Multidrug Combinations and CAR T-Cell Therapies for Heavily Pretreated Multiple Myeloma Shine at ASCO

Meletios A. Dimopoulos, MD

Breakthrough data for systemic therapies in the treatment of various hematologic malignancies impressed attendees at the American Society of Clinical Oncology 2020 Virtual Scientific Program (ASCO20), with treatments for highly relapsed or refractory (R/R) multiple myeloma dominating headlines and showing the greatest potential for practice-changing results.

Popular strategies explored in abstracts involved improving on known multiple myeloma backbone therapies by adding a single drug, such as selinexor (Xpovio), venetoclax (Venclexta), or belantamab mafodotin, in hopes of improving efficacy while maintaining tolerability.

In addition to improvements on systemic therapy backbones, exciting reports discussed chimeric antigen receptor (CAR) T-cell therapies for heavily pretreated patients, leaving thought leaders optimistic about this modality in the years to come. “As the myeloma cellular community, in the next 5 years, we should aim to cure at least 20% to 30% of our patients,” Krina K. Patel, MD, MSc, said during a presentation summarizing data from 3 major abstracts related to CAR T-cell therapy that were released during the conference.¹ “For the ones we can’t cure, we should try to double or triple the PFS [progression-free survival].”

Selinexor

The exportin-1 inhibitor selinexor helps regulate the export of proteins across the nuclear membrane,² forcing nuclear retention and activation of tumor suppressor proteins such as p53.³ The novel, first-in-class selective inhibitor of nuclear export was granted accelerated approval in combination with dexamethasone for the treatment of penta-refractory multiple myeloma based on results of the phase 2 STORM trial (NCT02336815) in July 2019.⁴

The agent continues to be explored in combination with other drugs designed to treat multiple myeloma and was a focus of numerous abstracts presented at ASCO20.

Most notably, the phase 3 BOSTON trial (NCT03110562) randomized patients 1:1 to either selinexor plus bortezomib (Velcade) and dexamethasone (SVd) or bortezomib and dexamethasone alone (Vd).5 Patients had received 1 to 3 prior lines of therapy for multiple myeloma, with about half of patients in each arm receiving at least 2 prior therapies. In the experimental and control arms, prior therapies included bortezomib (68.7% vs 70.0%, respectively), lenalidomide (Revlimid; 39.5% vs 37.2%), and carfilzomib (Kyprolis; 10.3% vs 10.1%).

Median PFS was longer with SVd at 13.9 months compared with Vd at 9.5 months, representing a 30% reduction in the risk of disease progression or death (HR, 0.70; 95% CI, 0.53-0.93; P = .0075).

“The [Kaplan-Meier curves for PFS] separated early, and you can see a growing separation of the curves over time,” Meletios A. Dimopoulos, MD, said during his presentation of the data. “The progression-free survival [benefit] was seen consistently across all patient subgroups. In this study, despite using a bortezomib backbone, the weekly triplet of SVd demonstrated a significant benefit in patients with high-risk cytogenetics [chromosomal aberrations such as del(17p), t(14;16), and t(4;14)].”

There was a higher rate of deep responses, defined as a very good partial response (VGPR) or better, with SVd versus Vd (44.6% vs 32.4%; P = .0082). Median duration of response was 20.3 months versus 12.9 months, respectively.

Although overall survival (OS) data were not mature, an interim analysis showed a trend toward SVd superiority (HR, 0.84; 95% CI, 0.57-1.23; P = .19). Additional benefits of the combination included the once-weekly administration, which resulted in fewer bortezomib-induced peripheral neuropathy events versus twice-weekly Vd.

These results led investigators to conclude that the novel combination offers an effective, immunomodulatory drug (IMiD)–free option, including for patients with prior lenalidomide or proteasome inhibitor (PI) treatment. “Overall, these data indicate that once-weekly regimen of selinexor plus bortezomib and dexamethasone could be a new standard of care and a convenient triplet therapy,” said Dimopoulos, who is professor and chairman in the Department of Clinical Therapeutics at the National Kapodistrain University of Athens School of Medicine in Athens, Greece.

The phase 1/2 STOMP trial (NCT02343042) is further exploring these agents in patients with newly diagnosed or R/R multiple myeloma in 9 treatment arms, each exploring the safety and efficacy of adding selinexor to different multiple myeloma backbone therapies (TABLE).^2,6

In arm 5, the combination of selinexor plus daratumumab (Darzalex) and dexamethasone (SDd) was administered to patients with 3 or more prior lines of therapy for multiple myeloma, including a PI and an IMiD.⁶ All patients previously were treated with a PI or an IMiD, and 85% and 76%, respectively, were refractory. Additionally, 23.5% were considered to be quad exposed (pretreated with bortezomib, carfilzomib, lenalidomide, and pomalidomide [Pomalyst]).

