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Key Studies in Myeloma: CCO Independent Conference Highlights of the 2020 Virtual ASH Annual Meeting
  • CME

Shaji K. Kumar, MD
Sagar Lonial, MD
Released: March 22, 2021

Novel Targeted Agents for Relapsed/Refractory Multiple Myeloma

Cevostamab in R/R MM: Introduction

Sagar Lonial, MD:
With the success of the various anti-BCMA modalities, researchers have been turning to additional antimyeloma targets to develop the next generation of CAR T-cells, bispecific antibodies, and antibody–drug conjugates. Cevostamab is a bispecific antibody that targets FcRH5, which is a specific marker on the surface of B-cells, including plasma cells, malignant B-cells, and myeloma cells.

Cevostamab in R/R MM: Study Design

Sagar Lonial, MD:
In an international, multicenter, dose-escalation phase I study of cevostamab, 33 patients with R/R MM and no available or appropriate treatment options were enrolled.[73,74] Cevostamab is a humanized bispecific antibody that engages CD3 on the T-cells and FcRH5 on myeloma cells. Patients in this study were permitted to have previous therapy with CAR T-cells, bispecific antibodies, or antibody–drug conjugates. Cevostamab was given in 21-day cycles by IV for a maximum of 17 cycles or until progressive disease or unacceptable toxicity. This agent was given with step-up dosing to reduce the risk of CRS: 3.6 mg on Day 1 of cycle 1, followed by dose escalation from 20-160 mg on Day 8 of cycle 1 and continuing at the target dose on Day 1 of subsequent cycles.

The primary endpoints for this study were safety, tolerability, maximum tolerated dose, dose-limiting toxicities, and RP2D. Secondary endpoints included pharmacokinetic and pharmacodynamic biomarkers and activity.

Cevostamab in R/R MM: Baseline Characteristics

Sagar Lonial, MD:
Patients in this study had a median of 6 previous therapies (range: 2-15). All patients had a history of PI and IMiD therapy, and 81% had previous anti-CD38 monoclonal antibody therapy. Also, 21% had previously received anti-BCMA therapy.

In this heavily pretreated population, 94% of patients were refractory to their last therapy, 72% were triple refractory, and 45% were penta refractory.

Cevostamab in R/R MM: Safety

Sagar Lonial, MD:
During the follow-up period (median: 8.1 months; range: 0.2-30.4 months), CRS was the most common nonhematologic AE, but only 1 patient had grade 3/4 CRS. Most patients (76%) had grade 1/2 CRS, which is typical for bispecific antibodies. Hematologic AEs included decreased platelets (32%), anemia (28%), neutropenia (17%), and decreased lymphocytes (15%).

Five patients developed AEs that led to discontinuation, and 2 of those patients developed TRAEs (pneumonitis and meningitis). A dose-limiting toxicity of grade 3 pneumonia was reported in 1 patient receiving 3.6/90 mg of cevostamab.

A heavily pretreated patient population like this is generally at risk for developing significant infections, so these data were not surprising.

Cevostamab in R/R MM: CRS

Sagar Lonial, MD:
Of the 40 cases of CRS, 34% were grade 1 and 40% were grade 2, and the median time to onset was 6-12 hours. All cases of CRS were resolved. A total of 22 patients received tocilizumab and/or steroids.

In total, 19% patients developed grade 1 neurotoxicity and 5% experienced grade 2 neurotoxicity. The median time to onset in these cases was 12-24 hours. Of interest, neurotoxicity occurred exclusively in patients who also had developed CRS. 

Cevostamab in R/R MM: Response

Sagar Lonial, MD:
Efficacy data are available for 51 of the first 53 patients who were treated. For patients in the higher-dosing cohorts (≥ 3.6/20 mg), the ORR was 53%, with 18% achieving ≥ CR. In the 18 patients who received 3.6/90 mg to 3.6 mg/132 mg, the ORR was 61%.

Cevostamab in R/R MM: DoR

Sagar Lonial, MD:
At a median follow-up of 10.3 months (range: 2.7-19.5), some patients’ responses lasted for > 12 months, with some of those in the highest doses still receiving therapy. Responses occurred quickly (within 3 months), suggesting that disease control can be achieved rapidly in this patient population.

Cevostamab in R/R MM: Conclusion

Sagar Lonial, MD:
This is early data, but we are seeing encouraging efficacy for cevostamab, with some responses lasting well over a year. This speaks to the power of this potential new immune target. It is exciting to potentially have even more options for our patients with R/R MM. Of more importance, as we begin to think about how to potentially cure myeloma, we now have new options that we can bring into earlier lines of therapy.

