Paul G. Richardson, MD

Clinical Program Leader

Director of Clinical Research

Jerome Lipper Multiple Myeloma Center

Institute Physician

Dana-Farber Cancer Institute

R.J. Corman Professor of Medicine

Harvard Medical Center

Boston, MA

Many classes of agents are available for patients with multiple myeloma (MM), and most patients receive multiple regimens over the course of their treatment. Despite this, the majority of patients with MM eventually relapse. Further, the remission duration, rate of response, and depth of response in relapsed MM decrease with each subsequent regimen.¹ Although clinical practice guidelines list several preferred regimens for patients with relapsed or refractory MM (RRMM),² finding therapeutic alternatives for patients who have already been exposed to all available drug classes can be difficult. Fortunately, new agents are continuously emerging for alternative treatment options. Newer approaches for patients with RRMM are moving away from chemoimmunotherapy and toward drugs with novel mechanisms of action. Here we highlight select new agents from presentations at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition in December 2022.

Elranatamab

Elranatamab (PF-06863135) is a bispecific antibody that targets both B-cell maturation antigen (BCMA) on MM cells and CD3 on T cells, thereby activating the T cell–mediated immune response and redirecting it against MM cells.³

MagnetisMM-1 (NCT03269136) is a first-in- human phase 1 study evaluating the pharmacokinetics, pharmacodynamics, safety, and efficacy of elranatamab monotherapy for patients with RRMM. Participants had received a median of 5 prior regimens (range, 2-14). Of the participants, 91% were triple-class refractory and 24% had received prior BCMA-targeted therapy. The study found that elranatamab induced durable clinical and molecular responses. The objective response rate (ORR) among 55 patients, who were followed for a median of 12.0 months, was 64% (95% CI, 50%-75%), with 56% achieving at least a very good partial response (VGPR), 38% achieving a complete response (CR) or better, and 100% of evaluable patients with confirmed CR or better (n = 12) achieving minimal residual disease negativity. Among patients who responded, the 12-month event-free survival rate was 59% (95% CI, 39%-74%) and the median duration of response (DOR) was 17.1 months (95% CI, 10.6-not evaluable [NE]). The most common treatment-emergent adverse events (AEs) were cytokine release syndrome (CRS), neutropenia, anemia, injection site reaction, and lymphopenia.³

The FDA recently granted breakthrough therapy designation to elranatamab for the treatment of patients with RRMM based on 6-month follow-up data from the phase 2, open-label, multicenter, single-arm MagnetisMM-3 trial (NCT04649359).⁴ The study evaluated the safety and efficacy of single-agent subcutaneous elranatamab in 123 patients with RRMM whose disease was refractory to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody. Patients in cohort A received a median of 5 prior regimens (range, 2-22), and 96.7% were triple-class refractory and 42.3% were penta-drug refractory, but no patients in the cohort had received prior BCMA-targeted therapy (patients in cohort B had received prior BCMA-targeted therapy). At a median follow-up of 6.8 months, elranatamab led to an ORR of 61.0% (95% CI, 51.8%-69.6%) with a manageable safety profile. The probability of maintaining response at 6 months was 90.4% (95% CI, 79.8%-95.6%).⁵

The agent is being investigated in the phase 3 MagnetisMM-5 trial (NCT05020236) both as a monotherapy and in combination with daratumumab (Darzalex) in patients with RRMM who have received prior lenalidomide (Revlimid) and a PI.

Talquetamab

Talquetamab is a first-in-class bispecific T-cell engager antibody that targets GPRC5D as well as CD3.⁶ GPRC5D is highly expressed on MM cells and is a novel target for RRMM treatment, whereas CD3 is expressed on T cells and plays a role in activating them. In 2022, talquetamab received FDA breakthrough therapy designation for the treatment of patients with RRMM who have previously received at least 4 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 antibody.⁶ A biologics license application (BLA) for talquetamab to treat patients with RRMM has been submitted to the FDA.⁷

The BLA is supported by data from the first-in-human phase 1 /2 MonumenTAL-1 study of talquetamab (NCT03399799/ NCT04634552) in patients with RRMM who had received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody (phase 2).

Initial results from phases 1 and 2 were presented at ASH 2022 in an oral scientific session and featured as part of the ASH press briefing.

