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Hematologic Malignancies: A Review of Key Clinical Studies

Ian W. Flinn, MD, PhD
Shaji K. Kumar, MD
Farhad Ravandi, MD
Released: September 23, 2020

Multiple Myeloma

Phase III ENDURANCE: Carfilzomib/Len/Dex vs Bortezomib/Len/Dex in Newly Diagnosed Multiple Myeloma

Shaji Kumar, MD
The randomized phase III ENDURANCE trial was designed to determine whether carfilzomib (K) is a better proteasome inhibitor (PI) than bortezomib (V) in combination with lenalidomide/dexamethasone (Rd) for patients with newly diagnosed MM. This trial was also designed to determine whether lenalidomide maintenance given until progression improves OS compared with 2 years of maintenance therapy with lenalidomide after induction therapy with one of these 2 triplets. This analysis is based on induction-phase endpoints.

My colleagues and I enrolled patients with newly diagnosed MM with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 who were not being considered for an early autologous stem cell transplant (ASCT) as part of the initial therapy and did not have any high-risk features such as a translocation 14;20, 14;16, or deletion 17p; high lactate dehydrogenase (LDH) levels; or plasma cell leukemia. Patients with translocation 4;14 were enrolled on this study because they were considered to be at intermediate risk.

Patients were stratified by intent to undergo stem cell transplant at disease progression and were assigned to either VRd or KRd. VRd was administered in 3-week cycles for a total of 12 cycles, as indicated. KRd was administered in nine 4-week cycles, as indicated.

The primary endpoint for the first randomization was PFS for VRd vs KRd. Secondary endpoints included ORR, measurable residual disease (MRD) negativity status, thrombotic thrombocytopenic purpura disease, OS, and safety. Patients who completed the induction therapy were randomized a second time to lenalidomide maintenance therapy indefinitely or for 2 years after randomization.

ENDURANCE: Survival From Induction Randomization

Shaji Kumar, MD
Median PFS was identical in both arms at 34.5 months (HR: 1.04; 95% CI: 0.83-1.31; P = .742). In patients aged 70 years or older, the median PFS was 37 months for VRd and 28 months for KRd. OS after a 29-month follow-up was identical in both groups (HR: 0.98; 95% CI: 0.71-1.36; P = .923); median has not been reached for either group. The 3‑year OS was approximately 85% in both arms.

ENDURANCE: PFS After Induction, by Subgroup

Shaji Kumar, MD
When the PFS was evaluated in various subgroups, it remained comparable between the 2 study arms irrespective of subgroup (HR: 1.04; 95% CI: 0.83-1.31). Of interest, patients with abnormal metaphase cytogenetics trended toward a better PFS with KRd, whereas all patients aged 70 years or older and male patients trended toward a better PFS with VRd compared with KRd.

ENDURANCE: Response to Induction

Shaji Kumar, MD
Nearly 85% of patients had a PR or better, including 74% with a VGPR in the KRd arm vs 64.7% with a VGPR in the VRd arm; the difference is statistically significant (P = .002). The CR rate was also better in the KRd arm at 18.3% compared with 14.8% in the VRd arm.

ENDURANCE: Overall Treatment-Related Adverse Events

Shaji Kumar, MD
The percentage of nonhematologic treatment‑related adverse events and grade ≥ 3 AEs was higher for KRd compared with VRd.

ENDURANCE: Specific Treatment-Related AEs and Treatment-Related AEs of Interest

Shaji Kumar, MD
As expected, a significantly higher rate of peripheral neuropathy was seen in the VRd arm (53.4%; P < .001), and higher rates of cardiac, pulmonary, and renal toxicity were seen in the KRd arm.

ENDURANCE: Second Primary Malignancies

Shaji Kumar, MD
Despite the short follow-up, the cumulative incidence of second primary malignancies was similar between the 2 arms for both hematologic and solid tumors.

