ASCO 2023: Multiple Myeloma

TRiMM-2: Response Rate of 78% Seen in Patients Who Receive Talquetamab With Subcutaneous Daratumumab for Multiple Myeloma

Updated results from the phase 2 TRiMM-2 study (NCT04108195) reported June 3 at the American Society of Clinical Oncology (ASCO) Annual Meeting showed an overall response rate of 78% in patients with multiple myeloma who were treated with a combination of talquetamab and subcutaneous daratumumab (Darzalex Faspro).¹

Lead investigator Bhagirathbhai R. Dholaria, MBBS, assistant professor of medicine in the Division of Hematology-Oncology at Vanderbilt University Medical Center, explained during an oral abstract session—and in an interview with The American Journal of Managed Care®—how the immunomodulatory effects of the 2 therapies could create a synergy to treat multiple myeloma.

Dholaria

“Daratumumab is one of the most effective therapies for newly diagnosed or relapsed/refractory multiple myeloma. And one of the important immunomodulatory effects of daratumumab is actually that it also depletes the CD38-expressing regulatory T cell,” he said in the interview.

“The hope was that you can potentially improve the efficacy of talquetamab, which relies on the host T-cell function to attack the cancer and control the myeloma. If you combine both of these together, maybe you can potentiate the antimyeloma activity of talquetamab,” Dholaria said.

Talquetamab received breakthrough therapy status nearly a year ago and is being studied both as a monotherapy and in combination with other drugs²; as Dholaria explained during the session, it appears that blood counts are preserved with this combination, making talquetamab “a potentially good partner” that can combine well with other therapies to treat multiple myeloma.

That’s important because for all the success over the past decade in identifying new treatments for multiple myeloma, it does not have a cure, so the hunt is always on for more options, especially for patients who have received multiple lines of therapy. In 2023, an estimated 35,000 people in the United States are expected receive a diagnosis of multiple myeloma, and more than 12,000 will die from the disease.³

TRiMM-2 included patients who were treated with 3 prior lines of therapy, including anti-CD38, BCMA-targeted, and T-cell redirecting therapies. Patients were treated with 0.4 mg/kg or 0.8 mg/kg of talquetamab every 2 weeks, with step-up doses in addition to subcutaneous daratumumab.

Results reported at the meeting showed the following:

• The overall response rate was 78%, and responses deepened over time.
  Responses were seen in 84% (42 of 50 patients) in the 0.8 mg/kg arm, including 74% who achieved a very good partial response or better, 16% with a complete response and 36% who had a stringent complete response.
• The overall response rate among patients previously treated with an anti-CD38 antibody was 82.2% (37/45) and 78.9% (15/19) among patients with prior T-cell redirection therapy in 0.8 mg/kg cohort.
• With a median follow-up of 16.8 months, 71.4% (10/14) of those in treated weekly with the 0.4 mg/kg dose achieved a response, 57.1% achieved a very good response or better, 14.3% reached a complete response, and 28.6% achieved a stringent complete response.
• For patients treated weekly with the 0.4 mg/kg dose, response rates for those previously treated with an anti-CD38 antibody were 63.6% (7/11), and the overall response rate was 66.7% (4/6) for those with prior treatment with T-cell redirection therapy.
• Median time to onset of cytokine release syndrome (CRS) was 1 day, with a median duration of 2 days; 63% of patients had infections, and 22% were grade 3 or 4. There were 3 deaths, 2 for pneumonia and 1 possibly related to the study treatment. Immune effector cell–associated neurotoxicity syndrome occurred in 3 patients, all grade 1 or 2, and resolved in 2 days or less.

At the time of data cutoff, 65.4% of responders were still on therapy, and median duration of response was 20.3 months on the 0.8 mg/kg dose given every 2 weeks and not reached among those taking the 0.4 mg/kg dose weekly. Median progression-free survival (PFS) was 19.4 months for those taking the higher dose every 2 weeks and not reached for those on the lower dose taken weekly; 12-month median PFS rate was 67.4% and 77.4%, respectively. Median overall survival was not reached in either arm.

