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Key Studies in Hematologic Malignancies: Independent Conference Coverage of the 2021 ASCO Scientific Meeting
  • CME

Ian W. Flinn, MD, PhD
Shaji K. Kumar, MD
Eunice S. Wang, MD
Released: September 13, 2021

Key Studies in MM

Daratumumab Maintenance vs Observation After VTd or D-VTd Induction and Consolidation in ND MM (CASSIOPEIA Part 2): Study Design

Shaji Kumar, MD:
The CASSIOPEIA study is a multicenter, open-label, randomized phase III trial of patients 18-65 years of age with transplant-eligible newly diagnosed (ND) MM.1 In part 1 of this trial, 1085 patients were randomized to receive daratumumab (D) plus bortezomib, thalidomide, and dexamethasone (VTd) or VTd alone as induction/consolidation therapy. Results from part 1 showed superior median PFS, depth of response, and higher rates of measurable residual disease (MRD) negativity with D-VTd, leading to the approval of this regimen for ND transplant-eligible patients with MM. In the ongoing part 2 portion of the CASSIOPEIA study, 886 patients who had at least a partial response (PR) after the completion of part 1 were randomized to receive maintenance therapy with daratumumab or observation until disease progression or up to 2 years.

The primary endpoint of part 2 is PFS after the second randomization and key secondary endpoints including time to progression (TTP), rates of CR or better, MRD negativity rates, and OS.

CASSIOPEIA Part 2: Baseline Characteristics

Shaji Kumar, MD:
At the time of second randomization, baseline patient characteristics were comparable between the daratumumab maintenance arm and the observation arm, with approximately 75% of patients having achieved MRD negativity with at least a very good PR (VGPR).1 A further 15% of patients had not achieved MRD negativity but had at least a VGPR.

CASSIOPEIA Part 2: PFS (Primary Endpoint)

Shaji Kumar, MD:
At a median follow-up of 35.4 months from the randomization, there was a significant difference in median PFS between the arms, with median PFS not yet reached in the daratumumab maintenance arm and 46.7 months in the observation arm (HR: 0.53; P <.0001).1

CASSIOPEIA Part 2: PFS by Subgroups

Shaji Kumar, MD:
Looking at the various subgroups, there is a PFS benefit regardless of most baseline characteristics, except for ISS stage III. In addition, the benefit from daratumumab maintenance therapy was limited to patients who did not receive daratumumab as part of induction therapy.1 These data suggest that a quadruplet regimen might help limit the duration of therapy, something we have been hoping to achieve. However, daratumumab maintenance therapy every 8 weeks may be insufficient for disease control, so combining daratumumab with other drugs or using more intense regimens such as monthly daratumumab may be necessary to see a benefit.

CASSIOPEIA Part 2: Secondary Efficacy Endpoints

Shaji Kumar, MD:
Daratumumab maintenance resulted in 58.6% of patients achieving MRD negativity vs 47.1% for the observation arm (odds ratio: 1.80; 95% CI: 1.33-2.43; P <.0001).1

CASSIOPEIA Part 2: Safety

Shaji Kumar, MD:
Patients receiving daratumumab maintenance had a higher rate of infections compared with patients in the observation arm (77.5% vs 64.0%).1 Infusion-related reactions occurred in 54.5% of patients who had not previously received daratumumab, but 89.6% were grade 1/2. There was no clear signal for increased risk of second primary malignancies or any other cumulative toxicities from daratumumab maintenance.

CASSIOPEIA Part 2: PFS by Combination of Induction/Consolidation and Maintenance Therapy

Shaji Kumar, MD:
Daratumumab had a similar PFS benefit when given at induction/consolidation, at induction/consolidation plus maintenance, and as maintenance only.1 However, we need to wait for longer follow-up to see if these curves may separate and possibly provide any insights on the optimal duration of daratumumab when given as a maintenance therapy.

CASSIOPEIA Part 2: Response by Combination of Induction/Consolidation and Maintenance Therapy

Shaji Kumar, MD:
The results based on the first randomization to induction/maintenance were also updated. The rates of CR or better and MRD negativity were similar in patients who received daratumumab as induction/consolidation alone (71.6% and 57.6%), as induction/consolidation and maintenance therapy (76.4% and 64.2%), and as maintenance therapy alone (69.0% and 52.6%).1

CASSIOPEIA Part 2: Updated Analyses From Induction/Consolidation Randomization

Shaji Kumar, MD:
At a median follow-up of 44.5 months, median PFS was not yet reached in patients who received D-VTd as induction/consolidation therapy and was 51.5 months in patients who received VTd induction/consolidation therapy (HR: 0.58; 95% CI: 0.47-0.72; P <.0001).1 There also appears to be an OS benefit with D-VTd induction/consolidation therapy, even though the median OS has not been reached in either arm (HR: 0.54; 95% CI: 0.37-0.79).

