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Shaji Kumar, MD:
In addition to its utility in the first-line setting, daratumumab is approved by the FDA as a single agent and in various combinations with other standard treatments for R/R.[10] In the R/R setting, daratumumab is FDA approved in combination with Vd after ≥ 1 previous therapy; with carfilzomib plus dexamethasone (Kd) after 1-3 previous lines of therapy; with pomalidomide plus dexamethasone (Pd) after ≥ 2 previous lines of therapy, including lenalidomide and a PI; as a single agent for R/R MM after ≥ 3 previous lines of therapy, including a PI and an immunomodulatory drug (IMiD), or if double refractory to a PI and IMiD; and as a single agent after ≥ 3 previous lines of therapy, including a PI and an IMiD, or if double refractory to a PI and IMiD.[10]
In the phase III COLUMBA trial, comparable efficacy and pharmacokinetics were demonstrated for daratumumab administered through SC vs IV dosing in R/R MM, with fewer infusion-related reactions and shorter administration time with SC dosing.[22] Daratumumab SC is FDA approved in combination with bortezomib, melphalan, and prednisone or Rd for newly diagnosed, ASCT-ineligible MM, in combination with Rd or Vd for R/R MM after ≥ 1 previous line of therapy, and as a single agent for R/R MM after ≥ 3 previous lines of therapy.[23]
The phase III APOLLO trial explored the efficacy and safety of daratumumab SC in combination with Pd in patients with R/R MM.
Shaji Kumar, MD:
The APOLLO study was a randomized phase III trial to evaluate whether the addition of daratumumab to Pd (D-Pd) would improve PFS in patients who had received ≥ 1 previous line of therapy with both lenalidomide and a PI.[24,25] The 304 enrolled patients had R/R MM, creatinine clearance ≥ 30 mL/min, and an ECOG PS of 0-2. Stratification was based on the number of lines of previous therapy (1 vs 2-3 vs ≥ 4) and ISS disease stage (I vs II vs III). Patients were randomized to receive combination D-Pd (n = 151) or Pd alone (n = 153) in 28-day cycles.
Before a protocol amendment, patients received 16 mg/kg of IV daratumumab. Patients who initially received IV dosing switched to SC dosing on Day 1 of any cycle 3+. When administered SC, daratumumab was given at 180 mg weekly in cycles 1-2, every 2 weeks in cycles 3-6, and every 4 weeks in cycles ≥ 7. Pomalidomide was given at 4 mg PO on Days 1-21+. Dexamethasone was given at 40 mg PO on Days 1, 8, 15, and 22 of each cycle (patients 75 years of age or older instead received 20 mg of dexamethasone weekly). Patients continued treatment until disease progression or unacceptable toxicity. Every 4 weeks, there was a follow-up assessment for patients who discontinued treatment, as well as a survival follow-up 12 weeks after disease progression or the start of subsequent therapy.
The primary endpoint was PFS, with secondary endpoints of response, time to response, DoR, MRD negativity, OS, and safety.
Shaji Kumar, MD:
The baseline characteristics of the patients were fairly balanced. The median age was approximately 67 years, with nearly 20% of patients 75 years of age or older. An ECOG PS of 0/1 was most common in both groups. An ISS disease stage of I was most common (45% in both groups), followed by stage II (33%) and III (22%). Patients had a median of 2 previous lines of therapy. Of importance, approximately 80% of patients in both groups were refractory to lenalidomide, 50% were refractory to PIs, and 42% were refractory to both lenalidomide and PIs. In addition, 80% of patients were refractory to their last therapy.
Shaji Kumar, MD:
Patients receiving D-Pd had a significantly improved PFS compared with patients receiving Pd, with a 12‑month PFS of 52% for D-Pd and 35% for Pd (HR: 0.63; 95% CI: 0.47-0.85; P = .0018). The median PFS with D-Pd was 12.4 months vs 6.9 months with Pd. Among patients who were refractory to lenalidomide, median PFS was 9.9 months with D-Pd vs 6.5 months with Pd.
Shaji Kumar, MD:
The response rate was improved in favor of D-Pd, with an ORR of 69% vs 46% for Pd alone (OR: 2.68; 95% CI: 1.65-4.35; P < .0001). In addition, 24% of patients receiving D-Pd had ≥ CR compared with 4% of patients receiving Pd. VGPR also was significantly higher in patients receiving D-Pd (50% vs 20% for Pd). Even though these patients had relapsed disease, there was still a significant improvement in MRD negativity among patients receiving D-Pd—approximately 9% achieved MRD negativity vs 2% of patients receiving Pd (P = .0102).