ENDURANCE: Conclusions

Shaji Kumar, MD
The ENDURANCE trial provided the much-awaited results of comparing 2 triplets that are commonly used in frontline MM. Based on the phase II trials, there was enthusiasm that the carfilzomib combination might significantly improve outcomes for these patients. It shows us that among standard-risk patients and patients with newly diagnosed MM who are not eligible to undergo a stem cell transplant or who defer an early stem cell transplant, there is no advantage to using KRd over VRd. In fact, there is an increased risk of significant cardiac, pulmonary, and renal toxicity with the carfilzomib‑based combination, especially in older patients. Based on these data for this particular group of patients, it is clear that VRd should be preferred as the standard-of-care regimen.

Another triplet approved for this patient population is daratumumab/lenalidomide/dexamethasone (DRd).[1] To date, there have been no head-to-head comparisons of VRd and DRd, so both remain reasonable options. The results of the ENDURANCE trial also suggest that VRd may be considered the backbone for developing 4‑drug combinations in future clinical trials.

SWOG 1211: Phase I/II Trial of Elotuzumab Plus VRd vs VRd Alone in Newly Diagnosed, High-Risk Myeloma

Shaji Kumar, MD
Heterogeneous treatment outcomes in MM are driven by high-risk abnormalities, including underlying cytogenetic abnormalities. The SWOG 1211 trial was carried out in patients with high-risk MM. It was parallel to the ENDURANCE (E1A11) trial, in that both trials were designed to examine standard-risk and high-risk patients, with risk defined by the presence of the high-risk abnormalities such as translocation 14;16, 14;20, 1q amplification, 17p deletion and high LDH levels.

SWOG 1211 was designed to determine whether adding the monoclonal antibody (mAb) elotuzumab to VRd would improve outcomes in patients with high-risk disease.

Patients with newly diagnosed MM who had high-risk MM defined by ≥ 1 high-risk criterion (poor risk by gene expression profiling , ≥ 1 cytogenetic/FISH abnormality, primary plasma cell leukemia, or LDH ≥ twice the upper limit of normal) were randomized to receive VRd using the twice-weekly bortezomib regimen for eight 3-week cycles with or without elotuzumab at 10 mg/kg weekly. Patients who completed induction therapy continued maintenance therapy with the same drugs used at the initial randomization, with a reduced dose and schedule, until disease progression. The primary endpoint was PFS.

Baseline characteristics were well balanced, with the majority of patients having del(17p) or amp(1q21).

SWOG 1211: PFS and OS

Shaji Kumar, MD
Median PFS was comparable between the 2 arms, with a median PFS of 31 months for elotuzumab plus VRd vs 34 months for VRd (P = .449). Median OS was not reached for VRd and was 68 months for elotuzumab plus VRd (P = .239).

SWOG 1211: Responses

Shaji Kumar, MD
The ORR for elotuzumab plus VRd was 83% vs 88% for VRd.

SWOG 1211: Safety

Shaji Kumar, MD
Both regimens were well tolerated, with no significantly increased hematologic toxicity with 4 drugs compared with 3, although there was an increased risk of infection with the addition of elotuzumab to VRd vs VRd alone (32% vs 23%, any grade).

SWOG 1211: Conclusions

Shaji Kumar, MD
The SWOG 1211 study represents the first attempt to conduct clinical trials differently for high‑risk vs low‑risk patients with newly diagnosed MM. Trial results showed that clinical trials in high‑risk patients are feasible. The addition of elotuzumab to VRd, did not improve patient outcomes. When the results of this trial were compared with the results of the ENDURANCE trial, the median PFS was found to be approximately 34 months in both trials, suggesting that the strategy of using VRd induction therapy and continuing maintenance with VRd improves outcomes in high‑risk patients, with a PFS comparable to that seen in the standard‑risk or intermediate‑risk patients in ENDURANCE.

These results suggest that VRd remains an effective treatment option for these patients. Unlike standard‑risk patients, in whom lenalidomide maintenance is often sufficient after induction therapy, adding a PI to lenalidomide maintenance for high‑risk patients is associated with better outcomes.