CASSIOPEIA Part 2: Outcomes in Patients Not Randomized in Part 2

Shaji Kumar, MD:
Of the patients who received D-VTd or VTd induction/consolidation therapy in part 1, 15.7% and 21.0%, respectively, were not randomized to part 2 due to adverse events (AEs) or not achieving at least a PR.1 However, given the small number of these patients, it is unclear what this means for clinical practice.

CASSIOPEIA Part 2: Conclusions

Shaji Kumar, MD:
There are 2 main takeaway points from the trial so far. Among patients receiving autologous stem cell transplant (ASCT) as part of initial therapy, the use of a 4-drug induction regimen is associated with better survival outcomes. Whether the same improvement can be seen with bortezomib, lenalidomide, and dexamethasone (VRd) vs daratumumab plus VRd (D-VRd) for induction and consolidation remains to be seen but is likely. D-VRd combinations are being evaluated in the ongoing PERSEUS and GRIFFIN trials for newly diagnosed, transplant-eligible patients with MM. We are eagerly awaiting those data.

The current analysis also demonstrates that daratumumab maintenance therapy significantly improved post–ASCT outcomes, particularly PFS, but only in patients who were not exposed to daratumumab during induction and consolidation (VTd induction/consolidation therapy).1

I think the CASSIOPEIA part 2 data raise the question of what the ideal maintenance therapy approach and duration of therapy is in patients who receive a quadruplet induction therapy regimen before transplantation and consolidation post-ASCT. The results seen here could be a reflection of the trial design, since this trial only including patients with a specified level of response for the second randomization, or it could be a reflection of the dose and schedule used in the trial. In particular, these data also raise important questions about the potential ability to limit daratumumab therapy, perhaps based on depth of response.

Efficacy of KCd vs KRd ± ASCT Followed By R vs KR Maintenance in ND MM by Cytogenic Risk (FORTE): Study Design

Shaji Kumar, MD:
FORTE is an ongoing open-label, multicenter, randomized phase II trial of 474 patients older than 65 years of age with ND MM eligible for ASCT.2 Patients were randomized to receive carfilzomib, cyclophosphamide, and dexamethasone (KCd) or carfilzomib, lenalidomide, and dexamethasone (KRd) induction therapy followed by single ASCT (KCd-ASCT and KRd-ASCT) or further KRd without transplant (12 cycles of KRd [KRd12]). All patients received consolidation therapy before a second randomization to maintenance therapy with lenalidomide (R) or carfilzomib and lenalidomide (KR).

The first endpoint is postinduction VGPR, with additional endpoints of premaintenance VGPR, stringent CR (sCR), MRD negativity, safety, and rate of early relapse. The analysis of FORTE presented at ASCO 2021 focused on patients with high-risk disease. 

FORTE Efficacy by Cytogenic Risk: Baseline Characteristics at First Randomization

Shaji Kumar, MD:
The percentage of patients with high-risk cytogenetics was 67% of the KCd-ASCT arm, 61% of the KRd-ASCT arm, and 56% of the KRd12 arm.2 Patients with double-hit cytogenetics ranged from 24% to 30% of each arm.

FORTE Efficacy by Cytogenic Risk: PFS Following First Randomization

Shaji Kumar, MD:
At a median follow-up of 51 months following first randomization, KRd-ASCT was superior to both KCd-ASCT (HR: 0.54; 95% CI: 0.38-0.78; P <.001) and KRd12 (HR: 0.61; 95% CI: 0.43-0.88; P = .0084).2 Among patients with the chromosomal abnormality gain(1q), KRd-ASCT significantly improved median PFS vs KCd-ASCT and KRd12, with a 65% and 55% reduced risk for progression or death, respectively.

FORTE Efficacy by Cytogenic Risk: MRD in High-Risk Patients

Shaji Kumar, MD:
Sustained 1-year MRD negativity was achieved by 50% of patients with high-risk cytogenetics and 47% of patients with double-hit cytogenetics who received KRd-ASCT, which was substantially higher than the rates with KCd-ASCT or KRd12.2 Among patients with 1-year sustained MRD negativity, 4-year PFS was 87% in patients with high-risk cytogenetics and 84% in patients with double-hit cytogenetics

FORTE Efficacy by Cytogenic Risk: Baseline Characteristics at Second Randomization

Shaji Kumar, MD:
At the time of second randomization to maintenance therapy, high-risk patients made up 63% of the KR maintenance arm and 55% of the R maintenance arm, but both arms had a similar frequency of patients with double-hit cytogenetics (20% vs 23%).2 Chromosomal abnormalities also were well-balanced between the arms.