Shaji Kumar, MD:
The addition of daratumumab to Pd was well‑tolerated, as was seen in other clinical trials with daratumumab combinations. A significant number of patients developed hematological AEs, but this was not surprising based on previous data for combination daratumumab and pomalidomide, as well as the similar monoclonal antibody isatuximab and pomalidomide.
Neutropenia was the most common hematologic AE, affecting 70% of patients receiving D-Pd vs 53% of patients receiving Pd alone. Neutropenia was grade 3/4 in 68% of patients in the D-Pd arm vs 51% of patients in the Pd arm. The infection rate was slightly higher in the D-Pd arm vs the Pd arm (70% vs 55%), and the most common serious TEAEs with D-Pd vs Pd were pneumonia (15% vs 8%) and lower respiratory tract infections (12% vs 9%).
Overall, the injections were well‑tolerated, with a small number of patients getting grade 1/2 infusion‑related reactions (5% of the D-Pd group) and local injection site reactions with SC daratumumab (2% of the D-Pd group).
The rate of TEAEs leading to death was 7% in both arms, and the rate of discontinuation due to TEAEs also was comparable (2% for D-Pd vs 3% for Pd).
Shaji Kumar, MD:
The phase III APOLLO study met its primary endpoint of significantly improved PFS with D-Pd vs Pd in patients with R/R MM, and D-Pd was associated with a 37% reduction in the risk of progression or death vs Pd. D-Pd also induced significantly deeper responses and a greater rate of MRD negativity. In the subgroup of patients refractory to lenalidomide, D-Pd prolonged the median PFS from 6.6 months to 9.9 months. No new safety signals were observed in this study, and the investigators concluded that D-Pd represents an efficacious treatment option with short administration time for patients with R/R MM previously treated with lenalidomide and PI.
The data from the APOLLO trial should be put in the context of other 3‑drug combinations that have been studied in patients with 1-3 previous lines of therapy. Because the majority of patients who relapse after first‑line therapy are refractory or significantly exposed to lenalidomide, an important question is which regimen to start these patients on. Should we treat them with the pomalidomide and monoclonal antibody–based combination, or should we be using a PI with a monoclonal antibody–based combination? We now have several phase III trials that can help guide our selection of therapy.
Sagar Lonial, MD:
I do not think any of us were really surprised by the results of this trial. The challenge with these kinds of trials is—as you discussed, Dr. Kumar—whether daratumumab is the backbone for first relapse and whether to partner it with a PI or an IMiD, especially in the lenalidomide‑resistant patient population.
This comes up often in routine clinical practice: do you consider a patient progressing on lenalidomide maintenance to be lenalidomide resistant? In my mind, the answer is yes, so I would consider treatment with either a newer IMiD or a PI in combination with an anti-CD38 antibody, but there are certainly arguments on both sides about the best partner for daratumumab or isatuximab. Unfortunately, I do not think this trial gave us data on what to do in the first-relapse setting, whereas we have PI trials that do.
Data from the phase II MM-014 trial assessed the use of D-Pd in lenalidomide-exposed patients with R/R MM after only 1-2 previous lines of therapy and found that the PFS was longer with D-Pd (1-year PFS rate of 71%).[26] Our institution’s experience also is that, at first relapse, the median PFS with D-Pd is longer vs waiting to use D-Pd in later lines of therapy. These data do give us reason to feel comfortable using D-Pd in the first-relapse setting.
Sagar Lonial, MD:
Exportin 1 is a vital nuclear exporter of tumor suppressor proteins (eg, p53) and eIF4E-bound oncoprotein mRNAs (eg, c-Myc, Bcl-xL).[27-30] Exportin 1 is overexpressed in MM, and high levels correlate with poor prognosis and treatment resistance. Selinexor (S) is a first-in-class, oral, selective inhibitor of exportin 1 that restores activity of tumor suppressor proteins, reactivates glucocorticoid receptor signaling, and inhibits oncogenic signaling pathways.[31]
Selinexor initially received accelerated FDA approval in combination with dexamethasone for R/R MM after ≥ 4 previous lines of treatment and being refractory to ≥ 2 PIs, ≥ 3 IMiDs, and an anti-CD38 antibody.[32] Since the first approval, selinexor has been studied in various combinations and is now also FDA approved in combination with Vd after ≥ 1 previous therapy based on the BOSTON trial. In the STOMP trial, efficacy and safety of selinexor plus various backbone combinations was explored.