Talquetamab demonstrated robust efficacy and manageable safety in patients with RRMM who were heavily pretreated with a median of 5 prior lines of therapy (range, 2-13); 74% were triple-class refractory and 29% were penta-drug refractory.⁸

In the 143 patients treated with subcutaneous talquetamab at 0.4 mg/kg weekly, the ORR was 74.1% (≥ VGPR, 59.4%; ≥ CR, 33.6%) with a median time to first response of 1.2 months. The investigators also reported a median time to CR of 2.1 months, a median DOR of 9.3 months (95% CI, 6.6-20.2), and a median progression-free survival (PFS) of 7.5 months (95% CI, 5.7-9.4) (TABLE 1, P.28⁸).

In the 145 patients who received the 0.8-mg/kg dose every 2 weeks, the ORR was 73.1% (≥ VGPR, 57.2%; ≥ CR, 29%) and the median DOR was 13.0 months (95% CI, 10.6-NE).

The median PFS was 11.9 months (95% CI, 8.4-NE) in this group. The most common AEs observed with talquetamab at either dose level were cytopenias, infections, CRS, skin-related events, nail-related events, and dysgeusia.⁸

Daratumumab, an anti-CD38 antibody, is approved in combination with pomalidomide (Pomalyst) and dexamethasone (DPd) for patients with RRMM after at least 1 prior line of therapy, including lenalidomide and a PI.

However, patients often relapse and their disease almost always becomes refractory to existing regimens.^1,9

There is a critical need for new and better treatments in the highly refractory setting.⁹

MonumenTAL-3 (NCT05455320) is a phase 3, randomized, open-label, multicenter study comparing talquetamab in combination with daratumumab (with or without pomalidomide) with the approved combination DPd.

Results from this ongoing study are expected in early 2026 and should provide valuable insights into the comparative efficacy and safety of these combination regimens in patients with RRMM.⁹

Mezigdomide

Mezigdomide (CC-92480) is a potent, novel, oral cereblon (CRBN) E3 ligase modulatory drug (CELMoD) that works by tagging cancer-promoting proteins for destruction.

Mezigdomide specifically targets the CRBN E3 ligase complex with the goal of inducing ubiquitin-mediated maximal degradation of 2 key transcription factors, Ikaros and Aiolos, which leads to an increase in MM cell apoptosis.

Compared with IMiDs, mezigdomide has demonstrated enhanced tumoricidal and immune-stimulatory effects. As such, it is considered particularly effective in patients whose disease is refractory to IMiDs. The agent has also demonstrated potent synergy with dexamethasone, PIs, and anti-CD38 monoclonal antibodies.^10,11

CC-92480-MM-001 (NCT03374085) is an ongoing phase 1/2 trial evaluating the safety and efficacy of mezigdomide as monotherapy or in combination with dexamethasone in patients with heavily pretreated, triple- class refractory RRMM.

Among 101 participants who received the combination therapy, the median number of prior regimens was 6 (range, 3-15); 29.7% had received prior BCMA-targeted therapies; and 39.6% were refractory to lenalidomide, pomalidomide, at least 2 PIs, and an anti-CD38 monoclonal antibody.

The investigators observed that the combination of 1 mg of mezigdomide given on days 1 through 21 of each 28-day cycle and weekly 40-mg dexamethasone demonstrated promising efficacy with a manageable safety profile. The overall response rate in the overall population was 40.6%, with 2.0% of patients achieving stringent CRs, 3.0% CRs, 19.8% VGPRs, and 15.8% PRs (TABLE 2, P.29).¹¹

Among the 30 patients with prior antiBCMA therapy, the ORR was 50.0%, with 3.3% CRs, 30.0% VGPRs, and 16.7% PRs. Median time to first response was 0.95 months in all patients and 2.1 months in those with prior anti-BCMA exposure.

The median PFS was 4.6 months (95% CI, 3.2-6.3) and the median DOR was 8.3 months (95% CI, 5.4-not reached).¹¹

In an interview with Targeted Therapies in Oncology™, Paul G. Richardson, MD, said, “CELMoDs as a particular class of new agent provide such an example of an important therapeutic option for our patients with multiple myeloma, in my view.”

“Moreover, they can be readily added to existing platforms, such as proteasome inhibitors and monoclonal antibodies,” Richardson, the R.J. Corman Professor of Medicine at Harvard Medical Center and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston, Massachusetts, said.

“As we combine these powerful, orally bioavailable agents with backbone drugs to target multiple aspects of myeloma pathobiology, we can significantly improve patient outcomes,” Richardson said.

Purinostat Mesylate

Purinostat mesylate is a novel, selective inhibitor of class I and IIb histone deacetylases (HDACs) that is approved by the FDA as an investigational new drug for relapsed and refractory B-cell malignancies.¹² HDAC inhibitors target lysine in histones and nonhistone cellular proteins to alter gene transcription. As a result, tumor cell growth is arrested, apoptosis is induced, and tumor angiogenesis is inhibited.^13,14

Purinostat mesylate monotherapy demonstrated antitumor activity with good tolerability in a first-in-human, phase 1, open-label study (ChiCTR20191121) in China in patients with relapsed or refractory lymphoma (n = 16) or MM (n = 11).