FORTE Efficacy by Cytogenic Risk: PFS Following Second Randomization

Shaji Kumar, MD:
At a median follow-up of 37 months after the second randomization, the 3-year PFS rate with KR maintenance therapy was 75% vs 65% with R (HR: 0.64).2 Patients with standard-risk MM had a 3-year PFS rate of 90% with KR vs 73% with R (HR: 0.40), patients with high-risk disease had a 3-year PFS rate of 69% vs 56% (HR: 0.60), and patients with double-hit cytogenetics had a 3-year PFS rate of 67% vs 42% (HR: 0.53). Only patients with amp(1q) did not have an improved 3-year PFS rate with KR maintenance therapy compared with R maintenance therapy (46% vs 45%; HR: 0.83).

FORTE Efficacy by Cytogenic Risk: Conclusions

Shaji Kumar, MD:
This analysis of the FORTE trial in patients with ND MM provides 2 important take-home points. First, KRd induction/consolidation with ASCT significantly prolongs 4-year PFS vs 12 cycles of KRd without ASCT across cytogenetic risk groups.2 KRd induction/consolidation with ASCT also increased the rate of 1-year sustained MRD negativity vs 12 cycles of KRd without ASCT in patients with high-risk MM (50% vs 39%) and double-hit MM (47% vs 25%). This trial once again confirms the important role of high dose therapy with ASCT as part of upfront therapy in MM, especially in the high-risk patients as well as the importance of having a PI and IMiD in combination.

Second, maintenance therapy with KR significantly prolonged 3-year PFS vs R alone across cytogenetic risk groups. This is consistent with other retrospective and prospective observations of a benefit for the dual maintenance in patients with high-risk MM.

OPTIMUM Trial: Dara-CVRd + ASCT in MM and Plasma Cell Leukemia

Shaji Kumar, MD:
Another study of note in ND MM was the prospective phase II OPTIMUM trial, which enrolled 107 patients with ultra–high-risk MM or primary plasma cell leukemia as determined by genetic and gene expression profiling.3 Patients were treated with up to 6 cycles of daratumumab, bortezomib, lenalidomide, cyclophosphamide, and dexamethasone (Dara-CVRd) for induction therapy prior to ASCT, followed by 6 cycles of consolidation with Dara-VRd, 12 cycles of consolidation with Dara-VR, and then maintenance with Dara-R until progression.

Dara-CVRd induction therapy was generally safe, with the most frequently reported grade 3/4 AEs including neutropenia (21%), thrombocytopenia (12%), and infection (12%). Following Dara-CVRd induction therapy and 100 days after ASCT, the ORR was 83%, with 46.7% of patients achieving a CR and 31.8% achieving a VGPR with deep responses. However, 6.5% of patients had disease progression, highlighting again the challenge of treating high-risk patients, particularly patients with plasma cell leukemia.

Isa-Kd vs Kd for R/R MM (IKEMA): Study Design

Shaji Kumar, MD:
The multicenter, open-label, randomized phase III IKEMA trial is evaluating the addition of isatuximab to carfilzomib and dexamethasone (Kd) vs Kd alone in 302 patients with relapsed MM.4 The primary endpoint is PFS, and key secondary endpoints include ORR, VGPR or better, and MRD negativity. Three subgroup analyses of IKEMA focused on the impact of adding isatuximab by age, prior therapy, and high-risk cytogenetics.

IKEMA: Baseline Characteristics

Shaji Kumar, MD:
Most patients in the isatuximab-Kd and Kd arm had standard cytogenic risk (63.7% vs 63.4%) and had received a median of 2 prior lines of therapy.5

IKEMA Subgroup Analyses: Efficacy by Age Group

Shaji Kumar, MD:
The addition of isatuximab to Kd resulted in improved PFS in patients of all ages, but particularly among patients 70 years of age and older, who had an HR of 0.364 with combination therapy (95% CI: 0.176-0.751).6

IKEMA Subgroup Analyses: Safety by Age Group

Shaji Kumar, MD:
Among patients 70 years of age and older, grade ≥3 treatment-emergent AEs (TEAEs) occurred in 90.2% of patients receiving isatuximab-Kd compared with 76.5% of patients receiving Kd, but treatment was tolerable, and there were no excess serious TEAEs from the addition of isatuximab.6 The most common all-grade TEAE was respiratory infection, which affected 73.5% of patients 70 years of age and older receiving Kd and 73.9% of patients younger than 70 years of age. Rates of respiratory infection were increased with isatuximab-Kd in both of these age groups (92.2% vs 79.4%).