Both talquetamab and subcutaneous daratumumab, sold as Darzalex, are made by Janssen Pharmaceuticals.

Early Safety, Efficacy Seen in Teclistamab/Talquetamab Combo. What’s better than a bispecific therapy in relapsed/refractory multiple myeloma? How about 2 at once?

The phase 1b RedirecTT-1 study (NCT04586426), which combines the bispecific T-cell engager teclistamab-cqyv (Tecvayli) with talquetamab, a T-cell–redirecting GPRC5D bispecific antibody, showed early activity with acceptable safety levels, according to final results presented during the oral abstract session.⁴

The 93 patients in the study had measurable multiple myeloma and had received prior treatment with a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. Several doses were tested, and 34 patients received the recommended dose identified in study, which was teclistamab at 3.0 mg/kg every 2 weeks and talquetamab at 0.8 mg/kg every 2 weeks. A step-up strategy was employed before the first cycle to limit toxicity.

Investigators reported a 96.3% objective response rate (ORR) for the recommended phase 2 regimen dose and an 86.6% rate across all doses tested in the study. Combined complete response (CR) was 40.2% for all dose levels, and combined stringent response was 40.7% for the recommended dose. Safety profiles were consistent with those of the individual bispecific agents when used as a monotherapy, according to lead investigator Yael C. Cohen, MD, senior physician, Tel Aviv Sourasky Medical Center.

Results showed 88.2% of patients experienced a grade 3/4 treatment-emergent adverse effect (TEAE) and 76.3% of patients experienced cytokine release syndrome (CRS).

“Teclistamab plus talquetamab is the first-ever reported dual bispecific combination in hematologic malignancies,” said Cohen, a senior physician in the Department of Hematology at the Tel-Aviv Sourasky (Ichilov) Medical Center, and Sackler School of Medicine, Tel Aviv University. “These results support the initiation of larger studies with the combination of teclistamab and talquetamab.”

The median age of the study population was 65 years, and 51.6% of patients were male. Most patients were White (79.6%), and 21.8% had 60% or more bone marrow plasma cells. Patients were heavily pretreated; the median number of prior therapies was 4 (range, 1-11) and 79.6% were triple-drug refractory. Almost all, 89.72%, were refractory to their last therapy they received before entering the study.

Median duration of response had not been reached at the time of data cutoff on March 16, 2023, when 61% of patients remained on treatment. Median progression-free survival (PFS) was not yet reached in the recommended dose arm compared with 20.9 months in the full study population, (95% CI, 13.0-not evaluable [NE]). The 9-month PFS rate was 70.1% (95% CI, 58.0%-79.4%) across all doses and 77.1% in the RP2R group (95% CI, 50.8%-90.5%).

“This is the first combination of 2 bispecifics in myeloma, showing promising efficacy compared with single bispecifics, without an apparent increase of toxicity,” said ASCO discussant Andrzej J. Jakubowiak, MD, PhD, director, Myeloma Program, UChicago Medicine. “Regardless of what the next steps are, these results support strategies of combining immunotherapies, and I am looking forward to updated results from this study.”

Additional Results for MonumenTAL-1. Combined data for 288 patients taking talquetamab presented in December at the American Society of Hematology Annual Meeting in New Orleans, Louisiana, showed that more than 70% of patients with multiple myeloma saw responses that deepened over time.⁵

Updated results for the phase 1/2 MonumenTAL-1 study (NCT03399799), now totaling 339 patients, were treated with subcutaneous talquetamab at the recommended phase 2 dose of 0.8 mg/kg biweekly or 0.4 mg/kg weekly with step-up doses. The overall response to talquetamab was similar at both doses. After a median follow-up of 12.7 months, 71.7% of response-evaluable patients treated at the higher dose at 2-week intervals achieved a response, and 60.7% achieved a very good partial response or better, with 9% achieving a complete response and 29.7% a stringent complete response.⁶

After a median follow-up of 18.8 months, 74.1% of response-evaluable patients taking the lower weekly dose saw a 59.4% very good partial response or better, with a 9.8% complete response and a 23.8% stringent complete response.