Sagar Lonial, MD:
The STOMP study is an ongoing open-label, multi‑arm, dose-escalation, dose-expansion phase Ib/II study in patients with R/R MM.[33-35] At ASH 2020, the safety and efficacy of all-oral selinexor plus Pd (SPd) were presented for patients with R/R MM who had ≥ 2 previous therapies. In total, 65 patients were evaluated, including 20 who are on the recommended phase II dose (RP2D).
Key eligibility criteria were absolute neutrophil count ≥ 1000/mm3, hemoglobin ≥ 8.0 g/dL, platelet count ≥ 75,000 mm3, disease progression or refractory to previous treatment, and ≥ 2 previous cycles of lenalidomide and PI (in combination or separately). In this analysis, SPd was examined with a number of different dosing schedules. The first group received once-weekly dosing of selinexor and dexamethasone and pomalidomide on Days 1-21 of each cycle. The second group received twice-weekly dosing of selinexor and dexamethasone and pomalidomide on Days 1-21 of each cycle. Primary endpoints were maximum tolerated dose, RP2D, and ORR. Secondary endpoints were PFS and safety.
Sagar Lonial, MD:
In this analysis, patients received a median of 3-4 previous lines of therapy. This was less treatment exposed than the population enrolled in the STORM study, which led to the initial FDA approval for selinexor.
Sagar Lonial, MD:
Based on dose-limiting toxicities, 60 mg of selinexor weekly with 4 mg of pomalidomide daily on Days 1-21 was chosen as the RP2D and is being used in the expansion cohort.
Sagar Lonial, MD:
Many of the treatment-related AE (TRAE) issues observed with twice-weekly dosing of selinexor during the STORM study were reduced by switching to once-weekly administration, which is now commonly used in clinical practice. In the STOMP trial, rates of grade 3/4 thrombocytopenia, nausea, diarrhea, fatigue, and weight loss are considerably lower than those seen with once-weekly dosing.
Sagar Lonial, MD:
The ORR with SPd was 54.3% among pomalidomide‑naive/nonrefractory patients, with 10 patients achieving ≥ VGPR, and 35.7% among pomalidomide‑refractory patients, with 1 patient achieving ≥ VGPR. At the RP2D, 12 patients (60%) also achieved an ORR. The clinical benefit rate was approximately 70% across patient cohorts.
The waterfall plot also suggested that significant numbers of patients benefited from this therapy.
Sagar Lonial, MD:
The median PFS with SPd was 12.2 months in all patients and 12.3 months in pomalidomide−naïve or nonrefractory patients—significantly better than expected with selinexor or pomalidomide alone. These data suggest a potential synergy between the 2 drugs.
The median DoR was 11.3 months for all patients and was not yet reached for patients dosed at the RP2D. To me, DoR represents an amalgamated safety and efficacy endpoint, and a DoR of 11.3 months—as observed here—demonstrates that SPd with once-weekly dosing can result in effective responses and increase median PFS with a safer AE profile than single-agent selinexor at twice-weekly dosing.
These data represent an important step forward for selinexor and a nice combination therapy, as well.
Sagar Lonial, MD:
In the phase Ib/II STOMP trial, selinexor was safely combined with Pd in patients with R/R MM after ≥ 2 previous therapies. The RP2D is selinexor at 60 mg once weekly, pomalidomide at 4 mg every day, and dexamethasone at 40 mg once weekly. The most common TRAEs are neutropenia, anemia, thrombocytopenia, nausea, and fatigue. These AEs were expected and manageable with supportive care and/or dose modification. The all-oral SPd regimen is highly active, with durable responses at the RP2D, an ORR of 60% (≥ VGPR 30%), a clinical benefit rate of 75%, and median PFS not yet reached. This compares favorably with the expected ORR ≤ 30% with Pd alone based on historical data. The data support the planned phase III XPORT-MM-031 trial of SPd vs Pd in patients previously treated with a PI, IMiD, and anti-CD38 monoclonal antibody.