IKEMA Subgroup Analyses: Efficacy by Prior Therapy

Shaji Kumar, MD:
There were no significant differences in efficacy between isatuximab-Kd and Kd alone based on the number of prior lines of therapy or the type of therapies previously used.5

IKEMA Subgroup Analyses: Efficacy by Refractory Status

Shaji Kumar, MD:
Many patients with MM are lenalidomide refractory at the time of first relapse, so efficacy in this group was of particular interest. Although only 57 lenalidomide refractory patients were in the study, the efficacy of isatuximab-Kd appeared similar to that of nonrefractory patients (P = .5568).5 Patients who were refractory to bortezomib also benefited from combination therapy (HR: 0.559).

IKEMA Subgroup Analyses: PFS in Patients With High-Risk Cytogenetics

Shaji Kumar, MD:
Patients with ≥1 high-risk chromosomal abnormality defined as the presence of del(17p), t(4;14), and/or t(14;16) had a reduced PFS benefit with isatuximab-Kd vs patients without chromosomal abnormalities, but isatuximab-Kd did appear to improve PFS more than Kd alone (HR: 0.724).7

IKEMA Subgroup Analyses: Response in Patients With High-Risk Cytogenetics

Shaji Kumar, MD:
Patients with high-risk cytogenetics again defined as the presence of del(17p), t(4;14), and/or t(14;16) had a similar overall depth of response with isatuximab-Kd compared with Kd alone. The patients with 1q21 amplification had a reduced rate of VGPR or better (65.6% vs 78.9%) and CR (34.4% vs 46.5%) compared with patients with standard-risk cytogenetics.7 However, patients with 1q21 amplification who received isatuximab-Kd had a greater response than patients who received Kd alone, with a particularly large benefit in the rate of MRD negativity (31.3% vs 13.3%).

IKEMA Subgroup Analyses: Conclusions

Shaji Kumar, MD:
These subgroup analyses of the IKEMA trial showed that isatuximab-Kd increases PFS with R/R MM among patients of all ages, regardless of lenalidomide refractory status, number of prior treatment lines, or high-risk cytogenetics.5-7

ICARIA-MM Second Interim Analysis: Isatuximab-Pd vs Pd in R/R MM

Shaji Kumar, MD:
The open-label, prospective, randomized phase III ICARIA-MM trial is evaluating the addition of isatuximab to pomalidomide and dexamethasone (Pd) in 307 patients with R/R MM after ≥2 lines of therapy.8-9 Patients were randomized to receive isatuximab-Pd or Pd until disease progression.

The primary endpoint is PFS by IRC, and secondary endpoints include ORR, OS, and safety. Data from the second interim analysis of ICARIA were presented at ASCO 2021. 


Shaji Kumar, MD:
The median time to next treatment (TTNT) was significantly improved with isatuximab-Pd vs Pd alone (15.5 months vs 8.9 months; HR: 0.555).9 Median PFS was 11.1 months with isatuximab-Pd vs 5.8 months with Pd alone (HR: 0.599). Fewer patients who received isatuximab-Pd went on to receive daratumumab compared with patients in the Pd arm (23.9% vs 58.2%).

ICARIA-MM Update: Second PFS and OS

Shaji Kumar, MD:
There also was a significant improvement in second PFS with isatuximab-Pd vs Pd (17.51 months vs 12.88 months; HR: 0.759).9 Although there was a trend toward an OS benefit with isatuximab-Pd (24.57 months vs 17.71 months; HR: 0.760), the preset P-value significance level was not reached (NR).

ICARIA-MM Update: Depth of Response

Shaji Kumar, MD:
After an additional 2 years of therapy, ORR remains higher with isatuximab-Pd vs Pd alone, and responses continue to deepen.9

ICARIA-MM Update: Subsequent Daratumumab

Shaji Kumar, MD:
Patients who received isatuximab-Pd followed by daratumumab as first subsequent therapy had a shorter median PFS than patients who initially received Pd alone (2.2 months vs 5.1 months).9 When the first subsequent therapy was not daratumumab, median PFS was more comparable (4.2 months vs 5.0 months). ORR also was reduced in patients who received daratumumab monotherapy as subsequent therapy following isatuximab-Pd (14.3% vs 37.9%), but there was no difference in response between the arms when daratumumab was given in combination with a PI, immunomodulatory drug, or alkylator (30.8% vs 31.8%).