In this safety and dose-escalation trial, purinostat mesylate was started at 1.2 mg/m² and escalated to a maximum of 15 mg/m². Treatment was continued until disease progression or other treatment discontinuation criteria were met. The 11 heavily pretreated evaluable patients with RRMM had a disease control rate (DCR) of 72.7%, and patients with diffuse large B-cell lymphoma (n = 10) had a DCR of 70.0%.

The majority of AEs observed were grade 1 or 2, and there were no reports of dose-limiting toxicities.¹⁵

GEN3014

GEN3014 (HexaBody-CD38), a novel, hexamerization-enhanced human IgG1 anti-CD38 monoclonal antibody, has shown highly efficient complement-dependent cytotoxicity (CDC).

The presence of the E430G mutation in GEN3014 enhances hexamer formation, which potentiates CDC. This agent demonstrated approximately 2-fold more CDC-mediated tumor cell lysis than daratumumab in preclinical in vitro models of hematological malignancies, including MM.¹⁶

Preliminary data from a first-in-human dose-escalation phase 1/2 trial (NCT04824794) in patients with RRMM who had received at least 2 prior lines of treatment, including a PI and an IMiD, showed that GEN3014 was well tolerated with clinical activity.

Enrolled patients (N = 24) had a median of 7 prior lines of treatment (range, 3-13), and 67% were previously exposed to daratumumab or isatuximab (Sarclisa). Among 16 evaluable patients who were refractory to an anti-CD38 monoclonal antibody, 2 patients achieved minimal response (1 each at 8 mg/kg and 16 mg/kg) and 1 patient had a partial response.

Fifty-six percent of patients had stable disease. Targeting CD38 with GEN3014 could potentially be utilized in patients with RRMM who are daratumumab (Darzalex) naïve.¹⁷

Bispecific CS1-BCMA CAR T Cells

Results of novel bispecific chimeric antigen receptor (CAR) T-cell therapies were recently reported by multiple national and international professional societies, including at ASH, European Hematology Association, and American Society of Clinical Oncology meetings.

Both CS1 and BCMA are highly expressed on MM cells and used as targets for CAR T-cell therapy; however, resistance to treatment can occur because of downregulation of BCMA.^18,19 CS1 (also known as SLAMF7) is a natural killer cell receptor that regulates immune functions and plays a significant role in MM pathogenesis.²⁰

Thus, bispecific CS1-BCMA CAR T cells aim to provide effective MM therapy similar to bispecific CD19 x CD22, CD19 x CD20, and other CAR T-cell therapies developed to treat patients with leukemia.^19,21-23

Bispecific CS1-BCMA CAR consists of a murine anti-CS1 scFv (clone 7A8D5) and a murine anti-BCMA scFv (clone 4C8) in tandem.

In a phase 1 clinical trial (NCT04662099) in 16 evaluable patients with RRMM with at least 2 prior lines of therapy, CS1 and BCMA were highly expressed on participants’ MM cells.

Bispecific CS1-BCMA CAR T cells were found to be clinically active in heavily pretreated patients with MM (median prior lines of therapy, 5.4; range, 2-10), even among the 13% of patients who had received previous BCMA-targeted CAR T-cell therapy.

The ORR was 81% for all patients and 100% for the 13 patients with MM cells in bone marrow.

The 12-month overall survival (OS), PFS, and DOR rates were 83.9%, 55.2%, and 68.8%, respectively; the median values were not yet reached.

Bispecific CS1-BCMA CAR T cells also demonstrated a good safety profile, with 38% of patients experiencing CRS and no reports of neurotoxicity.²⁰

Telaglenastat

Telaglenastat (CB-839) is a first-in-class, selective, noncompetitive glutaminase 1 (GLS1) enzyme inhibitor that has demonstrated favorable pharmacokinetics, pharmacodynamics, and safety in a phase 1, first-in-human study (NCT02071862) in patients with advanced or metastatic solid tumors.²⁴

GLS1 converts glutamine to glutamate, which is required for the biosynthesis of various molecules in the tricarboxylic acid cycle that supports mitochondrial respiration.^25,26

Thus, GLS1 inhibitors are of interest for treating patients with MM with resistance to PIs, where increased mitochondrial respiration is required for energy production.²⁵

A multicenter, dose-escalation, phase 1 trial (NCT03798678) evaluated telaglenastat in combination with carfilzomib (Kyprolis) and dexamethasone in patients with RRMM treated with at least 2 prior lines of therapy, including a PI.