Median duration of response was not reached for those on the larger, biweekly dose and was 9.5 months for those on the smaller, weekly dose. The 12-month PFS rates were 54.4%, 34.9%, and 38.1%, respectively.

Discontinuation rates due to adverse events were low—8% at the larger dose and 5% at the smaller dose. Common AEs at both doses were CRS, which was comparable (74.5% at the larger dose and 79% at the smaller dose), but rates of grade 3 or higher were low (0.7% for the larger dose, 2.1% for the smaller dose). Other common AEs affecting more than 70% of patients were dysgeusia (all grade 1 and 2), skin-related AEs affected 73.1% of patients for the larger dose only. Safety profile was manageable. There were no talquetamab-related deaths. 

References
1. Dholaria BR, Weisel K, Mateos MV, et al. Talquetamab (tal) + daratumumab (dara) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): updated TRIMM-2 results. J Clin Oncol. 2023;41(suppl 16):abstract 8003. doi:10.1200/JCO.2023.41.16_suppl.8003
2. Janssen announces US FDA Breakthrough Therapy Designation granted for talquetamab for the treatment of relapsed or refractory multiple myeloma. News release. Johnson & Johnson. June 29, 2022. Accessed June 16, 2023. https://bit.ly/43LI5lg
3. Key statistics about multiple myeloma. American Cancer Society. January 12, 2023. Accessed June 16, 2023. https://bit.ly/42MwX6y
4. Cohen YC, Morillo D, Gatt ME, et al. First results from the RedirecTT-1 study with teclistamab (tec) + talquetamab (tal) simultaneously targeting BCMA and GPRC5D in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2023;41 (suppl 16):abstract 8002. doi:10.1200/JCO.2023.41.16_suppl.8002
5. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-cell–redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 2022;387(24):2232-2244. doi:10.1056/NEJMoa2204591
6. Schinke C, Touzeau C, Minnema MC, et al. Pivotal phase 2 MonumenTAL-1 results of talquetamab (tal), a GPRC5DxCD3 bispecific antibody (BsAb), for relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2023;41(suppl 16);abstract 8036. doi:10.1200/JCO.2023.41.16_suppl.8036

SPOTLIGHT: Bhagirathbhai R. Dholaria, MBBS, Discusses Updated TRiMM-2 Trial Findings

Bhagirathbhai R. Dholaria, MBBS, an assistant professor of medicine in the Division of Hematology-Oncology at Vanderbilt University Medical Center in Nashville, Tennessee, presented findings from the phase 2 TRiMM-2 trial of talquetamab plus daratumumab in relapsed/refractory multiple myeloma in an oral session at the American Society of Clinical Oncology 2023 Annual Meeting. He discussed the findings with Evidence-Based Oncology (EBO).

EBO: Can you discuss therapeutic rational for combining the bispecific antibody talquetamab with the subcutaneous anti-CD38 monoclonal antibody daratumumab (Darzalex Faspro) in patients who have been heavily pretreated for multiple myeloma?

Dholaria: Daratumumab is one of the most effective therapies for [patients with] newly diagnosed or relapsed/refractory multiple myeloma. And one of the important immunomodulatory effects of daratumumab is that it also depletes the CD38-expressing regulatory T cell. The hope was that you can potentially improve the efficacy of talquetamab, which relies on the host T cell function, to attack the cancer and control the myeloma. If you combine both of these together, maybe you can potentiate the antimyeloma activity of talquetamab.

EBO: Can you describe the patient population in this study? How many lines of treatment had most received, and how many had received chimeric antigen receptor (CAR) T-cell therapy?

Dholaria: These patients had relapsed/refractory multiple myeloma with 3 or more prior lines of therapy, and [they] had double refractory myeloma. We did allow prior exposure to CAR T-cell therapy or other bispecific monoclonal antibody therapy in this trial. These were a heavily pretreated group with a median of 5 or more lines of therapies. A majority of these patients—more than 90%—had [B-cell] disease, which is refractory to daratumumab. We also had [approximately] 11 patients who had prior CAR T-cell therapy and 15 patients who had prior bispecific antibody drug therapy exposure.¹

EBO: Can you characterize the quality of the responses in these patients?