ICARIA-MM Update: Summary of Safety Findings

Shaji Kumar, MD:
No new TEAEs were reported with longer-term use of isatuximab-Pd.9 Median treatment duration was 47.6 weeks with isatuximab-Pd and 24.0 weeks with Pd alone. Any-grade TEAEs were seen in >98% of patients in each group, but isatuximab-Pd was associated with an increased incidence of grade ≥3 treatment-related AEs vs Pd alone (75.7% vs 50.3%).


Shaji Kumar, MD:
The most common nonhematologic TEAEs were infusion reactions, infections, diarrhea, and fatigue.9 Hematologic abnormalities included anemia, neutropenia, and thrombocytopenia, which affected most patients in both arms.

ICARIA-MM Update: Summary

Shaji Kumar, MD:
In the second interim analysis of ICARIA-MM, isatuximab-Pd provided a significant median PFS benefit vs Pd alone (11.0 months vs 5.8 months; HR: 0.599), meeting the primary endpoint.9 Isatuximab-Pd also significantly improved the median TTNT and PFS2. This trial, along with data from the APOLLO trial evaluating daratumumab/pomalidomide/dexamethasone, demonstrates the efficacy of a lenalidomide-free regimen which can be important for patient who are refractory to lenalidomide after its use as maintenance or as part of treatment for first relapse. Of note, following progression on isatuximab-based therapy, single-agent daratumumab showed limited activity, highlighting the existing concept that isatuximab and daratumumab are comparable in terms of their mechanism of action and clinical activity.v

Ixazomib + Dex vs Pd in R/R MM: Study Design

Shaji Kumar, MD:
A global, open-label, randomized phase II trial of 122 patients with R/R MM who have received ≥2 prior lines of therapy is evaluating ixazomib plus dexamethasone vs Pd.10 The primary endpoint is PFS, and key secondary endpoints are OS, ORR, TTP, safety, and health-related quality of life. 

Ixazomib + Dex vs Pd in R/R MM: Baseline Characteristics

Shaji Kumar, MD:
Patients randomized to the ixazomib plus dexamethasone arm tended to be older than patients in the Pd arm, with 36% who were 75 years of age and older vs 18%, respectively.10 Other baseline characteristics were well matched between the arms, with 73% to 75% of patients having relapsed and refractory disease with a median of 3 prior lines of therapy.

Ixazomib + Dex vs Pd in R/R MM: PFS (Primary Endpoint)

Shaji Kumar, MD:
The primary endpoint was not met, as median PFS was not significantly different with ixazomib plus dexamethasone vs Pd (7.1 months vs 4.8 months; HR: 0.847; 95% CI: 0.535-1.341).10

Ixazomib + Dex vs Pd in R/R MM: PFS by Patient Subgroup

Shaji Kumar, MD:
Ixazomib plus dexamethasone and Pd had comparable PFS across patient subgroups, although there was a nonsignificant trend toward PFS benefit for ixazomib plus dexamethasone in patients with renal insufficiency (HR: 0.467; 95% CI: 0.172-1.267).10

Ixazomib + Dex vs Pd in R/R MM: TTP

Shaji Kumar, MD:
TTP was comparable across the treatment arms, at 8.4 months with ixazomib plus dexamethasone and 5.1 months with Pd (HR: 0.830; 95% CI: 0.506-1.361).10

Ixazomib + Dex vs Pd in R/R MM: Response

Shaji Kumar, MD:
The depth of response was comparable between the arms, with 38% to 41% of patients achieving ORR (HR: 0.90).10 Median TTR was 2.0 months with ixazomib plus dexamethasone vs 1.1 month with Pd (HR: 0.56). The median duration of response (DoR) was 14.8 months with ixazomib plus dexamethasone vs 14.3 months with Pd.

Ixazomib + Dex vs Pd in R/R MM: Safety

Shaji Kumar, MD:
Both regimens had a comparable safety profile, although grade ≥3 neutropenia occurred in 3% of patients receiving ixazomib plus dexamethasone vs 45% of patients receiving Pd.10 Grade ≥3 thrombocytopenia and peripheral neuropathy were more common among patients who received ixazomib plus dexamethasone.

Ixazomib + Dex vs Pd in R/R MM: Quality of Life

Shaji Kumar, MD:
Health-related quality of life was comparable with ixazomib plus dexamethasone and Pd.10

Ixazomib + Dex vs Pd in R/R MM: Conclusions

Shaji Kumar, MD:
In this phase II trial with heavily pretreated patients with R/R MM, PFS was comparable with ixazomib plus dexamethasone and Pd.10 Ixazomib plus dexamethasone had lower rates of grade ≥3 AEs and comparable quality of life compared with Pd.