Sagar Lonial, MD:
BCMA is a cell-membrane receptor expressed on malignant plasma cells that is essential for their proliferation and survival.[36] Belantamab mafodotin is a first-in-class antibody–drug conjugate targeting BCMA that eliminates MM cells by a multimodal mechanism of action.[36,37]
Belantamab mafodotin was approved in August 2020 by the FDA and EMA for treating patients with R/R MM who have received ≥ 4 previous therapies, including an anti-CD38 monoclonal antibody, a PI, and an IMiD.[38] Approval was based on results from the pivotal phase II DREAMM-2 study showing that belantamab mafodotin yielded deep and durable responses in patients with R/R MM.[39,40]
Shaji Kumar, MD:
DREAMM‑2 is an ongoing, open-label, randomized phase II trial comparing 2 dosing strategies for belantamab mafodotin (2.5 mg/kg or 3.4 mg/kg).[39] Enrolled patients (N = 196) had R/R MM after ≥ 3 previous lines of therapy and were refractory or intolerant to IMiDs, PIs, and CD38 antibodies. Patient stratification was based on high-risk cytogenetic features and previous lines of therapy (≤ 4 vs > 4). Patients were randomized to receive 2.5 mg/kg (n = 97) or 3.4 mg/kg (n = 99) of belantamab mafodotin IV every 3 weeks until progressive disease or unacceptable toxicity. Of note, patients were monitored for ocular toxicity by undergoing ocular exams at baseline and before each treatment cycle. The primary endpoint of DREAMM-2 was ORR, with key secondary endpoints of DoR, clinical benefit rate, PFS, OS, time to best response, time to response, and safety.
Shaji Kumar, MD:
Patients were divided into those who received 3-6 previous lines of therapy and those who received ≥ 7 previous lines of therapy, with approximately 50% of patients in each cohort. Baseline characteristics between cohorts were similar, and all patients were refractory to lenalidomide, daratumumab, and ≥ 1 PI.
Shaji Kumar, MD:
Patients who underwent 3-6 previous lines of therapy had an ORR of 34% (97.5% CI: 19.3-51.4). Even the more heavily treated patients (≥ 7 previous lines of therapy) benefitted, with an ORR of 30% (97.5% CI: 16.5-46.6). Of note, 4% of patients with 3-6 previous lines of therapy and 10% of patients with ≥ 7 previous lines of therapy achieved ≥ CR.
Although the median PFS was low at 2.8 months, the median DoR for all evaluated patients was 11.0 months. Among patients who responded, the probability of a DoR ≥ 6 months was 63% for patients with 3-6 previous lines of therapy (95% CI: 31-83) and 73% for patients with ≥ 7 previous lines of therapy (95% CI: 44-89).
Median OS was 13.7 months (97.5% CI: 9.1-NR) for patients with 3-6 previous lines of therapy and 13.4 months (97.5% CI: 8.7-NR) for patients with ≥ 7 previous lines of therapy.
Shaji Kumar, MD:
Nearly all patients experienced ≥ 1 AE. AEs led to dose reduction in 35% of patients and dose interruption or delay in 54% of patients. Permanent discontinuation occurred in only 9% of patients, and TRAEs leading to permanent discontinuation affected only 7%.
Serious AEs occurred in 42% of all patients, with fatal AEs occurring in approximately 3% of patients in both groups. Serious TRAEs occurred in 12% of patients and led to the death of 1 patient.
Shaji Kumar, MD:
The most common AE was ocular toxicity, which has been observed in other belantamab mafodotin trials. Keratopathy affected 71% of all patients, with 29% experiencing grade 3/4 events. This was similar regardless of the number of previous lines of therapy.
Grade 3/4 hematologic toxicity was slightly more common in the subgroup with more previous treatments. Grade 3/4 thrombocytopenia occurred in approximately 20% of all patients and lymphocytopenia in approximately 12%. These findings are consistent with what we have observed across the entire study.
Shaji Kumar, MD:
Corneal events are a known AE with belantamab mafodotin, and patients who receive this agent should be monitored closely with ocular exams. In this analysis, 30 patients (60% to 65%) in each group had corneal exam findings, with a median time to first occurrence of approximately 38 days. In total, 53% of patients in the 3-6 previous lines of therapy subgroup and 43% of patients in the ≥ 7 previous lines of therapy subgroup had resolution of their last ocular event. Approximately 10% of patients are still undergoing follow-up without resolution, and follow-up has ended for 20% to 30% of patients who did not have resolution of their last ocular event.
Shaji Kumar, MD:
Additional analyses were done to determine the relationship between exposure and response for corneal events.[42] The probability of grade ≥ 2/3 corneal events increased with higher belantamab mafodotin exposure, and the time to initial grade ≥ 3 corneal events decreased with higher belantamab mafodotin exposure.