Among all patients in arm 5 (n = 34), who had a median of 3 prior therapies, the median PFS was 12.5 months. The overall response rate (ORR) and clinical benefit rate in the total cohort were 69% and 81%, with corresponding rates in the daratumumab-naïve group of 73% and 87%, respectively.

With so many daratumumab-containing triplets, Sarah A. Holstein, MD, PhD, who summarized findings related to therapy combinations in a presentation at ASCO20, said that further rationale will be necessary to show which patients derive the most benefit from SDd. “It will be important moving forward to determine if selinexor can abrogate daratumumab-mediated resistance mechanisms and show efficacy in daratumumab-refractory patients,” she said.

A separate abstract described results for arm 6 of the STOMP trial, which enrolled 24 patients with a median of 3 prior lines of therapy who received selinexor added to the carfilzomib/dexamethasone backbone (SKd).² Prior therapies included bortezomib (100%), lenalidomide (95.8%), pomalidomide (62.5%), daratumumab (58.3%), and stem cell transplant (79.2%). Just 1 patient had received carfilzomib.

The SKd regimen demonstrated an ORR of 70.8%, consisting of 16.7% complete responses (CRs), 33.3% VGPRs, and 20.8% PRs. These data led investigators to conclude that this combination has activity in the indicated patient population and warrants further investigation.

Combinations Containing Venetoclax

Sarah A. Holstein, MD, PhD

Considerable focus at the meeting was directed at supplementing multiple myeloma therapy backbones with the BCL2-specific inhibitor venetoclax, particularly in combination with bortezomib, a PI.

“Preclinical studies have demonstrated synergy between venetoclax and bortezomib, thought to be due to effects on NOXA and MCL1,” Holstein said. NOXA and MCL1 are members of the BCL2 family, a large group of proteins that either promote or inhibit apoptosis.⁷ MCL1, like other prosurvival BCL2 proteins, protects against apoptosis and promotes tumorigenesis and drug resistance of malignant cells. Bortezomib indirectly inhibits MCL1 by inducing and stabilizing the MCL1-inhibitory protein NOXA. Once inhibited, MCL1 can no longer bind the proapoptotic factor BAK; thus released, the latter protein is activated and helps the proapoptotic BAX initiate tumor cell apoptosis.⁸ Coadministration of venetoclax and bortezomib targets both BCL2 and MCL1, tilting the complex interplay between proapoptotic and prosurvival proteins toward enhancement of myeloma cell apoptosis.

This understanding of the interaction between venetoclax and bortezomib led to the design of several trials, including the phase 3 BELLINI trial (NCT02755597), in which patients with relapsed or refractory multiple myeloma who had been treated with 1 to 3 prior lines of therapy were randomized 2:1 to venetoclax (n = 194) or placebo (n = 97) in combination with bortezomib and dexamethasone.9 Patients receiving 2 or 3 lines of prior therapy comprised 54% of the patient population.

In March 2019, a partial clinical hold was placed on all clinical trials investigating venetoclax following review of BELLINI because of a higher proportion of deaths in the experimental arm compared with the control.10 An updated analysis presented at the 2019 American Society of Hematology (ASH) Annual Meeting indicated that patients with translocation t(11;14) and high BCL2 protein expression had superior PFS with venetoclax, whereas placebo treatment favored those with high-risk cytogenetics.¹¹

Results presented at ASCO20 further supported these findings, with the venetoclax arm showing significantly improved PFS (HR, 0.60; 95% CI, 0.43-0.82; P = .0013) but a nonsignificant trend toward poorer OS (HR, 1.46; 95% CI, 0.91-2.34; P = .112).9 According to Holstein, who is an associate professor of internal medicine in the Division of Oncology and Hematology at University of Nebraska Medical Center in Omaha, analysis of key subgroups revealed that patients with t(11;14) saw improvement in PFS (HR, 0.18; 95% CI, 0.05-0.76), but this did not translate to a significant benefit in OS. Similar outcomes were observed in patients with high BCL2 gene expression by quantitative polymerase chain reaction. The BELLINI investigators concluded that the trial results support a biomarker-driven approach in the current venetoclax development program for patients with t(11;14)-positive multiple myeloma.