STaMINA Long-term Follow-up: Post-ASCT Strategies for MM

Shaji Kumar, MD
ASCT continues to play an important role in upfront MM therapy. The phase III STaMINA trial was designed to determine whether additional consolidation with ASCT followed by lenalidomide maintenance therapy will improve outcomes for newly diagnosed MM. This trial enrolled transplant-eligible patients (N = 758) younger than 70 years of age. Each patient received a single ASCT then was randomized to one of 3 groups: lenalidomide maintenance, consolidation with 4 cycles of VRd followed by lenalidomide maintenance, or a second ASCT followed by lenalidomide maintenance. The original trial results demonstrated no significant difference in PFS or OS among treatment groups.[2]

The updated analysis presented at ASCO assessed patients who remained progression free at 38 months (n = 431) and asked 3 questions: First, what are the outcomes with a longer follow-up for the 3 groups? Second, what impact does the duration of lenalidomide maintenance have on outcomes? Third, is there any advantage for high‑risk patients among the protocols?

STaMINA Long-term Follow-up: Patient Characteristics

Shaji Kumar, MD
By 38 months, 48% of patients (n = 207) had discontinued lenalidomide maintenance, including 56% of tandem transplant patients, 45% of ASCT/VRd patients, and 48% of ASCT/maintenance patients.

STaMINA Long-term Follow-up: PFS and OS

Shaji Kumar, MD
Both PFS (P = .685) and OS (P = .797) remained comparable among the 3 arms.

STaMINA Long-term Follow-up: Multivariate Analysis of PFS and Second Primary Malignancy at 6 Years

Shaji Kumar, MD
The incidence of second primary malignancy was similar among the 3 arms at 6 years (P = .745). As may be expected, an analysis of PFS showed that patients with high‑risk disease (HR: 1.53; P < .0001) and older patients (HR: 1.01; P < .03) had worse outcomes.

Patients with high‑risk disease (HR: 1.54; P = .0001) and patients who discontinued lenalidomide (HR: 3.82; P < .0001) after 3 years of maintenance therapy had a higher risk for disease progression. Of note, duration of lenalidomide use had no impact on the incidence of a second primary malignancy (HR: 1.15; P = .6), which was only influenced by the age of the patient (HR: 1.07; P < .0001).

STaMINA Long-term Follow-up: PFS and OS Landmark Analysis

Shaji Kumar, MD
In the landmark analysis, patients who discontinued maintenance therapy had a higher risk for subsequent progression at 5 years vs those who continued maintenance therapy with lenalidomide (PFS: 86.3% vs 66.7%; P < .001). These results suggest that continued lenalidomide maintenance therapy provides some degree of disease control but does not result in a significant difference in OS (P = .353).

It is important to note that the current study does not report all the factors that may be related to discontinuation, such as toxicity, depth of response, etc.

STaMINA Long-term Follow-up: PFS and OS Treatment Received

Shaji Kumar, MD
High‑risk patients who had a tandem ASCT showed a significantly better 5-year PFS benefit compared with ASCT/VRd or ASCT/maintenance (43.7% vs 37.3% vs 32.0%, respectively; P = .015), but there was no OS difference in this cohort. The PFS data are similar to the results of the EMN02 trial, which also showed that high‑risk patients may benefit from a tandem ASCT.[3]

STaMINA Long-term Follow-up: Conclusions Short Title: Conclusions

Shaji Kumar, MD
The STaMINA trial provides important, although inconclusive, data. Results of the 3 trial strategies after SCT were comparable in terms of PFS and OS, suggesting that most patients in our practice who are receiving VRd induction therapy and a single SCT can proceed to lenalidomide maintenance therapy.

However, patients with high-risk disease may benefit from more intensive approaches because they have a greater risk of progression. A strategy of maintenance therapy with the combination of a PI and an immunomodulatory imide drug (IMiD), such as VRd, continued until disease progression, or an alternate approach with tandem transplants, should be considered for these patients.