Dholaria: Responses were encouraging. In the 0.4 mg/kg cohort in combination with daratumumab, [approximately] 70% of patients had an overall response rate. Among the patient who were in the 0.8 mg/kg biweekly cohort with daratumumab, the overall response rate was more than 80%, which is slightly better than what we achieve with monotherapy talquetamab now. These responses were rapid and also deepened over time, and very few patients actually required those interruptions [or came] off the trial because of the [adverse] effects.¹

EBO: How did cytokine release syndrome (CRS) compare with what is seen following other treatments for multiple myeloma?

Dholaria: CRS was one of the most commonly reported [adverse] effects, so it happened to the majority of the patients, typically during the cycle 1 of the therapy during this step of dosing. However, most CRS events were grade 1 or grade 2, and they were managed quite well. In terms of neurotoxicity, the overall incidence was low, and all events with neurotoxicity were grade 1 or grade 2.1.

Reference
Dholaria BR, Weisel K, Mateos MV, et al. Talquetamab (tal) + daratumumab (dara) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Updated TRIMM-2 results. J Clin Oncol. 2023;41(suppl 16):8003. doi:10.1200/JCO.2023.41.16_suppl.8003

Analysis Finds Daratumumab Combo Offers Better PFS Than Bortezomib Combo in Newly Diagnosed MM

When multiple therapeutic combinations are listed in the National Comprehensive Cancer Network guidelines, how do clinicians select the best one for patients?

An analysis presented at American Society of Clinical Oncology (ASCO) Annual Meeting offered answers to this question in newly diagnosed multiple myeloma (MM). Investigators used data from a pair of key trials to compare results for daratumumab with lenalidomide (Revlimid) and dexamethasone (DRd) vs bortezomib (Velcade) with lenalidomide and dexamethasone (VRd).¹

Using trial data from the MAIA and SWOG S0777 trials, investigators drilled down into individual patient-level data to create an indirect treatment comparison of DRd (MAIA) and VRd (SWOG S0777). The analysis adjusted for the trials’ differences in inclusion criteria and baseline patient characteristics. According to the abstract, 65 years or older served as a proxy for transplant ineligible status because the SWOG S0777 trial enrolled a mix of transplant ineligible and transplant-not-intended patients. The median age of patients evaluated was 63 years.

According to the study authors, propensity score reweighting allowed for balancing of the different trial populations’ age, sex, cancer stage, ECOG performance status, and other factors. After this reweighting, the authors wrote, “an anchored indirect comparison was performed wherein within-trial progression-free survival (PFS) hazard ratios (HRs) for DRd vs Rd and VRd vs Rd were estimated,” and these evaluations were then used to make indirect comparison about PFS between DRd and VRd.

In total, 727 patients from the MAIA trial and 198 from the SWOG S0777 trial were eligible for the analysis. Results showed the following:

• The adjusted PFS HRs for DRd vs Rd was 0.53 (95% CI, 0.41-0.68; P < .0001) and VRd vs Rd was 0.88 (0.63-1.23; P = .46).
• The adjusted Rd-anchored indirect comparison found the PFS HR for DRd vs VRd was 0.60 (0.39-0.90; P = .02).

Study authors concluded that in this indirect comparison, PFS was significantly longer for DRd relative to VRd. Lacking a head-to-head trial comparing the 2 regimens, they concluded, “the present study may help to inform treatment selection in transplant ineligible patients with newly diagnosed multiple myeloma.”

At-home Subcutaneous Daratumumab Evaluated. A poster session at ASCO featured details of an open-label, single-arm trial that will evaluate the implementation of home administration of subcutaneous daratumumab.

As the authors stated in their abstract, MM has a high burden for patients and their caregivers, requiring frequent visits to hospitals or clinics, and new care delivery models are needed to alleviate patient burden and improve quality of life.²

“Chemotherapy at home remains uncommon in the US, though models for its use exist globally,” they wrote. “In these models, home-based chemotherapy is safe, preferred by patients, and can be administered at lower cost.”