“This serves to remind us that MRD [minimal residual disease] negativity, complete response rates, overall response rates, and progression-free survival are ultimately only surrogates for OS and may not always accurately predict this,” Holstein said. “We need to determine whether there are other biomarkers, aside from translocation t(11;14), for response, but we also need to determine whether there are biomarkers for toxicity. It will be important in understanding this combination’s effect on the immune system, as well as on myeloma resistance mechanisms.”

Another phase 1/2 trial looked at venetoclax in combination with daratumumab and dexamethasone with or without bortezomib in patients with R/R disease (NCT03314181). The study involved 2 arms: In part 1, venetoclax, daratumumab, and dexamethasone (VenDd) was given to patients with t(11;14)-positive myeloma and at least 1 prior line of therapy, including a PI and an IMiD. In part 2, VenDd with bortezomib (VenDVd) was used in patients unselected for t(11;14) status who were nonrefractory to PIs.¹²

Part 1 showed notable efficacy of VenDd in patients with heavily pretreated t(11;14)-positive myeloma following prior PI and IMiD. The confirmed ORR was 95.8%, with a stringent CR (sCR) rate of 25.0% and a CR rate of 29.2%. Corresponding rates in part 2 were 91.7%, 20.8%, and 20.8%.

PFS results were not mature, but rates at 12 months were 94.1% in part 1 and 84.8% in part 2. Holstein compared the part 2 results with those of the phase 3 CASTOR trial of daratumumab, bortezomib, and dexamethasone (DVd), which showed a 12-month PFS rate of 60.7% for the experimental arm (NCT02136134).¹³

“The [patient population] in part 2 is small, so it is not fair to make comparisons. However, there is perhaps a hint of a benefit activity from the addition of venetoclax to the DVd backbone,” Holstein said. She went on to say that the planned part 3 of the trial, comparing VenDd versus DVd in patients with t(11;14)-positive multiple myeloma, will address the relative benefit of adding venetoclax versus bortezomib to the daratumumab/dexamethasone backbone but will not address the safety or efficacy of adding daratumumab to the venetoclax/dexamethasone backbone.

Belantamab Mafodotin Explored as Combination Therapy

Krina K. Patel, MD, MSc

Adding belantamab mafodotin, a BCMA-targeting immunoconjugate, to combination therapy backbones is being examined in the ongoing 2-arm, phase 2 DREAMM-6 trial (NCT03544281). Results of arm B, in which the agent is added to Vd in a dose-escalation and -expansion design, were presented at ASCO20.¹⁴

Patients had to have received at least 1 prior therapy, which could include bortezomib. The median number of prior therapies was 3, with 22% of patients having 7 or more regimens for multiple myeloma.

The ORR for belantamab mafodotin plus Vd was 78%, consisting of 50% VGPRs and 28% PRs. For comparison, in previous trials of patients with at least 1 prior therapy treated with Vd alone, ORRs were between 50% and 63%.

There were no grade 5 adverse events, there was no grade 4 corneal toxicity, and the overall safety profile was consistent with that of the regimen’s individual components.

Single-agent belantamab mafodotin had already demonstrated safety and clinically meaningful activity in patients with heavily pretreated multiple myeloma in the DREAMM-2 trial (NCT03525678).¹⁵ Updated data showed that patients with high-risk cytogenetics treated with belantamab mafodotin monotherapy maintained deep and durable responses comparable to those reported in the standard-risk population, with similar duration of response, PFS, and OS in both groups.¹⁶

Impressive Results for BCMA CAR T-Cell Therapy

Three major abstracts addressed the use of BCMA-targeting CAR T-cell therapy in patients with heavily pretreated relapsed/refractory multiple myeloma. Patient characteristics regarding prior therapies tended to be similar across the trial populations.

“Median prior lines of therapy [in these trials] were similar, between 5 [and] 6, with a range of 3 through 18 prior therapies,” Patel, who is an assistant professor in the Department of Lymphoma/Myeloma of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, said during her presentation. “Triple-refractory patients, who we know tend to not do as well, made up about 80% to 90% of the population in all 3 trials.”

The phase 2 KarMMa trial (NCT03361748) evaluated the efficacy and safety of idecabtagene vicleucel (ide-cel; bb2121) in patients with at least 3 (median, 6; range, 3-16) prior therapies, of whom 94% were refractory to an anti-CD38 antibody.¹⁷ Additionally, more than half had high tumor burden and 35% had high-risk cytogenetics.