The ideal duration of lenalidomide maintenance remains unanswered based on these data, although the data show that continuing lenalidomide will delay disease progression even after 3 years of treatment. The lack of OS suggests that these patients can easily be salvaged with currently available regimens, which, again, reduces the sense that patients continue maintenance therapy until disease progression. Ongoing trials will give us additional information, but the patients in this trial who continued lenalidomide maintenance were not at increased risk of a second malignancy compared with those who discontinued after 38 months.[4]

BOSTON: Phase III Trial of Weekly Selinexor, Bortezomib, and Dexamethasone vs Twice-Weekly Bortezomib and Dexamethasone in Pretreated Patients With MM

Shaji Kumar, MD
Patients with MM continue to relapse despite all of the new therapies, which indicates a need for therapies with new mechanisms of action. Selinexor is a first-in-class selective inhibitor of the nuclear export targeting the nuclear transport protein, exportin 1, to interfere with the transport of proto-oncogenes and apoptosis‑related proteins between the cytoplasm and the nucleus.[5] This drug is effective in combination with dexamethasone in relapsed MM and, based on the data from single‑arm trials, the FDA approved selinexor in combination with dexamethasone for patients who have had ≥ 3 previous therapies and have been exposed to ≥ 2 IMiDs and ≥ 2 PIs, and have received an anti-CD38 monoclonal antibody.[6] The BOSTON trial was designed to explore the role of selinexor in patients who had received 1-3 previous therapies.

Patients with relapsed MM who had 1-3 previous lines of therapy and measurable disease were randomized to receive a standard dose of Vd at a schedule of twice weekly bortezomib in 3‑week cycles for a total of 8 cycles, followed by maintenance therapy with a weekly injection of Vd in 5-week cycles. In the experimental arm, patients received selinexor in combination with Vd. However, bortezomib was administered weekly in the experimental arm from the beginning, in 5-week cycles. The primary endpoint was PFS.

BOSTON: PFS

Shaji Kumar, MD
The primary endpoint was met because the addition of selinexor to Vd significantly improved the PFS by 4.5 months (HR: 0.70; P = .0075).

BOSTON: PFS According to Patient Subsets

Shaji Kumar, MD
Subgroup PFS analysis showed that selinexor added benefit in all patient groups, particularly in patients with deletion 17p and patients who had not previously been exposed to PIs.

BOSTON: Response and OS

Shaji Kumar, MD
The addition of selinexor improved the ORR from 62% to 76% (P = .0012) compared with Vd alone. This improvement was seen in all patient subgroups, including patients 65 years of age and older (P = .0243), patients with high‑risk cytogenetics (P = .0008), and patients with previous bortezomib treatment (P = .0005), and it was independent of the underlying renal function (P = .0055).

The time to next therapy was also significantly longer at 16.1 months for selinexor plus Vd vs 10.8 months for Vd (HR: 0.66; P = .0012). The duration of response among the 72% of patients who responded was 20.3 months for the selinexor plus Vd arm vs 12.9 months for the Vd arm.

BOSTON: Selected Treatment-Emergent AEs

Shaji Kumar, MD
Several specific toxicities—including nausea (50.3%), fatigue (42.1%), and anorexia (35.4%)—were the most common AEs of any grade seen in patients treated with selinexor and were more common in these patients than in those treated with Vd. A significant burden of GI AEs was seen with the addition of selinexor. Based on some of the results from this study as well as others, prophylactic use of antiemetics can help alleviate this toxicity.

Weight loss and asthenia were more strongly associated with selinexor, which was expected based on the GI toxicity of this drug. Thrombocytopenia of any grade was 60.0% with selinexor plus Vd vs 27.0% with Vd. Thirty-five patients in the selinexor plus Vd arm required thrombopoietin receptor agonists compared with 2 patients in the Vd arm.

BOSTON: Peripheral Neuropathy

Shaji Kumar, MD
Peripheral neuropathy was the most common cause of discontinuation but was seen significantly less often in patients in the selinexor plus Vd arm vs patients in Vd arm (32.3% vs 47.1%; P = .0010). This is probably due to the fact that patients in the selinexor plus Vd arm were receiving bortezomib weekly compared with twice-weekly dosing of bortezomib in the Vd arm.

BOSTON: Conclusions

Shaji Kumar, MD
The BOSTON trial confirms the results of the phase II studies in terms of the efficacy of selinexor,[7] but it also highlights its significant toxicity, which requires careful management with antiemetics and appetite stimulants.

A different class of drugs for the treatment of MM will always be welcome. Selinexor is convenient, because it is taken orally, once a week. This allows us to create more all-oral combinations, which is especially important for the treatment of older patients with MM.