Although doublet therapies are no longer the standard of care for patients with MM, their lower toxicity allows us to use them as the basis of new combination regimens with the addition of antibodies and other classes of drugs. Because some patients are unable to tolerate triplet regimens, it is still important for us to explore and understand the contribution of these newer drugs in doublet regimens.

Idecabtagene Vicleucel in R/R MM (KarMMa Update): Study Design

Shaji Kumar, MD:
The multicenter, single-arm phase II KarMMa trial is evaluating idecabtagene vicleucel in 140 patients with R/R MM who received ≥3 prior regimens and who were refractory to their last therapy.11

The primary endpoint is ORR, and secondary endpoints include complete remission rate, safety, DoR, PFS, and OS. An update from the KarMMa trial was reported at ASCO 2021. 

KarMMa Update: Baseline Characteristics

Shaji Kumar, MD:
Only 15 patients received 3 prior lines of therapy, and the remaining 113 patients had ≥4 previous lines of therapy.11 Overall, patients with fewer prior lines of therapy had less advanced disease at baseline.

KarMMa Update: ORR

Shaji Kumar, MD:
The ORR with nearly 2 years of follow-up was 73% in all patients, regardless of whether they received 3 or ≥4 prior lines of therapy.11 The depth of response appeared slightly higher for patients in earlier lines of therapy, with a CR/sCR of 53% vs 30% for 3 and ≥4 previous lines of therapy, respectively.

KarMMa Update: DoR

Shaji Kumar, MD:
The median DoR was 10.9 months across all patients and was comparable in patients who received 3 vs ≥4 prior lines of therapy (8.0 months vs 10.9 months).11

KarMMa Update: Survival

Shaji Kumar, MD:
Survival with idecabtagene vicleucel was similar in patients who had received 3 and ≥4 lines of prior therapy. Median PFS was 8.6 months vs 8.9 months, and median OS was 22.0 months vs 25.2 months.11 Among patients with the highest risk of progression, median OS was ≥20 months.

KarMMa Update: CRS

Shaji Kumar, MD:
At least 1 cytokine release syndrome (CRS) event occurred in 84% of the patients, but the maximum grade was 1 or 2 in 78% of patients.11 The median onset of CRS was 1 day, and the median duration was 5 days.

KarMMa Update: Neurotoxicity

Shaji Kumar, MD:
Neurotoxicity occurred in 23 patients (18%), and all events occurred within ≤1 week of a CRS event.12 Neurotoxicity was grade 1 or 2 in 18 patients, with grade 3 neurotoxicity occurring in 5 patients who were all 65 years of age and older. Neurotoxicity was manageable with treatment.

KarMMa Update: AEs of Interest

Shaji Kumar, MD:
Hematologic AEs were common across all lines of therapy, with a majority of patients developing any-grade neutropenia (91%), anemia (70%), and thrombocytopenia (64%).11 Infections were the most common nonhematologic AE and occurred in 70% of patients.

KarMMa Update: Conclusions

Shaji Kumar, MD:
An important observation from this longer follow-up of the KarMMa trial in patients with R/R MM is that idecabtagene vicleucel CAR T-cell therapy resulted in comparable benefit in earlier and later lines of therapy.11 However, the caveat is that only a small number of patients received idecabtagene vicleucel after 3 prior lines of treatment.

The median DoR was 10.9 months and median PFS was 8.6 months, with a median OS of 24.8 months, which is quite good for this disease setting. The safety of idecabtagene vicleucel and incidence of CRS and neurotoxicity were consistent with previous reports.

Overall, the results confirm the role of idecabtagene vicleucel as a treatment option for patients with heavily pretreated R/R MM, regardless of the number of prior therapy lines.

CARTITUDE-1 Trial: Ciltacabtagene Autoleucel in MM

Shaji Kumar, MD:
There also was an update on ciltacabtagene autoleucel (cilta-cel), a BCMA-targeting CAR T-cell therapy under evaluation in the phase Ib/II CARTITUDE-1 trial.13 In total, 97 heavily pretreated patients with MM received treatment with cilta-cel, with 29 patients receiving treatment in phase Ib (23 ongoing) and 68 receiving treatment in phase II (53 ongoing).

At a median follow-up of 18 months, a single dose of cilta-cel led to an impressive ORR of 97.9% across all patients, with 80.4% achieving sCR. MRD negativity was achieved in 91.8% of the 61 evaluable patients, with a median time to negativity of 1 month. Of the patients who achieved CR or better, 89.4% achieved MRD negativity, so clearly cilta-cel is quite effective in terms of tumor control.