The likelihood of corneal events also increased for patients with a history of dry eye. Corneal events will have to be carefully managed in patients receiving belantamab mafodotin alone or in combination. Under the current risk evaluation and mitigation strategies (REMS) program, patients must receive an eye exam at baseline and before each dose of belantamab mafodotin. It is important to note that ocular symptoms gradually improved over time in the majority of patients. Although ocular events led to a dose delay in some patients, many patients who were responding to therapy were able to maintain their response despite the delay.
Shaji Kumar, MD:
In the phase II DREAMM-2 trial, 2.5 mg/kg of belantamab mafodotin every 3 weeks led to deep and durable responses with a manageable safety profile. ORR, DoR, and PFS were comparable regardless of how heavily pretreated patients were. There also was no apparent difference in occurrences of AEs including keratopathy, serious AEs, or events leading to discontinuation, dose delay, or dose reduction between the 2 groups based on number of previous therapies. Investigators concluded that belantamab mafodotin at 2.5 mg/kg represents a new treatment option for patients with R/R MM, particularly those who have become refractory to multiple previous therapies.
Sagar Lonial, MD:
Belantamab mafodotin ultimately received FDA approval based on the ORR results of the DREAMM-2 trial at the approved dose of 2.5 mg/kg.[43] Additional trials are exploring the efficacy and safety of belantamab mafodotin in combination with various MM backbone regimens.
The ongoing 2-arm phase I/II DREAMM-6 trial is evaluating belantamab mafodotin plus Rd (Arm A) and belantamab mafodotin plus Vd (Arm B) in patients with R/R MM and ≥ 1 previous therapy.[44] The initial analysis of this trial reported manageable AEs and clinical activity in Arm B patients who received belantamab mafodotin at 2.5 mg/kg as single dose per cycle (vs split dosing) plus Vd.
Sagar Lonial, MD:
Preliminary observational data from Arm B of the DREAMM-6 trial were presented at ASH 2020.[45] This analysis focused on 18 patients who received belantamab mafodotin at 2.5 mg on Day 1 of each 21-day cycle in combination with Vd for 8 cycles, followed by belantamab mafodotin as a single agent until progression or unacceptable toxicity. The primary study objectives were safety, tolerability, and ORR with belantamab mafodotin plus Vd.
Sagar Lonial, MD:
In this analysis, the majority of patients had an ECOG PS of 0/1 (15/18; 83%) and most were ISS stage II (8/18; 44%). Although cytogenic data were not available for 6 patients, 5/12 patients (28%) had high-risk cytogenetics, and 28% had extramedullary disease. This patient cohort had a median of 3 previous lines of therapy, although this ranged from 1-11, and most patients received previous bortezomib (89%).
Sagar Lonial, MD:
The median duration of exposure to belantamab mafodotin in this analysis was 25.5 weeks (range: 6.4-46.4). No dose-limiting toxicity was observed during dose escalation. However, ocular events (keratopathy) and, to a lesser degree, thrombocytopenia were the most common AEs of interest that occurred.
Keratopathy led to dose reductions in 39% of patients (7/18) and dose interruption/delay in 83% (15/18). Thrombocytopenia also resulted in dose reductions in 28% of patients (5/18) and dose interruption/delay in 39% (7/18).
Sagar Lonial, MD:
All 18 patients experienced keratopathy events, of which 39% (n = 7) were grade 2, 61% (n = 11) were grade 3, and none was grade 4. Blurred vision was observed in 67% of patients (grade 3 in 28%). Dry eye was observed in 22% of patients (4/18; all grade ≤ 2).
Thrombocytopenia was observed in 78% of patients (n = 14). Infusion-related reactions occurred in 17% of patients, but all were grade 2, with no dose modifications/delays required. Peripheral neuropathy was observed in 33% of patients (all grade ≤ 2). These data are similar to what is observed with belantamab mafodotin as a single agent, suggesting that the combination of belantamab mafodotin with Vd did not compound the rates of AEs, including keratopathy, thrombocytopenia, or peripheral neuropathy.
Sagar Lonial, MD:
The investigator-assessed best confirmed response for all patients in this cohort was 78%. Patients who were previously exposed and potentially resistant to bortezomib had a similar ORR at 75%, with 63% achieving ≥ VGPR, suggesting that this combination is effective even after previous bortezomib exposure.
