belantamab mafodotin with the existing VRd backbone in the upfront setting. This strategy of building on the current standard of care in the first-line setting has been used in various ongoing studies, including the DREAMM-9 trial, and I think we will see it again moving forward.
The primary endpoint of this study was to safely deliver this combination by monitoring AEs and serious AEs and to find the optimal dosing schedule. The secondary endpoints were relative dose intensity and cumulative dose after 4 cycles. I think that a better understanding of the optimal dose and timing of belantamab mafodotin administration may help mitigate ocular toxicity, including corneal events, that are associated with this agent and may reduce the patient’s dependence on an ophthalmologist.
Sagar Lonial, MD:
Cohort 1 enrolled 12 patients, and the remaining 4 cohorts included in this analysis enrolled 6 patients each. The median age ranged from 72.5-74.5 years, and baseline characteristics were relatively balanced in terms of race, ISS disease stage, and other risk factors.
Sagar Lonial, MD:
When you look at safety, the dose and schedule of belantamab mafodotin administration can make a difference. The 1.9 mg/kg Q3/4W dose had the highest incidence of grade 3/4 AEs. But at lower dose levels or with less frequent administration, the rate of these AEs began to drop. This is similar to the ALGONQUIN study that looked at alternative doses and schedules of belantamab mafodotin in combination with pomalidomide and dexamethasone.8
All patients in the DREAMM-9 cohorts who received the 1.9 mg/kg Q3/4W dose experienced dose reduction and delay; however, the alternative dose cohorts showed less need for dose reduction and delay. I think although we will not be able to combine belantamab mafodotin with backbone therapies at the regular dose and schedule, I do think the ability to change dosing schedules will result in a more tolerable regimen while maintaining efficacy.
Sagar Lonial, MD:
Corneal events reported in in this study underscore the potential impact of belantamab mafodotin dose and intensity on ocular toxicity. The median time to onset of grade ≥3 corneal events and the rate of grade ≥3 corneal events varied with the dose of belantamab mafodotin used.
Belantamab mafodotin given with Q6/8W dosing resulted in a lower rate of grade ≥3 corneal events (33%-50% with 1.4 mg/kg and 1.9 mg/kg vs 67%-83% with Q3/4W dosing) and a longer time to onset of grade ≥3 corneal events (median 126 days with 1.4 mg/kg and 103 days with 1.9 mg/kg vs 57.5-81.0 days with Q3/4W dosing).
There is also a distinction in the rate of decline of 3 or more lines in best corrected visual acuity (BCVA) based on dosing and administration. With the 1.9 mg/kg Q3/4W cohort, 5 patients (42%) had a decline of 3 or more lines in BCVA in their best seeing eye, but no patients in the 1.9 mg/kg Q6/8W cohort had a decline of ≥3 lines in BCVA, and only 1 patient (17%) in each of the other cohorts had a decline of ≥3 lines in BCVA.
The currently approved dose for belantamab mafodotin is 2.5 mg/kg once every 3 weeks, so this study may also teach us important lessons on how to dose belantamab mafodotin as a single agent, but in this combination approach, it suggests that alternative dosing and administration frequency may allow for combination therapy with belantamab mafodotin.
Sagar Lonial, MD:
The overall response rate (ORR) with the combination of belantamab mafodotin plus VRd in the DREAMM-9 study was quite high, ranging from 83% in cohorts 2 and 4 to 100% in cohorts 1, 3, and 5. These efficacy results are not a surprise, given the effectiveness of VRd in first-line therapy and belantamab mafodotin as a single agent in the R/R setting. Although the numbers are small, the efficacy and safety results of cohort 3 (1.9 mg/kg Q6/8W) were promising, with a relatively high proportion of CR (17%) and VGPR (33%), and none of its patients had a decline ≥3 lines of BCVA.
Sagar Lonial, MD:
Additional analyses evaluated the effect of soluble BCMA (sBCMA) on the pharmacokinetics in this study.7 These data suggest that belantamab mafodotin binds sBCMA and may reduce the circulating or free levels of belantamab mafodotin available. However, highly effective therapies, where the tumor burden drops precipitously, can leave more belantamab mafodotin not bound to sBCMA, resulting in a higher effective drug concentration over time.
The pharmacokinetic profile of belantamab mafodotin in DREAMM-9 was similar to that previously demonstrated in studies of patients with R/R MM.7,9,10 Assessing how sBCMA may affect the bioavailability of belantamab mafodotin over time is going to be key.
Sagar Lonial, MD:
The DREAMM-9 study showed the feasibility of combining belantamab mafodotin with VRd to improve its efficacy, but determining optimal dosing schedules will be critical.
In this phase I study (part 1 of the overall DREAMM-9 trial), the 1.9 mg/kg Q3/4W or Q6/8W regimens likely will go on to be tested in a phase II or phase III setting with belantamab mafodotin plus VRd vs VRd alone.