Other combinations now being investigated in phase II trials include selinexor combined with carfilzomib or daratumumab. Phase I and II trial data presented at ASCO 2020 showed that selinexor has a similar ORR when combined with carfilzomib (72%) or daratumumab (73%) in patients who had had multiple lines of previous therapy. This further suggests the efficacy of selinexor in refractory MM.[8,9]

DREAMM-6: Belantamab Mafodotin Plus Bortezomib/Dexamethasone in Relapsed/Refractory MM

Shaji Kumar, MD
The introduction of mAbs has significantly changed outcomes for patients with MM. The mAbs daratumumab and isatuximab, which target CD38 expressed by MM cells, have been approved for treatment of patients with newly diagnosed and relapsed MM.[1,10]

Other targets have shown promise in MM, particularly the B-cell maturation antigen (BCMA), which has fairly restricted expression on plasma cells. Belantamab mafodotin is an antibody–drug conjugate, or immunoconjugate, that targets BCMA and has been studied in MM.

The original phase II DREAMM‑2 study showed that single‑agent belantamab mafodotin is active in R/R MM, with an ORR of approximately 30%.[11] DREAMM‑6 is a subsequent trial of the combination of belantamab mafodotin with standard-of-care MM agents, including bortezomib and lenalidomide. The results of the bortezomib combination in the DREAMM‑6 trial were presented at ASCO 2020.

Patients with R/R MM with ≥ 1 previous line of therapy received either 2.5 mg/kg or 3.4 mg/kg belantamab mafodotin as a single dose every 3 weeks plus bortezomib and dexamethasone on the standard twice-weekly schedule.

There was a dose expansion phase following dose escalation that included both the 2.5-mg/kg and 3.4-mg/kg doses, which were given once every 3 weeks and in fractionated dosing that included half the dose on Day 1 and the other half on Day 2. The presented results primarily pertain to 3.4 mg/kg given once every 3 weeks.

Treated patients (N = 18) had a median of 3 previous lines of therapy with the distribution expected in a R/R study.

DREAMM 6: Safety

Shaji Kumar, MD
The DREAMM 6 toxicity profile is similar to that seen for single-agent belantamab mafodotin in earlier studies.[12] The most common AEs of interest were ocular toxicity with keratopathy in 100% of patients and thrombocytopenia in 67%. These 2 AEs led to dose reductions in 39% of patients with keratopathy and 33% with thrombocytopenia and some degree of dose interruption or dose delay in nearly 100% of these patients.

DREAMM 6: Clinical Response

Shaji Kumar, MD
The ORR was 78%; the median duration of response has not been reached. There have been some deep responses, including VGPR in 50% of patients.

DREAMM 6: Conclusion

Shaji Kumar, MD
DREAMM 6 demonstrated that belantamab mafodotin, is an effective anti-MM agent. Unfortunately, it is associated with some toxicity that requires careful management, particularly toxicity to the eye. Thrombocytopenia also becomes a significant issue, particularly when it is combined with drugs such as bortezomib; therefore, it must be monitored carefully. As more patients are enrolled on these studies, we will get a better sense of its durability of response and the best way to manage the ocular toxicity in these patients.

Phase III BELLINI: Updated Results With Venetoclax or Placebo Plus Bortezomib/Dexamethasone in Relapsed/Refractory MM

Shaji Kumar, MD
Venetoclax is an oral small-molecule targeted inhibitor of BCL-2 protein. This drug is approved for and very active in AML and has been studied in the preclinical setting in MM, showing activity against MM cells, particularly when they carry the t(11;14) mutation. This activity led to phase I trials using venetoclax alone, in combination with dexamethasone, or in combination with Vd. Every treatment demonstrated a significant degree of activity, particularly in patients carrying t(11;14).[13]

Based on these data, patients in the BELLINI trial with R/R disease after 1-3 previous lines of therapy who were not refractory to a PI were randomized to a standard dose of Vd given twice weekly for 2 out of 3 weeks in combination with either venetoclax or placebo. In this randomized phase III trial, patients were assigned in a 2:1 fashion to venetoclax (67%) or placebo (33%). The primary endpoint of this trial was PFS by independent review. The results of this trial were presented earlier; these updated data provide additional information about the original findings.