Overall, these data are encouraging and suggest that you can safely combine bortezomib with belantamab mafodotin. Additional trials are ongoing to better understand the dosing schedule in a larger patient population to confirm these results.
Sagar Lonial, MD:
In this analysis of Arm B of the DREAMM-6 trial, the combination of belantamab mafodotin as a single 2.5-mg/kg dose per cycle with Vd was associated with a manageable safety profile in patients with R/R MM. All 18 patients experienced keratopathy events, but these AEs were manageable with dose modifications/delays. No new safety signals were observed. Clinical activity was observed with an ORR in 78% of patients and ≥ VGPR in 67% of patients. This does not appear to be affected by dose modifications/delays.
Investigators concluded that belantamab mafodotin plus Vd has an acceptable safety profile and promising activity. The results support phase III trials assessing this combination earlier in the treatment sequence, along with studies into other belantamab mafodotin combination regimens in multiple settings.
Shaji Kumar, MD:
As mentioned previously, belantamab mafodotin is FDA approved for the treatment of adults with R/R MM who have received ≥ 4 previous therapies including an anti-CD38 antibody, PI, and IMiD.[38] Pomalidomide enhances T-cell and NK-cell–mediated immunity, providing a rationale for combination therapy with belantamab mafodotin.[46] The phase I ALGONQUIN study was designed to assess the safety and efficacy of belantamab mafodotin plus Pd in patients with R/R MM.[47,48]
Shaji Kumar, MD:
The ALGONQUIN study is an ongoing multicenter, nonrandomized, 2-part phase I trial combining belantamab mafodotin and Pd in patients with R/R MM who have received ≥ 1 previous line of therapy (N = 37; planned N = 62).[47] Patients were lenalidomide refractory, PI exposed, pomalidomide naive, and progressed on or within 60 days of their last MM therapy. Part 1 of ALGONQUIN, which was reported by Trudel and colleagues[47] at ASH 2020, was the dose-escalation phase with 2 different dosing schedules for belantamab mafodotin.
In the dose-escalation cohort, all patients received IV belantamab mafodotin in 21-day cycles in combination with 4 mg PO pomalidomide on Days 1-21 and 40 mg PO dexamethasone weekly (20 mg in patients 75 years of age or older). Belantamab mafodotin dosing included single dosing at 2.5 mg/kg or 1.92 mg/kg and split dosing at 2.5 mg/kg or 3.4 mg/kg over the course of each cycle, split evenly into 2 doses on Days 1 and 8 every 4 weeks.
The primary outcome in Part 1 was the maximum tolerated dose and/or RP2D, which will be used in dose expansion during Part 2. The primary outcome for Part 2 will be ORR. Secondary outcomes are DoR, PFS, OS, and safety.
Shaji Kumar, MD:
This group of patients is heavily pretreated, with a median of 3 previous lines of therapy; 24 patients also received previous ASCT (64.9%). Most patients are refractory to lenalidomide (33; 89.2%), and 30 (81.1%) are PI refractory. A little more than one third of patients are refractory to lenalidomide, a PI, and daratumumab.
Shaji Kumar, MD:
Combination belantamab mafodotin plus Pd was associated with AEs in 36 patients (97.3%), of which 34 cases (91.9%) were treatment related, and 28 patients had a grade 3/4 TRAE (75.7%). Hematologic and ocular toxicities were the most common AEs, consistent with previous data for belantamab mafodotin.
AEs led to dose reduction in 14 patients (37.8%) and dose interruption/delay in 27 patients (73%). The most common AE leading to dose reduction was keratopathy, closely followed by thrombocytopenia.
The maximum tolerated dose was a single dose of belantamab mafodotin at 2.5 mg/kg or split dosing of 1.25 mg/kg on Days 1 and 8 (every 4 weeks) in combination with the standard dosing for Pd.
Shaji Kumar, MD:
Approximately 75% of patients developed keratopathy of any grade, with slightly more than one half developing grade ≥ 3 keratopathy. However, overall eye toxicity is comparable with belantamab mafodotin in other studies.
Thrombocytopenia and neutropenia of grade ≥ 3 developed in 12 patients (32.4%) and 15 patients (40.5%), respectively. Again, this reflects the cumulative hematologic toxicity that develops from combining belantamab mafodotin with other drugs.