Patients were treated at dose levels of 150 × 106 (n = 4), 300 × 106 (n = 70), and 450 × 106 (n = 54) CAR-positive T cells, with ORRs of 50%, 69%, and 82%, respectively. Median peak CAR T-cell expansion occurred at 11 days, with peak exposure being highest in responders.

In the entire ide-cel–treated population (N = 128), the ORR was 73% with a CR plus sCR rate of 33%, meeting the trial’s primary and key secondary end points. In the overall cohort, MRD negativity with at least CR or VGPR was achieved by 26% and 39% of patients, respectively. In patients whose best response was CR/sCR or VGPR, the median PFS was 20.2 months and 11.3 months, respectively. The median OS was 19.4 months, and 78% of all ide-cel–treated patients were event free at 12 months.

Cytokine release syndrome (CRS) incidence increased with the dose level but was mostly low grade. In total, 84% of patients had CRS, including 1 grade 5 event. Similarly, neurotoxicity was mostly low grade and consistent across dose levels, with no grade 4 or greater events. Corticosteroids were used infrequently to manage CRS or neurotoxicity.

In a poster presentation of the noninterventional, retrospective KarMMa-RW study, investigators reported real-world data collected from databases to construct a cohort for comparison with the patients treated in KarMMa. Included patients had characteristics similar to those in KarMMa, such as having at least 3 prior regimens, including an IMiD, a PI, and an anti-CD38 antibody.¹⁸ Several baseline characteristics differed significantly between KarMMa and KarMMa-RW, such as the former having almost double the number of patients with triple-class–refractory disease (84% vs 43%). The investigators applied a statistical adjustment method to reduce these differences and create more balanced cohorts.

At the time of analysis, the ORR in KarMMa 92%, respectively. Robust T-cell expansion was observed at all dose levels through day 29, and persistence of CAR-positive T cells was detected in 69% of patients at 6 months.

The entire patient population (N = 62) had an ORR of 92% composed of 36% CRs/sCRs, 32% VGPRs, and 24% PRs. For patients in the overall cohort, the MRD negativity rate was 84%.

The toxicity profile of orva-cel was encouraging, with any-grade and grade 3 or greater CRS occurring in 89% and 3% of the total patient cohort, respectively. Rates of neurological events were 13% for all grades and 3% for grade 3 and above. Management of CRS and neurological events involved tocilizumab in 76% of patients and steroids in 52%.

The recommended phase 2 dose was identified as 600 × 106 CAR-positive T cells, and enrollment is ongoing. The trial protocol was recently amended to include patients who progressed after BCMA-directed therapies.

Updated data from the phase 1b/2 CARTITUDE-1 trial (NCT03548207) of the BCMA-targeting CAR T-cell therapy JNJ-68284528 (JNJ-4528) were also presented at the meeting and supported previous findings reported at the 2019 ASH Annual Meeting.^20,21

At the update, of the 29 patients treated at the target dose of 0.75 × 106 CAR+ T cells, 25 (86%) had achieved sCR; the remainder experienced a VGPR (n = 3) or a PR (n = 1).21 Median time to first response was 1 month, and median time to CR was 3 months. At the median follow-up of 11.5 months, 22 patients were still alive and progression free, with a 9-month PFS rate of 86% (95% CI, 67%-95%). Of the 16 patients in CR who were evaluable for MRD negativity, 13 (81%) were MRD negative at an MRD sensitivity threshold of 10^-5 or 10^-6.

Grade 3 or greater CRS occurred in 7% of patients. Patel pointed out that the median time to CRS was 7 days, differing from results in the KarMMa and EVOLVE studies, which had median CRS onset at 1 and 2 days, respectively. “This may have to do with the fact that [JNJ-4528 is administered] at a lower dose initially…but it does peak later,” she said.

JNJ-4528 was granted breakthrough therapy designation in 2019 for the treatment of patients with R/R multiple myeloma, which was supported by initial data from CARTITUDE-1.22 The investigators reported that the phase 2 portion of this trial is fully enrolled, and other phase 2 and 3 studies have begun.

“In terms of efficacy, response rates were between 73% and 100%, and this is in patients who have had [an average of] 5 to 6 prior lines of therapy, which is amazing,” Patel said when discussing the major CAR T-cell therapy data. “MRD negatively at 106 among all the evaluable patients occurred at high rates, as well.”

Patel concluded by stating that some issues will need to be addressed to identify the optimal patient population for receipt of this therapy.