Baseline characteristics were equally balanced between the 2 groups (N = 291). One of the study endpoints was outcomes based on BCL-2 expression identified by immunohistochemistry. The investigators determined that nearly 80% of the patients expressed high levels of BCL-2.

BELLINI: Efficacy

Shaji Kumar, MD
Venetoclax plus Vd doubled the median PFS to 23.2 months from 11.4 months with placebo plus Vd (HR: 0.60; P = .0013). This did not result in an improved OS with venetoclax (median: 33.5 months vs not reached for placebo; HR: 1.46; P = .112), and unlike the original OS results, this difference is not statistically significant in favor of placebo. ORR was 84% vs 70% for venetoclax vs placebo (P = .013), and the MRD negativity rate was significantly higher for the venetoclax arm.

BELLINI: PFS and OS in Key Patient Subgroups

Shaji Kumar, MD
The original data analysis noted an increased mortality in patients receiving venetoclax plus Vd; this lead to an early inferior OS on this treatment arm. Additional analysis with a longer follow-up period allowed us to determine which factors negatively influenced PFS and OS in this patient population.

Patients with high-risk cytogenetics, particularly with the t(4;14) mutation or low BCL-2 expression, did not demonstrate significant improvement in PFS with venetoclax compared with other subgroups and showed a worsening OS. This was particularly evident in patients with the t(4;14) mutation (HR: 3.75; 95% CI: 0.79-17.80).

BELLINI: Safety

Shaji Kumar, MD
Regarding safety, the addition of venetoclax to bortezomib clearly increased the risk of GI toxicity, especially nausea and diarrhea. Neutropenia was also more prevalent with the addition of venetoclax (21% vs 8%). The overall rate of infection was comparable for the 2 groups (81% vs 78% in venetoclax plus Vd and placebo plus Vd, respectively), but there was a trend toward increased severity of infections with the addition of venetoclax (32% vs 28%). The deaths that were observed in the venetoclax arm early in the trial were primarily related to infections, but this effect was not evident beyond the initial treatment period.

BELLINI: Conclusions

Shaji Kumar, MD
The updated follow-up of the BELLINI trial demonstrated that venetoclax is effective in MM. However, its activity seems to be limited to certain subgroups of patients with MM, particularly those with a t(11;14) translocation and a high level of BCL-2 expression. Hopefully, this information will allow us to develop a biomarker‑derived strategy for using venetoclax in these patients. It is quite possible that the patients expressing high levels of BCL-2, even in the absence of t(11;14) translocation, may also benefit. However, development of a dedicated biomarker for use in the clinical setting is needed. The results of the BELLINI trial also highlights the potential adverse impacts in patients with high‑risk MM.

Phase II KarMMa: Idecabtagene Vicleucel for R/R MM

Shaji Kumar, MD
One of the most fascinating areas of study in MM has been in the context of CAR T-cells. Clinical trial results thus far have shown that CAR T-cells can be an effective approach to relapsed MM. The majority of CAR T-cells in these trials have targeted BCMA, a relatively specific target for plasma cells. In one trial, idecabtagene vicleucel (bb2121), an investigational BCMA-directed CAR T-cell therapy that has been studied in phase I/II settings, demonstrated an ORR of 85%, with a median PFS of 11.8 months in the setting of advanced relapsed disease.[14]

The phase II KarMMa trial examined the efficacy and toxicity of idecabtagene vicleucel in patients with R/R disease. The study included patients (N = 158 screened, n = 128 treated) with ≥ 3 previous regimens (an IMiD, a PI, and an anti-CD38 mAb) who were refractory to their last therapy. The primary endpoint was ORR; the secondary endpoints included PFS, duration of response (DoR), safety, MRD negativity status, and QoL.

Patients enrolled on this study underwent leukapheresis with bridging therapy as needed. Patients then underwent lymphodepletion with cyclophosphamide and fludarabine, which is commonly used in this setting, followed by reinfusion of the CAR T-cells. Three dose levels were studied: 150 x 106 CAR T-cells (n = 4), 300 x 106 CAR T-cells (n = 70), and 450 x 106 CAR T-cells (n = 54).