Shaji Kumar, MD:
For the ORR, 88% of all patients responded to belantamab mafodotin plus Pd. Similarly, 92% of patients refractory to IMiD/PI (n = 24) and 100% of patients refractory to IMiD/PI/daratumumab (n = 11) achieved an ORR. Median PFS has not been reached in the overall patient population or for patients who were refractory to IMiD/PI, but triple‑refractory patients reached a median PFS of 11.1 months.
Shaji Kumar, MD:
When assessing the efficacy by dose, patients receiving 1.92 mg/kg of belantamab mafodotin every 4 weeks had a median PFS of 14.1 months, but median PFS has not been reached yet for patients receiving 2.5 mg/kg every 4 weeks. These data show deep and durable responses with belantamab mafodotin plus Pd, but additional data are needed to fully understand the best dosing strategy.
Shaji Kumar, MD:
The combination of belantamab mafodotin plus Pd resulted in high response rates in patients with MM, even those with disease that is refractory to PIs, IMiD, and daratumumab. In this trial, patients receiving belantamab mafodotin at 2.5 mg/kg as single dose or split doses have not yet reached median PFS. At this dose, grade 3/4 keratopathy has occurred in 70% of patients, but this AE is generally manageable with careful monitoring and follow-up.
Based on these data, investigators are evaluating other combination approaches and dosing schedules to improve the safety and efficacy of belantamab mafodotin for MM.
Sagar Lonial, MD:
The goal of the selinexor and belantamab mafodotin combination studies was to bring these recently approved agents into earlier lines of therapy while building on the success of current MM therapy backbones. When combining drugs, we often need to tweak the dosing schedule to make them more tolerable. In the STOMP study, this meant once-weekly dosing for selinexor in combination with Pd. In the ALGONQUIN study, the dosing frequency for belantamab mafodotin also was different from when it is given as a single agent. These trials help show us how best to combine these newer agents and use them in our daily practice.
Shaji Kumar, MD:
Yes, it is very interesting how these new agents are being used and introduced into earlier lines of therapy. As we discussed for patients with early relapse, we combine anti‑CD38 antibodies with IMiDs or PIs so, by the time a patient experiences a second or third relapse, they are often refractory to these various classes of MM therapies. The trials combining selinexor and belantamab mafodotin with standard-of-care agents can provide important data on the potential for use in earlier relapse. These data also make me wonder whether these drugs can move even earlier—to the first relapse setting—potentially replacing or being used in combination with anti‑CD38–based therapy, as has been done with selinexor and daratumumab combinations. How we use and combine PIs, IMiDs, selinexor, monoclonal antibodies, and BCMA‑targeted therapies such as belantamab mafodotin are clearly improving the outcomes for patients with MM, and additional trials will continue to build upon this for optimal outcomes.
Sagar Lonial, MD:
I agree. Another new agent, iberdomide (also known as CC-220), is an oral, potent, novel cereblon E3 ligase modulator (CELMoD) that enhances targeted degradation of proteins including the MM-relevant transcription factors Ikaros and Aiolos. Iberdomide has shown immune-stimulatory, antimyeloma activity in lenalidomide- and pomalidomide-resistant myeloma cell lines.[49,50] In addition, iberdomide has synergistic preclinical antitumor activity when combined with bortezomib or daratumumab.[51,52]
Sagar Lonial, MD:
We know that iberdomide/dexamethasone has activity (approximately 30% ORR in R/R MM), so the question is how to combine it with other drugs and bring it in earlier to improve efficacy in patients receiving earlier lines of treatment.
The CC-220-MM-001 study is an ongoing open-label, dose-escalation, dose-expansion phase I/II trial evaluating 5 cohorts of patients with R/R MM who have received ≥ 2 previous lines of therapy (only 1 in cohort F).[53,54] The current analysis, presented at ASH 2020 by Van De Donk and colleagues,[53] focused on the phase I dose escalation data for 2 cohorts: cohort E (n = 27), receiving iberdomide-Dd, and cohort F (n = 23), receiving iberdomide-Vd.
Patients in cohort E were on 28-day dosing cycles, receiving 1.0-1.6 mg/day of iberdomide on Days 1-21 and 40 mg of dexamethasone on Days 1, 8, 15, and 22. Cohort E patients also received 16 mg/kg of daratumumab on Days 1, 8, 15, and 22 of cycles 1-2, Days 1 and 15 of cycles 3-6, and Day 1 of cycle 7+. Patients in cohort F were on 21-day dosing cycles, receiving 1.0-1.6 mg/day of iberdomide on Days 1-14 and 40 mg of dexamethasone on Days 1, 8, and 15. Cohort F patients also received 1.3 mg/m2 of bortezomib on Days 1, 4, 8, and 11 for cycles 1-8 and on Days 1 and 8 for cycles 9+.