The study evaluated 4 dose levels of telaglenastat and carfilzomib ranging from 400 mg to 800 mg twice daily and 56 mg/m² to 70 mg/m², respectively.

Among the 21 patients in the study, the median number of prior therapies received was 4 (range, 2-8). More than half of the patients had a hematologic response; the best response rate was 58%, including 1 CR; and stable disease was observed in 32% of participants. The most common hematologic grade 3 or higher AEs were thrombocytopenia, lymphopenia, anemia, and neutropenia. The most common nonhematologic grade 3 or higher AEs were upper respiratory infection and fatigue. No deaths in the study were considered related to treatment.²⁶

Implications for Clinical Practice

Unfortunately, despite numerous advances in treatment over the past 2 decades, almost all patients with MM will relapse and become refractory to currently available therapy.^27-29

Patients who become refractory to multiple existing therapies have a very poor prognosis, with a median OS ranging from 5.6 to 9.2 months in those who are refractory to anti-CD38 monoclonal antibodies, IMiDs, and PI-backbone regimens.³⁰

Further, subsequent treatment options in those heavily pretreated patients are limited. There remains a critical need for new classes of agents to offer additional therapeutic options to patients.

Overall, multiple new agents and modalities presented at ASH 2022 showed considerable promise.

“It continues to be an exciting time for our field, and hemato-oncologists should expect treatment guidelines to be updated as we have more clinical data from these various approaches, as well as hopefully approvals, to improve access and provide meaningful clinical benefit to our patients,” Richardson said.

Richardson says he particularly looks forward to offering new treatment options to frailer, older, underserved, and more vulnerable patient populations who are less likely to benefit from other intensive or more complicated therapy regimens. “As an example, mezigdomide is appealing as a highly active oral agent that offers convenience to the broader MM community of patients and providers. It is potent with a manageable safety profile and is effective where other treatment options have failed, including BCMA-based approaches. The ability to use these new agents in combination with other generic strategies to serve a broader patient population is similarly attractive and very applicable to real-world practice,” he said.

References

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2. NCCN Clinical Practice Guidelines in Oncology. Multiple myeloma, version 3.2023. Accessed February 2, 2023. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf

3. Raje N, Bahlis NJ, Costello C, et al. Elranatamab, a BCMA targeted T-cell engaging bispecific antibody, induces durable clinical and molecular responses for patients with relapsed or refractory multiple myeloma. Blood. 2022;140(suppl 1):388-390. doi:10.1182/blood-2022-166494

4. Pfizer’s elranatamab granted FDA breakthrough therapy designation for relapsed or refractory multiple myeloma. Pfizer. November 3, 2022. Accessed January 17, 2023. https://bit.ly/3j1teB5

5. Bahlis NJ, Tomasson M, Mohty M, et al. Efficacy and safety of elranatamab in patients with relapsed/refractory multiple myeloma naïve to B-cell maturation antigen (BCMA)-directed therapies: results from cohort a of the Magnetismm-3 study. Blood. 2022;140(suppl 1):391-393. doi:10.1182/blood-2022-162440

6. Janssen announces U.S. FDA breakthrough therapy designation granted for talquetamab for the treatment of relapsed or refractory multiple myeloma. Johnson & Johnson. June 29, 2022. Accessed January 17, 2023. https://bit.ly/3D8zvlt

7. Janssen submits biologics license application to U.S. FDA for talquetamab for the treatment of patients with relapsed or refractory multiple myeloma. Johnson & Johnson. December 9, 2022. Accessed January 17, 2023. https://bit.ly/3D8zvlt

8. Chari A, Touzeau C, Schinke C, et al. Talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): phase 1/2 results from MonumenTAL-1. Blood. 2022;140(suppl 1):384-387. doi:10.1182/blood-2022-159707

9. Cohen YC, Moreau P, Tolbert J, et al. MonumenTAL-3: phase 3 trial of talquetamab + daratumumab ± pomalidomide versus daratumumab + pomalidomide + dexamethasone in relapsed/refractory multiple myeloma following ≥1 prior line of therapy. Blood. 2022;140(suppl 1):4418-4419. doi:10.1182/blood-2022-162733

10. Watson ER, Novick S, Matyskiela ME, et al. Molecular glue CELMoD compounds are regulators of cereblon conformation. Science. 2022;378(6619):549-553. doi:10.1126/science.add7574

