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Therapeutic Strategies in Myeloma

CE / CME

Therapeutic Strategies in Multiple Myeloma: Overview of Current and Emerging Treatment Options

Pharmacists: 1.00 contact hour (0.1 CEUs)

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Nurses: 1.00 Nursing contact hour

Released: April 26, 2023

Expiration: April 25, 2024

Shaji K. Kumar
Shaji K. Kumar, MD
CME/CE Information

Activity

Progress
1
Course Completed

Overview of Bispecific Antibodies With Novel Targets in R/R MM

In spite of the success with BCMA-targeted therapies, patients who receive these agents do relapse over time and therefore additional treatment options after relapse should be considered. Talquetamab is a bispecific antibody that targets GPRC5D and cevostamab is a bispecific antibody targeting FcRH5. Both investigational agents have shown significant activity in trials to date.136,137

Talquetamab has a response rate of over 60%, similar to what we have seen with teclistamab, but it does come with some unique toxicity, particularly skin toxicity related to the presence of the target on epidermal tissue.

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Phase I First-in-Human MonumenTAL-1 Study of Talquetamab in R/R MM: Study Design and Patients

The phase I MonumenTAL-1 trial was a first-in-human study of talquetamab with the key objectives of RP2D (part 1), RP2D safety/tolerability (part 2), antitumor activity, PK, and PD.136,138

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MonumenTAL-1: ORR

The MonumenTAL trial showed an overall response rate of over 70% in a R/R patient population when talquetamab was administered subcutaneously once every 1 or 2 weeks.138 Hopefully some of these newer drugs will be approved in the near future.

Increasingly, many of these bispecific antibodies are administered in a step up dosing fashion to minimize the CRS toxicity and they do require very close monitoring, especially during the initial doses.

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Cevostamab in R/R MM: Study Design

Cevostamab, which targets FcRH5, was studied in an open-label, multicenter phase I trial in R/R MM.137

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Cevostamab in R/R MM: Response

Cevostamab has demonstrated comparable efficacy in this patient population.137 Larger studies are ongoing (NCT05535244).

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MCARH109 in R/R MM: Study Design

Other studies are also looking at CAR T cells with alternate targets. MCARH109 is a GPRC5D-targerted autologous CAR T cell therapy that has been studied in a limited number of patients to date.139

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MCARH109: GPRC5D-Targeted Auto CAR T-Cell Therapy Clinical Responses

MCARH109 has shown very good efficacy thus far.139 Again, trials are ongoing, so we hope to gain a better sense of how effective these therapies are, particularly in the context of previous treatment with BCMA-targeted therapies.

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Iberdomide: CC-220-MM-001 Trial

Small molecules and other antibodies are also in development. Iberdomide is a cereblon-modulating agent (CELMoD) with a mechanism similar to lenalidomide and pomalidomide, but appears to be much more effective, including in patients who are R/R to lenalidomide and pomalidomide. In the initial clinical trial, iberdomide in combination with dexamethasone showed a response rate of approximately 30%.140

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Iberdomide + Dd or Vd in R/R MM: Phase I/II Study Design

Subsequent studies have evaluated the combination of iberdomide with daratumumab or bortezomib and dexamethasone and have shown response rates of approximately 40% to 60% in this patient population.141

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Iberdomide + Dd or Vd in R/R MM: Safety

Significant hematologic toxicity is associated with the CELMoDs, which may limit combinations with these agents.141

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Iberdomide + Dd or Vd in R/R MM: Efficacy

The response rates are high with these combinations—approximately 40% to 60%—in a heavily exposed and highly refractory patient population.141

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Mezigdomide (CC-92480) + Bortezomib/Dex in R/R MM: Phase I/II Trial to Determine MTD/RP2D

Mezigdomide is another CELMoD that is being explored and has been studied in combination with dexamethasone as well as bortezomib/dexamethasone.142,143

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Phase II CC-92480-MM-001: Dose-Expansion Cohort Analysis of Mezigdomide + Dex in R/R MM

In combination with dexamethasone, we have response rates of upwards of 40% in a heavily pretreated patient population.143

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Phase I/II Trial of Modakafusp Alfa in R/R MM

More recently, we saw data from a novel agent called modakafusp alfa, which is an anti CD38 targeted mAb into which an attenuated interferon molecule is fused. Interesting data were recently presented at the ASH Annual Meeting 2022, where a response rate of 43% was reported in a heavily pretreated patient population. In those who had been previously exposed to BCMA, approximately one quarter (27%) appeared to benefit from this therapy.144

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Key Points for Clinical Practice: Novel Therapies for R/R MM

  • For heavily pretreated patients, 3 BCMA-targeted therapies are currently approved after ≥4 lines of therapy including IMiD, PI, and anti-CD38 mAb—the CAR T-cell therapies ciltacabtagene autoleucel and idecabtagene vicleucel, and the bispecific antibody teclistamab—all demonstrated high response rates.
  • Many patients will progress after BCMA-targeted therapies and may be candidates for investigational therapies targeting other cellular proteins found on MM cells including GPRC5D and FcRH5.
  • Investigational CELMoDs have shown activity in patients refractory to currently available IMiDs.
  • Healthcare professionals should be encouraged to discuss clinical trials with their patients with heavily pretreated R/R MM.

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