Patients in this study had a median of 6 previous regimens; 88% received bridging therapy after leukapheresis, but only 4% responded. Eighty-four percent were triple refractory to a PI, an IMiD, and a mAb; 51% had a high tumor burden, and the median time from diagnosis was 6 years.

KarMMa: Best Overall Response

Shaji Kumar, MD
Almost all of the treated patients (n = 124/128, 97%) received the 300 x 106 or 450 x 106 CAR T-cell doses. The ORR was 73% overall and dose dependent, with ORRs of 50%, 69%, and 82% at a dose of 150, 300, and 450 x 106 CAR T-cells, respectively. The overall CR was 33% (25% at 150, 29% at 300, and 39% at 450 x 106 CAR T-cells), which is impressive, considering that these patients had a median of 6 previous lines of therapy.

The median time to the first response was 1 month, and the median time to CR was 2.8 months. The onset of deep responses was rapid, and many of these responses have persisted for more than a year.

KarMMa: Key Secondary Endpoints

Shaji Kumar, MD
The median DoR was 10.7 months, with a median PFS of 8.8 months. As expected, patients with deeper responses had a better PFS: 11.3 months for VGPR and 20.2 months for CR.

KarMMa: Common AEs

Shaji Kumar, MD
Hematologic toxicity was fairly uniform across all doses and probably associated with lymphodepletion, with persistent cytopenias that may have been ascribed to the CAR T-cell treatment as well. Infections were common, with no clear relationship to the CAR T-cell dose received. Five patients died within 8 weeks of treatment: 2 due to progression and 1 each due to cytokine-release syndrome (CRS), infection, and GI hemorrhage.

KarMMa: CRS

Shaji Kumar, MD
CRS was noted in 84% of patients and in 96% of patients who had received the 450 x 106 dose. The maximum grade of CRS was 3, with the majority of the patients having grade 1/2. The median time to onset was 1-2 days at the higher CAR T-cell doses and lasted a median of 4-7 days. More than 50% of patients were treated with tocilizumab. A cell dosage effect in the frequency and severity of CRS was apparent between the 300 x 106 and 450 x 106 CAR T-cell doses.

KarMMa: Neurotoxicity

Shaji Kumar, MD
Neurotoxicity in the context of CAR T-cell treatment is of concern, but no significant neurotoxicity was observed in this trial. Overall, 3% of patients experienced grade 3 neurotoxicity, which appeared on average at Day 2 postinfusion and lasted a median of 3 days. As with CRS, we see a trend toward a higher risk for neurotoxicity with the 450 x 106 dose compared with the 300 x 106 dose.

KarMMa: Conclusions

Shaji Kumar, MD
The KarMMa trial clearly confirms the phase I trial data with the same CAR T-cell dose that has previously been published. In this study, a larger group of patients (n =128) were treated with this modality and showed that despite having been refractory to multiple previous therapies, the median duration of response for those achieving a deep response (CR/stringent CR) was 19 months (95% CI: 11.3-not evaluable). There is a need to study the use of CAR T-cells for earlier lines of therapy to see if the responses could be even more durable in less heavily pretreated disease. Clinical trials comparing CAR T-cells vs standard of care therapy in earlier lines of therapy are currently ongoing, even in the setting of newly diagnosed, high‑risk patients. More data will allow us to understand the true value of this treatment modality, considering that it is likely to be an expensive therapy compared with the other available MM therapies. Unfortunately, all the data to this point do not indicate that CAR T-cells are curative for any of these heavily pretreated patients.

EVOLVE: Phase I/II Study of BCMA-Targeted CAR T-Cell Therapy Orvacabtagene Autoleucel in Relapsed/Refractory MM

Shaji Kumar, MD
Another BCMA‑directed CAR T-cell under investigation is orvacabtagene autoleucel (orva-cel). The ongoing phase I/II EVOLVE study is investigating orva-cel in patients heavily pretreated for R/R MM. Early efficacy data were presented at ASCO 2020.[15]

The EVOLVE trial enrolled patients with R/R disease with ≥ 3 previous lines of therapy (N = 62). Patients underwent leukapheresis with bridging chemotherapy optional before they underwent lymphodepletion with the cyclophosphamide/fludarabine regimen and received an infusion of autologous CAR T-cells. Patients received CAR T-cells at doses of 50 x 106 to 600 x 106, but this analysis focuses on patients who received the 300, 450 or 600 x 106 doses. The primary endpoints were safety, tolerability, and recommended phase II dose.