Talquetamab in R/R MM: Introduction

Shaji Kumar, MD:
Another recently identified target for myeloma is the G-protein–coupled receptor family C group 5 member D (GPCR5D), which is present on the majority of the myeloma cells.[75] Using the same approach that has been taken for other bispecific antibodies, talquetamab is a first-in-class bispecific IgG4 antibody that targets CD3 and GPCR5D. This bispecific antibody can be given SC, which is advantageous for patients, and it can be given less often than the standard weekly dosing required for many other bispecific antibodies.

Talquetamab in R/R MM: Phase I Study Design

Shaji Kumar, MD:
This was an open-label phase I trial with step-up dosing of talquetamab followed by weekly or biweekly dosing.[76,77] Patients (N = 157) with R/R MM intolerant to established treatment were enrolled. A history of anti-BCMA therapy was allowed for this study. Patients received talquetamab by IV (n = 102) at 0.5 180 µg/kg or SC (n = 55) at 5-800 µg/kg. In total, 19 patients enrolled in the study were treated at the RP2D (405 µg/kg SC, with a 10 µg/kg and 60 µg/kg step-up dose).

Primary endpoints for this study were RP2D, safety and tolerability at the recommended dose, antitumor activity, and pharmacokinetic/pharmacodynamic data. Secondary endpoints include ORR, DoR, and PFS.

Talquetamab in R/R MM: Baseline Characteristics

Shaji Kumar, MD:
Patients who were enrolled in this study had received a median of 6 previous therapies (range: 2-20), and 87% were refractory to their last therapy. In the total population, 82% were triple-class refractory, and 22% were penta refractory. Those at the RP2D were 68% triple refractory and 21% penta refractory.

Talquetamab in R/R MM: Safety

Shaji Kumar, MD:
The toxicity profile was similar to what has been seen with the other bispecific antibodies. CRS of all grades was reported in 54% of patients, and the median time to onset and duration of CRS was 2 days. Nearly one half of the patients (52%) received supportive care for CRS, and the majority of those treated received tocilizumab.

Hematological toxicities also developed with treatment. The most common were anemia (48%), neutropenia (47%), and lymphopenia (40%). A small percentage of patients (6%) also developed neurotoxicity (3% grade ≥ 3).

Talquetamab in R/R MM: Responses

Shaji Kumar, MD:
At the RP2D (405 µg/kg SC), the ORR was 69%, including 23% with VGPR and 15% with sCR or CR. Of the patients who had triple-refractory disease (n = 9), 67% achieved a response, and both patients with penta-refractory disease responded to the therapy. For doses below 20 µg/kg IV or 135 µg/kg SC, the bispecific antibody had little activity.

Talquetamab in R/R MM: DoR

Shaji Kumar, MD:

With the IV and SC dosing strategies, patients had durable responses, with some responses lasting > 2 years. At the RP2D, none of the 17 responders had progressed at the median follow-up of 3.7 months.

Talquetamab in R/R MM: Pharmacokinetics/Pharmacodynamics

Shaji Kumar, MD:
SC dosing had a similar, and maybe more persistent, level of talquetamab compared with IV dosing. Overall, this agent had low immunogenicity, with antidrug antibodies being present in 12% of patients receiving IV dosing and 8% receiving SC dosing. At the RP2D, consistent T-cell activity was seen as PD-L1–positive cells were observed in the periphery. 

Conclusions: Immunotherapy and Novel Targeted Agents for R/R MM

Shaji Kumar, MD:
The number of novel agents—either those targeting BCMA or other new targets—is rapidly expanding in myeloma. Multiple targets and multiple types of products (CAR T-cells, bispecific antibodies, and antibody–drug conjugates) are going through clinical trials. Some of these agents are already being tested in early relapse, and others are being explored in the setting of newly diagnosed MM.

In the next 3 or 4 years, we’re going to see a dramatic change in terms of which immunotherapies we use and when we use them. ASCT will continue to play an important role in the foreseeable future, but we potentially have therapeutics that can challenge the use of ASCT in the upfront setting, and many of the ongoing clinical trials are addressing this idea.

Sagar Lonial, MD:
I agree. The various BCMA-targeted therapies have shown great promise. To me, the data with both talquetamab and cevostamab are an exciting development. Two more immune targets means that we can potentially alternate treatments early on while using PIs and IMiDs as backbone therapy. I expect there may still be a role for high-dose melphalan and ASCT in certain subsets of patients to try to get to MRD negativity earlier, but it really portends us putting together a modern total therapy approach to eliminate myeloma. It’s exciting because these drugs are active in refractory myeloma, but they are going to be equally as active—if not more so—when we use them earlier.

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