11. Richardson PG, Trudel S, Quach H, et al. Mezigdomide (CC-92480), a potent, novel cereblon E3 ligase modulator (CELMoD), combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): preliminary results from the dose-expansion phase of the CC-92480-MM-001 trial. Blood. 2022;140(suppl 1):1366-1368. doi:10.1182/blood-2022-157945

12. Qiu Q, Yang L, Feng Y, et al. HDAC I/IIb selective inhibitor purinostat mesylate combined with GLS1 inhibition effectively eliminates CML stem cells. Bioact Mater. 2022;21:483-498. doi:10.1016/j.bioactmat.2022.08.006

13. Eckschlager T, Plch J, Stiborova M, Hrabeta J. Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci. 2017;18(7):1414. doi:10.3390/ijms18071414

14. Marks PA. The clinical development of histone deacetylase inhibitors as targeted anticancer drugs. Expert Opin Investig Drugs. 2010;19(9):1049-1066. doi:10.1517/13543784.2010.510514

15. Wang J, Li H, Yang L, et al. Phase 1 safety and dose escalation of purinostat mesylate, a uniquely potent and selective inhibitor of HDAC I and IIb in relapsed or refractory lymphoma and multiple myeloma. Blood. 2022;140(suppl 1):6612-6613. doi:10.1182/blood-2022-167079

16. De Goeij BE, Janmaat ML, Andringa G, et al. Hexabody-CD38, a novel CD38 antibody with a hexamerization enhancing mutation, demonstrates enhanced complement-dependent cytotoxicity and shows potent anti-tumor activity in preclinical models of hematological malignancies. Blood. 2019;134(suppl 1):3106. doi:10.1182/blood-2019-125788

17. Spencer A, Iversen KF, Dhakal B, et al. Preliminary dose-escalation results from a phase 1/2 study of GEN3014 (HexaBody-CD38) in patients (pts) with relapsed or refractory multiple myeloma (RRMM). Blood. 2022;140(suppl 1):7320-7321. doi:10.1182/blood-2022-159116

18. Puertas B, Mateos MV, González-Calle V. Anti-BCMA CAR T-cell therapy: changing the natural history of multiple myeloma. Hemasphere. 2022;6(3):e691. doi:10.1097/HS9.0000000000000691

19. Ohmine K, Uchibori R. Novel immunotherapies in multiple myeloma. Int J Hematol. 2022;115(6):799-810. doi:10.1007/s12185-022-03365-1

20. Li C, Wang X, Wu Z, et al. Bispecific CS1-BCMA CAR-T cells are clinically active in relapsed or refractory multiple myeloma: an updated clinical study. Blood. 2022;140(suppl 1):4573-4574. doi:10.1182/blood-2022-170686

21. Fry TJ, Shah NN, Orentas RJ, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018;24(1):20-28. doi:10.1038/nm.4441

22. Schneider D, Xiong Y, Wu D, et al. A tandem CD19/CD20 CAR lentiviral vector drives on-target and off-target antigen modulation in leukemia cell lines. J Immunother Cancer. 2017;5:42. doi:10.1186/s40425-017-0246-1

23. Zhukovsky EA, Morse RJ, Maus MV. Bispecific antibodies and CARs: generalized immunotherapeutics harnessing T cell redirection. Curr Opin Immunol. 2016;40:24-35. doi:10.1016/j.coi.2016.02.006

24. Harding JJ, Telli M, Munster P, et al. A phase I dose-escalation and expansion study of telaglenastat in patients with advanced or metastatic solid tumors. Clin Cancer Res. 2021;27(18):4994-5003. doi:10.1158/1078-0432.CCR-21-1204

25. Johnson MO, Wolf MM, Madden MZ, et al. Distinct regulation of Th17 and Th1 cell differentiation by glutaminase-dependent metabolism. Cell. 2018;175(7):1780-1795.e19. doi:10.1016/j.cell.2018.10.001

26. Gonsalves WI, Neparidze N, Allred JB, et al. A multicenter phase I dose-escalation trial of a novel glutaminase inhibitor telaglenastat in combination with carfilzomib and dexamethasone in relapsed and refractory multiple myeloma. Blood. 2022;140(suppl 1):7315-7316. doi:10.1182/blood-2022-164966

27. Dimopoulos M, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396(10245):186-197. doi:10.1016/S0140-6736(20)30734-0

28. Dimopoulos MA, Oriol A, Nahi H, et al; for the POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331. doi:10.1056/NEJMoa1607751

29. Attal M, Richardson PG, Rajkumar SV, et al; ICARIA-MM study group. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394(10214):2096-2107. doi:10.1016/S0140-6736(19)32556-5

30. Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266-2275. doi:10.1038/s41375-019-0435-7