Median time from diagnosis was 7 years, and patients had a median of 6 previous lines of therapy. The majority of patients (94%) were triple refractory (PI, IMiD, and anti-CD38), and 48% of patients were penta-refractory (2 IMiDs, PI, and anti-CD38). Overall, the patient population appears to be comparable to the population in the KarMMa dataset.

EVOLVE: Safety

Shaji Kumar, MD
The cytopenias are similar to what we have seen in other CAR T-cell trials. At this point in the EVOLVE trial, no clear dose‑response relationship has been observed in terms of type of toxicity. CRS was seen in 3% of patients overall, with 1 patient each in the 450 x 106 and 600 x106 dose cohorts. Only 2 patients experienced neurologic events, and 3 experienced macrophage activation syndrome or hemophagocytic lymphohistiocytosis).

EVOLVE: CRS and Neurologic Events

Shaji Kumar, MD
Overall, the incidence of CRS and neurologic toxicity appears to be lower in this trial compared with other CAR T-cell trials such as KarMMa. Supportive measures, such as tocilizumab with or without steroids, were used in nearly all patients. The median time to CRS was approximately 2 days (range: 1-4), and the median time to onset of neurologic events was 4 days (range: 1-6).

EVOLVE: Response

Shaji Kumar, MD
The total ORR was 92%. Among patients who received the 450 x 106 or 600 x 106 dose who were tested for MRD, the majority of patients in CR were MRD negative.

EVOLVE: Tumor Burden Reduction According to Dose

Shaji Kumar, MD
This waterfall plot shows the depth of response obtained in these patients after receiving orva-cel. Of note, orva-cel activity was not affected by high baseline sBCMA: 12 of 12 patients achieved at least PR, and 8 of 12 patients achieved at least VGPR.

EVOLVE: Conclusions

Shaji Kumar, MD
The EVOLVE trial demonstrated the potential of another CAR T-cell product targeting BCMA; this is a platform that is continuing to evolve. We will see more improvements over time, both in terms of the immunologic competence of CAR T-cells that are infused and in the modification of cell expansion techniques to make this a faster process avoid the need for a bridging therapy. Additional improvements include use of allogeneic CAR T-cells. Trials with these products are starting up as well.

The data from the EVOLVE trial suggest that this orva-cel is as effective as some of the previous products such as idecabtagene vicleucel. There seems to be an early signal of decreased toxicities such as CRS and NT with this second-generation product. Additional data are needed from larger studies for a greater understanding of CAR T-cell therapy in MM. We look forward to results from these trials.

Summary: ASCO 2020 Myeloma

Shaji Kumar, MD
ASCO 2020 was an exciting meeting from a MM perspective, even though it was the first virtual ASCO meeting in history. In the setting of newly diagnosed MM, the phase III trial data clearly reiterate the importance of a combination triplet using bortezomib, lenalidomide, and dexamethasone. The addition of a 4th drug has been explored in phase II and phase III trials, including GRIFFIN, PERSEUS, and CASSIOPEIA. Future data will let us know who needs a triplet like VRd and who might benefit the most by adding an mAb such as daratumumab to that triplet.

The variety of exciting new agents in the setting of relapsed disease are greatly needed because MM remains incurable and most patients eventually relapse. The data for venetoclax in t(11;14)-positive patients is exciting and presents an opportunity for the first biomarker‑guided therapy in MM.

Selinexor is part of a new drug class that appears to be effective in many settings and may have a particularly important role in high‑risk disease, such as del(17p). Its potential needs further exploration, given that this drug is studied in other combination regimens.

Immunotherapy is a therapeutic modality of great interest. The anti‑BCMA–drug conjugate antibodies are efficacious. However, an understanding of how these therapies can be combined with other standard-of-care drugs is needed.

Lastly, CAR T-cell therapy appears to be coming of age in MM. How best to use this modality in the context of its considerable expense needs to be clarified.

Provided by Clinical Care Options, LLC.

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