The trial (NCT05511428) will study home-based subcutaneous daratumumab and hyaluronidase-fihj, sold as Darzalex Faspro, for patients with MM. The study authors hypothesize that this program will reduce patient treatment and financial burden and improve quality of life. Using the Cancer Therapy Satisfaction Questionnaire, investigators will evaluate 20 responses when patients receive at-home care, compared with standard of care.

Secondary outcomes will include assessing adherence, quality of life as measured the EORTC QLQ-30 scale, financial burden as measured by the COST survey, safety of home administration, and barriers to home administration. Investigators will also conduct semistructured interviews to evaluate patient experience with home administration of chemotherapy.
Eligible patients must have a diagnosis of MM and be in the monthly phase of daratumumab treatment, either as monotherapy or in combination with other agents. The study will last for 8 cycles of daratumumab—2 cycles in the infusion center, 4 cycles at home, and 2 cycles in the infusion center. Labs will be performed at a local lab or at home.

Of note, the investigators write, on at-home daratumumab days, the drug will be mixed and packaged by the study pharmacy, “then delivered at room temperature to the patient’s home by our home infusion courier,” where it will administered by a nurse, after the patient takes premedications 1 to 3 hours prior to the nurse’s arrival.

Both studies are funded by Janssen. 

References
1. Durie BG, Kumar S, Ammann EM et al. Adjusted indirect treatment comparison of progression-free survival (PFS) associated with DRd and VRd based on MAIA and SWOG S0777 individual patient-level data. J Clin Oncol. 2023;41 (suppl 16):8037. doi:10.1200/JCO.2023.41.16_suppl.8037
2. Binder AF, Martinez-Outschoorn UE, Wilde L, et al. Open label single arm study to assess the implementation of home based daratumumab administration in patients being treated for multiple myeloma. J Clin Oncol. 2023;41(suppl 16);TPS1609. doi:10.1200/JCO.2023.41.16_suppl.TPS1609

SPOTLIGHT: Hans C. Lee, MD, Shares Results for Linvoseltamab in R/R MM

Hans C. Lee, MD, associate professor, Department of Lymphoma/Myeloma, Multiple Myeloma Clinical Research, Department of Lymphoma/Myeloma,

Lee

Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses results from the phase 2 LINKER-MM1 study. He presented results from the investigation of the BCMA x CD3 bispecific antibody linvoseltamab (REGN5458) in patients with relapsed/refractory multiple myeloma at the 2023 American Society of Clinical Oncology Annual Meeting.

In the study, patients were divided into 2 cohorts; 104 patients were given a 50-mg dose, and 117 patients were given a 200-mg dose.

EBO: Can you discuss findings from LINKER MM-1?

Lee: According at the 50-mg dose cohort, the overall response rate was 50%. At the recommended 200-mg dose cohorts, the overall response rate was 71%, with a very good partial response rate or better of 89% and a complete response rate or better of 30%.

Notably, two-thirds of patients who are dosed at the 200-mg cohort remained on study at the time of the data cut off in February of 2023. And among patients with a stringent [complete response] or CR, across a 50 mg or 200 mg cohorts with evaluable [minimal residual disease] data, 54% of patients were MRD negative. In terms of duration, responses appear to be durable and deepened with time as 6-month probability of maintaining a response in the 200-mg cohort was 84%. At a median follow-up of 7.7 months, in the 50-mg cohort, the median progression free survival is 7.9 months. At a median follow-up of 5.6 months in the 200-mg cohort the median progression free survival had not been reached. And the 6-month probability of progression free survival was 73% in this 200-mg cohort. 

A version of this interview first appeared on OncLive.

Reference
Lee HC, Bumma N, Richter JR, et al. LINKER-MM1 study: Linvoseltamab (REGN5458) in patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2023;41(suppl 16):8006. doi:10.1200/JCO.2023.41.16_suppl.8006