Shaji Kumar, MD:
As Dr. Lonial mentioned, it is important to assess these new therapies in the frontline setting to determine what will be the optimal combination of therapies to give us the best long‑term outcomes for patients with newly diagnosed MM.
There are 2 takeaway messages for me from these data. First, belantamab mafodotin can be combined safely with VRd and should be explored further as a part of a 4-drug combination approach for newly diagnosed MM. The question now becomes: Will belantamab mafodotin be best suited as either competition for or an addition to current 4-drug regimens with anti‑CD38 monoclonal antibodies. These findings show the compatibility of belantamab mafodotin with VRd, but can belantamab mafodotin also be combined with DRd in the newly diagnosed setting?
The second takeaway is the difficulty in measuring the efficacy contribution of belantamab mafodotin (especially at the lower doses) in this combination because VRd itself yields an ORR of 80% to 90% in patients with newly diagnosed MM.11 Demonstrating the added value in a randomized trial will be key in moving belantamab mafodotin combinations forward because higher doses show the same toxicity issues that were seen in the relapse setting.
Sagar Lonial, MD:
I agree. One final question that these results raise is whether we need to employ continuous therapy for highly effective 4-drug regimens or whether we can move toward a fixed-duration therapy. The idea of continuous therapy because “we can” vs using a fixed duration of therapy for patients to allow for a prolonged treatment break may be something we now can explore, and these quadruplet‑based regimens may be ways to get to that question.
Shaji Kumar, MD:
This open-label, phase I/II dose-finding and dose-expansion study for newly diagnosed patients who are ASCT-ineligible continues along the same lines as the previous study we discussed. This study explored various combinations of belantamab mafodotin with lenalidomide and dexamethasone (Rd) for patients with newly diagnosed MM who were not eligible for ASCT (N = 18).12
Patients were equally divided into 3 cohorts to receive standard Rd treatment plus belantamab mafodotin in 1 of the 3 following doses: 2.5 mg/kg, 1.9 mg/kg, or 1.4 mg/kg every 8 weeks. The a priori choice of 8-week cycles, rather than shorter ones, suggests that this combination is likely to be explored in older patient populations where safety is paramount and tolerance of AEs is probably lower than in the transplant‑eligible patient population.
Shaji Kumar, MD:
The median age of the 18 enrolled patients was 72 years (range: 65-82), and 55.6% were male. Lytic bone lesions were present in 66.7% of patients. Most patients had Eastern Cooperative Oncology Group performance status of ≤1 and R-ISS stage ≤II. This study is in the early stages, and only 6 patients in each cohort were included in this analysis, but the overall distribution of the baseline demographic characteristics is fairly similar.
Shaji Kumar, MD:
Patients completed a median of 4 cycles (range: 2-5) of therapy, and the belantamab mafodotin and Rd combination seemed to be tolerated well. Treatment-emergent AEs (TEAEs) were reported in almost 89% of patients, and 16% (n = 3) experienced dose-limiting toxicity with the most common symptoms being fatigue and rash. Only 1 patient experienced a serious TEAE of grade 5 pneumonia that was considered unrelated to study treatment.
Shaji Kumar, MD:
The baseline ocular characteristics of this small population were well balanced, and the frequency of ocular AEs was within the expected range. In terms of ocular toxicity, as we go up on the dose, especially the 2.5-mg/kg dose, you see more grade 1 and grade 2 toxicities, including keratopathy. In patients treated at the lower dose levels (1.4 mg/kg and 1.9 mg/kg), there was not much of a noteworthy signal of eye toxicity.
Shaji Kumar, MD:
In the transplant‑ineligible patient population belantamab mafodotin can be safely combined with Rd with toxicity being tolerable, especially in the lower-dose combinations. Asthis drug continues through its clinical trials, we must consider where and how to use belantamab mafodotin. If it will be used as a part of combination therapy with other effective agents in the first-line setting, it will be important to find the optimal dose to be effective while reducing the risk of toxicity. Lower doses and/or less frequent administration of belantamab mafodotin may allow for maximum benefit without compromising safety in the upfront setting.
Sagar Lonial, MD:
This study is proof of principle that, like daratumumab, you can use belantamab mafodotin upfront as a combination partner with standard MM therapy. But, as Dr. Kumar mentioned, we need to find that right dose and schedule that adds benefit without high risk of ocular AEs and loss of visual acuity, which in older and frailer patients can be particularly important.
Over the last year, we have administered belantamab mafodotin to a growing number of patients who are not on clinical trials. Although guidelines for this drug are straightforward, there is a lot of room for interpretation. I have found that some patients who have received 5 or 6 prior lines of therapy already have some corneal dysfunction from age-related cataracts or from previous steroid therapy or other problems. Even in the absence of microcysts associated with belantamab mafodotin, visual acuity can be a problem. It is hard to know if vision issues are related to the MM drugs or to other conditions and their treatments. Vision is very malleable and may not be as reproducible a measure as we think. I encourage clinicians to discuss eye health with their patients' ophthalmologists to understand potential drug interactions and work to create a care plan for each patient.
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