“We know that we have other BCMA-targeting agents coming [to the market], so how do we decide who gets what first?” Patel asked. “Another important part of this should be improving patient access. Patients should be able to receive CAR T-cell [therapy] if they want [and] be supported financially, and their doctors, between both community and academic centers, should have an easier way of getting their patients to these trials.”

_References:

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_{8. Le Gouill S, Podar K, Harousseau JL, Anderson KC. Mcl-1 regulation and its role in multiple myeloma. Cell Cycle. 2004;3(10):1259‐1262. doi:10.4161/cc.3.10.1196}

_{9. Kumar S, Harrison SJ, Cavo M, et al. Updated results from BELLINI, a phase III study of venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. J Clin Oncol. 2020;38(suppl 15; abstr 8509). doi:10.1200/JCO.2020.38.15_suppl.8509}

_{10. AbbVie provides update on Venclexta/Venclyxto (venetoclax) multiple myeloma program. News release. AbbVie. March 19, 2019. Accessed June 3, 2020. https://bit.ly/2z1lCHZ}

_{11. Moreau P, Harrison S, Cavo M, et al. Updated analysis of BELLINI, a phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Blood. 2019;34(suppl 1;abstr 1888). doi:10.1182/blood-2019-126015}

_{12. Kaufman JL, Baz RC, Harrison SJ, et al. Updated analysis of a phase I/II study of venetoclax in combination with daratumumab and dexamethasone, +/- bortezomib, in patients with relapsed/refractory multiple myeloma. J ClinOncol. 2020;38(suppl 15; abstr 8511). doi:10.1200/JCO.2020.38.15_suppl.8511}

_{13. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375(8):754‐766. doi:10.1056/NEJMoa1606038}

_{14. Nooka AK, Stockerl-Goldstein K, Quach H, et al. DREAMM-6: safety and tolerability of belantamab mafodotin in combination with bortezomib/dexamethasone in relapsed/refractory multiple myeloma. J Clin Oncol. 2020;38(suppl 15; abstr 8502). doi:10.1200/JCO.2020.38.15_suppl.8502}

_{15. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21(2):207‐221. doi:10.1016/S1470-2045(19)30788-0}

_{16. Cohen AD, Trudal S, Lonial S, et al. DREAMM-2: single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) and high-risk (HR) cytogenetics. J Clin Oncol. 2020;38(suppl 15; abstr 8541). doi:10.1200/JCO.2020.38.15_suppl.8541}

_{17. Munshi NC, Anderson LD, Shah N, et al. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): Initial KarMMa results. J Clin Oncol. 2020;38(suppl 15; abstr 8503). doi:10.1200/JCO.2020.38.15_suppl.8503}

_{18. Jagannath S, Lin Y, Goldschmidt H, et al. KarMMa-RW: A study of real-world treatment patterns in heavily pretreated patients with relapsed and refractory multiple myeloma (RRMM) and comparison of outcomes to KarMMa. J ClinOncol. 2020;38(suppl 15; abstr 8525). doi:10.1200/JCO.2020.38.15_suppl.8525}

_{19. Mailankody S, Jakubowiak AJ, Luciano MH, et al. Orvacabtagene autoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T cell therapy for patients (pts) with relapsed/refractory multiple myeloma (RRMM): update of the phase 1/2 EVOLVE study (NCT03430011). J Clin Oncol. 2020;38(suppl 15; abstr 8504). doi:10.1200/JCO.2020.38.15_suppl.8504}

_{20. Madduri D, Usmani SZ, Jagannath S, et al. Results from CARTITUDE-1: a phase 1b/2 study of JNJ-4528, a CAR-T cell therapy directed against B-cell maturation antigen (BCMA), in patients with relapsed and/or refractory multiple myeloma (R/R MM). Blood. 2019;34(suppl 1;abstr 577). doi:10.1182/blood-2019-121731}

_{21. Berdeja JG, Madduri D, Usmani SZ, et al. Update of CARTITUDE-1: A phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy, in relapsed/refractory multiple myeloma. J Clin Oncol. 2020;38(suppl 15; abstr 8505). doi:10.1200/JCO.2020.38.15_suppl.8505}

_{22. Janssen announces BCMA CAR-T therapy JNJ-4528 granted U.S. FDA breakthrough therapy designation for the treatment of relapsed or refractory multiple myeloma. News release. The Janssen Pharmaceutical Company of Johnson & Johnson. Published December 6, 2019. Accessed June 3, 2020. https://bit.ly/2XXKSqX}