Sagar Lonial, MD:
Baseline characteristics are what you would expect for a phase I study. The median patient age is 63-66 years, with a median time since diagnosis of 7-8 years. Most patients have an ECOG PS of 0/1 and an ISS stage of I or II at entry.
The iberdomide-Dd group had a median of 4 previous lines of therapy, and the iberdomide-Vd group had a median of 6 previous lines of therapy. More than one half of the patients in this trial were refractory to an anti-CD38 antibody (most refractory to daratumumab), a little less than one half were bortezomib refractory (39.1% to 40.7%), and approximately 40% were triple-class refractory (39.1% to 48.1%).
Sagar Lonial, MD:
Patients have received a median of 4 cycles of therapy in the iberdomide-Dd group and 6 cycles in the iberdomide-Vd group. Treatment is ongoing in approximately 44% of the patients in each group, with a little more than 55% of patients having treatment discontinued.
Reasons for treatment discontinuation were similar across groups, with 10 patients (37.0%) in the iberdomide-Dd group and 7 patients (30.4%) in the iberdomide-Vd group discontinuing due to progressive disease. Approximately 15% of patients discontinued treatment due to physician decision, and 4% withdrew. Of note, no AE-related withdrawals occurred in the iberdomide-Dd group, but 2 patients (8.7%) in the iberdomide-Vd group discontinued treatment due to grade 2 AEs.
Iberdomide dose reduction occurred in 11 patients (40.7%) in the iberdomide-Dd group and 7 patients (30.4%) in the iberdomide-Vd group.
With the dose escalation schemas for each arm, 2 cases of dose-limiting toxicity related to grade 4 thrombocytopenia occurred in the iberdomide-Vd group, and the RP2D of iberdomide was determined to be 1.6 mg/day.
Sagar Lonial, MD:
I think the observed AEs are expected for this type of agent. Iberdomide-Dd was associated with a higher rate of grade 3/4 neutropenia, which is something that has been noted with other daratumumab-based combinations, particularly in the first cycle. This is not seen to the same extent in patients receiving iberdomide-Vd, although a higher frequency of patients in this group had grade 4 thrombocytopenia. Again, these AEs are not a surprise given what we know about these agents. No incidence of thrombotic events has been reported in either cohort.
Sagar Lonial, MD:
The ORR with iberdomide-Dd therapy was 42.3%, and the ORR with iberdomide-Vd was 60.9%.
Among the 27 patients in the iberdomide-Dd cohort, 26 were IMiD refractory, 15 were daratumumab refractory, and 13 were triple-class refractory. Four of the patients refractory to daratumumab achieved a PR.
Among the 23 patients in the iberdomide-Vd cohort, 18 were IMiD refractory, 15 were PI refractory, 9 were bortezomib refractory, and 9 were triple-class refractory. Durable responses were achieved in patients refractory to or with previous exposure to bortezomib. Because most of these patients were daratumumab and/or bortezomib resistant, the efficacy observed in this study suggested more than just an additive benefit for the combination of iberdomide with these drugs.
Sagar Lonial, MD:
In this phase I analysis, both iberdomide-Dd and iberdomide-Vd have a favorable safety profile in pretreated patients with R/R MM. The results also suggested promising antimyeloma activity, even in patients who are refractory to IMiDs, PIs, and/or anti-CD38 antibodies. A dose of iberdomide at 1.6 mg/day is being used in ongoing enrollment for the triplet cohorts to finalize the RP2D. The investigators support further evaluation of iberdomide-based combination therapies in R/R MM, and phase III trials are planned.
Shaji Kumar, MD:
The data are interesting, especially with newer IMiDs coming along. Having the luxury of more than just lenalidomide and pomalidomide in this class of drugs is going to be important for building new regimens, along with other immunotherapies. But I think the importance of iberdomide goes far beyond what has been shown here, because it sets the stage for additional combinations in the upfront setting.
Sagar Lonial, MD:
I completely agree and think it is an exciting time for drug combinations in earlier lines of therapy—and to perhaps challenge the idea that treatment for first relapse is a daratumumab-based combination. We will just have to see how it plays out with phase III studies.
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