The 18-month PFS was 66.0% in all patients (95% CI: 54.9-75.0) and 75.9% in patients who achieved sCR (95% CI: 63.6-84.5). OS at 18 months was 80.9% in all patients (95% CI: 71.4-87.6). Given the small number of patients and short follow-up, it is likely that median PFS will improve with time, which is encouraging.

There were no new safety signals with longer follow-up, despite earlier concerns about neurological toxicity. There also were data suggesting that neurotoxicity management strategies such as enhanced bridging therapy and early and aggressive treatment of CRS and immune effector cell–associated neurotoxicity syndrome helps decrease the risk of neurological toxicity. Overall, these were encouraging findings.

Belantamab Mafodotin in R/R MM (DREAMM-2): Study Design

Shaji Kumar, MD:
The ongoing open-label, randomized phase II DREAMM-2 trial is evaluating belantamab mafodotin, a BCMA-targeted antibody–drug conjugate, in 196 patients with R/R MM after ≥3 lines of prior therapy.14 Patients were randomized to receive belantamab mafodotin at a 2.5-mg/kg or 3.4-mg/kg dose via IV every 3 weeks until disease progression or unacceptable toxicity. Patients had ocular exams at baseline and prior to each treatment cycle.

Due to significant eye toxicity associated with belantamab mafodotin, the current analysis of the DREAMM-2 trial reported concordance and discordance between corneal exam findings, best-corrected visual acuity (BCVA) changes, and patient-reported symptoms from 773 evaluations in 95 patients treated at the 2.5-mg/kg dose.

DREAMM-2: Corneal Exam Findings and BCVA

Shaji Kumar, MD:
In 97 evaluations (12.5%), grade 3-4 keratopathy was associated with no or minimal (grade 0-1) BCVA changes.14 Among these patients, corneal examination revealed that 70% had diffuse microcystlike epithelial changes and 24% had severe keratopathy.

DREAMM-2: Corneal Exam Findings, BCVA, and Patient-Reported Ocular Symptoms

Shaji Kumar, MD:
In 58 evaluations (7.5%) with grade 3-4 keratopathy and grade 0-1 BCVA, there were no associated ocular symptoms.14 However, corneal examination revealed diffuse microcyst-like epithelial changes in 69% of these patients and severe keratopathy in 24%.

DREAMM-2: Type of Patient-Reported Ocular Symptom by Corneal Exam Findings

Shaji Kumar, MD:
The most common patient-reported ocular symptoms were vision blurring (22%) and dry eye (12%).14 Other reported symptoms included ocular discomfort, eye irritation, and photophobia. The frequency of photophobia was slightly higher in patients with grade 3-4 keratopathy compared with grade 0-2 keratopathy (8% vs 2%), but otherwise symptoms were similar across grades of keratopathy.

DREAMM-2: Patient-Reported Ocular Symptoms and OSDI

Shaji Kumar, MD:
Only 5% of patients with grade 3-4 keratopathy reported having no symptoms most of the time using Ocular Surface Disease Index (OSDI) evaluations.14

DREAMM-2: Conclusions

Shaji Kumar, MD:
This post-hoc analysis of DREAMM-2 found that BCVA changes and patient-reported ocular symptoms after belantamab mafodotin treatment are concordant with corneal exam findings in most cases.14 In patients with grade 0-1 BCVA and no ocular symptoms, the incidence of grade 3-4 keratopathy was 7.5%. Patients who reported no symptoms most of the time in their OSDI evaluations had a 5% incidence of grade 3-4 keratopathy. I hope these results will lead to future investigations of BCVA, patient-reported ocular symptoms, and the OSDI evaluation as possible surrogates for corneal alterations.

The need for frequent eye examinations can present a logistical challenge in the routine outpatient practice, but a better understanding of the relationship between symptoms, BCVA, the findings on eye exam, and the kinetics of onset and recovery for ocular toxicities, along with more accessible options for evaluation will allow a more informed use of this important agent in clinical practie.

Elranatamab Dose Escalation for R/R MM (MagnetisMM-1): Study Design

Shaji Kumar, MD:
The ongoing dose-escalation phase I MagnetisMM-1 trial has enrolled 30 patients with R/R MM and prior treatment with an immunomodulatory imide drug, PI, and anti-CD38 mAb to receive SC elranatamab, a bispecific antibody targeting BCMA on MM cells and CD3 on T-cells, once a week.15 The starting dose is 80 µg/kg, and the maximum dose is 1000 µg/kg.

The primary endpoints are safety/tolerability and recommended phase II dose (RP2D), and the secondary endpoint is anti-MM activity including DoR. 

MagnetisMM-1: Baseline Characteristics

Shaji Kumar, MD:
Patients enrolled on the MagnetisMM-1 trial were heavily pretreated, with a median of 8 prior therapies.15 In total, 26 patients (86.7%) were triple-class refractory, and 7 (23.3%) had previously received BCMA-targeted therapy.

MagnetisMM-1: TEAEs in ≥20% of Patients

Shaji Kumar, MD:
The most common hematologic TEAE associated with elranatamab was lymphopenia, which affected 25 patients (83.3%); lymphopenia was grade 4 in 19 of these patients (63.3%) and grade 3 in all of those remaining.15 CRS was the most common nonhematologic TEAE and affected 22 patients (73.3%); all cases were grade 1 or 2. No dose-limiting toxicities were observed.

MagnetisMM-1: CRS

Shaji Kumar, MD:
CRS occurred at all doses of elranatamab but occurred in only 2 patients (33.3%) receiving the 80-µg/kg dose vs 12 patients (100%) receiving the 600-µg/kg and 1000-µg/kg doses.15 The median time to CRS onset was 1 day, with a median duration of 3 days. There were no permanent treatment discontinuations, dose interruptions, or dose reductions due to CRS, and no premedication or priming/step-up dosing was done to mitigate CRS.

MagnetisMM-1: Investigator-Assessed Response by IMWG

Shaji Kumar, MD:
Responses to elranatamab were observed beginning at a dose of 215 µg/kg.15 Of the 4 patients who received prior BCMA-directed therapy, 2 patients achieved a VGPR, and 1 patient achieved sCR with elranatamab.

MagnetisMM-1: Pharmacokinetic Analysis

Shaji Kumar, MD:
The pharmacokinetic analysis, safety, and efficacy support the recommended phase II dose of 1000 µg/kg per week for elranatamab.15

MagnetisMM-1: Conclusions

Shaji Kumar, MD:
Elranatamab had a manageable safety profile in patients with R/R MM, and no dose-limiting toxicities were observed.15 Although CRS was reported in 73.3% of patients, all cases were grades 1 and 2. At doses ≥215 µg/kg, elranatamab yielded an ORR of 70% with a CR/sCR rate of 30%. The data support further development of elranatamab as monotherapy and in combination with other agents.

MajesTEC-1: Teclistamab in R/R MM

Shaji Kumar, MD:
Longer-term results for teclistamab, another BCMA- and CD3-targeted bispecific antibody, from the first-in-human phase I MajesTEC-1 trial also were presented at ASCO 2021.16 Enrolled patients were adults with measurable R/R MM. In total, 40 patients received teclistamab at the SC RP2D of 1500 µg/kg. The ORR was 65%, with 40% of patients achieving CR or better. The response appears durable, with a median DoR not yet reached.

CRS occurred in 70% of patients receiving the RP2D and was grade 1 or 2 in all patients. There were no treatment discontinuations due to CRS, and CRS resolved in all patients. The findings from this trial support further clinical development of teclistamab in heavily pretreated patients with R/R MM.

MonumenTAL-1: Talquetamab in R/R MM

Shaji Kumar, MD:
Updated results from a first-in-human phase I MonumenTAL-1 trial of talquetamab in patients with R/R MM also were presented at ASCO 2021.17 Talquetamab is a bispecific antibody that binds to CD3 and GPRC5D. Enrolled patients were adults with measurable R/R MM. In total, 30 patients were treated with the RP2D of SC 405 µg/kg/week. ORR was 70%, which was similar to teclistamab, and responses appeared durable.

CRS occurred in 73% of patients receiving RP2D and was mostly grade 1 or 2, with only 1 patient having grade 3. Skin-related AEs occurred in 77% of patients receiving RP2D, with a majority grade 1/2. However, there were no dose-limiting toxicities, and skin toxicity was consistent with GPRC5D expression on normal skin tissue.

Overall, the MonumenTAL-1 study supports the dosing schedule that is currently used for talquetamab and showed encouraging efficacy in heavily pretreated patients with R/R MM.

ASCO 2021 Myeloma Summary

Shaji Kumar, MD:
At ASCO 2021, we saw many studies that will help us refine the treatment of our patients with MM, along with new data on promising investigational therapies. In the setting of ND MM, the treatment paradigm is continuing to evolve, considering disease risk status with new data on the use of quadruplet therapy and even a 5-drug regimen in the induction/consolidation setting and exploration of more intense maintenance therapy options.

In the R/R setting, we saw new data including longer follow-up from studies of BCMA-targeted CAR T-cell therapies and bispecific antibodies. These therapies are likely to play an increasing role in the care of our patients in the future.

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