GMMG-CONCEPT Trial Homes in on High-Risk Patients With Multiple Myeloma

Emerging evidence from the phase 2 GMMG-CONCEPT trial suggests that the addition of an anti-CD38 monoclonal antibody to a standard proteasome inhibitor (PI), immunomodulatory drug, and dexamethasone-based backbone could serve as a way to overcome the negative impact of high-risk multiple myeloma, explained lead study author Katja Weisel, MD.

In the trial, patients with newly diagnosed high-risk multiple myeloma, defined by del(17p), t(11;14), t(14;16), more than 3 copies of 1q21, and International Staging System (ISS) II or III disease received isatuximab-irfc (Sarclisa), carfilzomib (Kyprolis), lenalidomide (Revlimid) and dexamethasone as induction, consolidation, and maintenance therapy. A total of 117 transplant-eligible patients were included in Arm A and 36 transplant-ineligible patients in Arm B.

Interim results, which were presented during the 2020 European Hematology Association Congress and analyzed after 6 cycles of induction therapy, demonstrated an overall response rate (ORR) of 100%, a very good partial response rate (VGPR) or better of 90%, and a complete response (CR)/stringent CR (sCR) rate of 46% among 50 evaluable patients.

Investigators also assessed the presence of minimal residual disease (MRD) in 33 patients in Arm A during induction and found that the majority, or 61%, were MRD negative.

“Normally, high-risk patients are included in all-comer trials and represent 15% to 20% of the total patient population, upon which we base our subgroup analyses,” said Weisel. “Our trial enabled us to better understand what high-risk patients need and whether [this quadruplet regimen] is the best way to overcome the negative impact of high-risk disease.”

In an interview with OncLive, Weisel, of the University Hospital Hamburg, explained the rationale for the trial, detailed the key interim findings, and provided foresight on future milestones in the field of multiple myeloma.

OncLive: What inspired the launch of the GMMG-CONCEPT trial?

Weisel: The GMMG-CONCEPT trialis a phase 2 investigator-initiated trial that is combining the mosteffective drugsin the frontline setting for patients with high-risk multiple myeloma, irrespective of transplant eligibility status. High risk is defined by cytogenetic abnormalities, and all patients have to have ISS stage II or III disease [in order to have participated].

The trial was conducted in 20 German centers. Eligible patients received quadruplet therapy that consisted of an anti-CD38 monoclonal antibody, carfilzomib which is a next-generation PI, lenalidomide, and dexamethasone to induce MRD-negative remissions. MRD negativity, especially in high-risk patients, translates into a better progression-free survival, and ultimately, hopefully also overall survival. To make this possible for this patient population with impaired prognosis, we started this trial.

What were the results from the interim analysis that were presented at the 2020 EHA Congress?

The interim analysis included data on the first 50 patients that were enrolled in the trial [and responded] during induction treatment with [the quadruplet regimen]. A total of 46 patients were transplant eligible and 4 patients were transplant ineligible.

The results showed that all 50 patients were evaluable for response and all achieved at least a partial remission. The ORR was 100%, and encouragingly, 90% of patients achieved a VGPR or better. Additionally, 46% of patients [achieved a] CR or sCR.

We also analyzed 33 patients for MRD. A total of 20 patients were MRD negative, while 11 were MRD positive. We hope [the patients who are MRD positive] become MRD negative with further treatment. These data are encouraging to see, as these were all high-risk patients.

What was the safety profile of this regimen?

The main toxicities reported were hematologic, predominantly neutropenia. The rate of grade 3/4 thrombocytopenia was low, at 14%. Regarding non-hematologic toxicities, we saw a few cardiovascular events. Twelve percent of patients experienced [severe grade] hypertension. However, the rate of all-grade peripheral neuropathy was low, at 16%. The predominant non-hematologic toxicity, as expected, was infection; however, this was mainly grade 1/2 in severity. Overall, the addition of the anti-CD38 antibody to triplet backbone did not significantly enhance the expected toxicity.

What does treatment typically look like for this patient population?

When we look at the breakthrough trials, the first trial investigating lenalidomide and dexamethasone in transplant-ineligible patients for example, or even the CASSIOPEIA trial investigating daratumumab (Darzalex) in combination with bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone, the high-risk patients always benefit [from the investigational regimen]. However, the impact of high-risk disease is never overcome.

On the contrary, we see that, for example, some standard-risk patients have tremendous benefit from a doublet or triplet regimen. [In the GMMG-CONCEPT trial], we also have a broad correlative program that’s investigating immune profiles and immune responses to further our insights.

What specific questions do you hope to address with further follow-up from this trial?

The trial just recently completed recruitment with 153 patients in April 2020. Hopefully, we’ll be able to report [our findings] on the full patient population at the end of 2021. The primary end point of the trial is MRD negativity after consolidation. We’ll gain more substantial data on this patient population [with further follow-up].

What other myeloma research was presented at this year’s meeting that you would like to highlight?

We saw very intriguing data on novel combinations. For example, we saw the results of the phase 3 BOSTON trial investigating selinexor (Xpovio) in combination with bortezomib and dexamethasone. We saw data on the BCMA-directed antibody-drug conjugate belantamab mafodotin in combination with bortezomib and dexamethasone. We also saw data on the novel cellular modulator CC-480. Moreover, for the first time, we saw very early, but very intriguing data on bispecific antibodies. Follow-up and new data on CAR T-cell therapy were also reported. We’re moving forward into a broad armamentarium, and in doing so, we’re optimizing our standard of care.

Reference

Weisel K, Asemissen AM, Besemer B, et al. Depth of response to isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in front-line treatment of high-risk multiple myeloma: interim analysis of the GMMG-CONCEPT trial. J Clin Oncol. 2020;38(15 suppl):8508. doi:10.1200/JCO.2020.38.15_suppl.8508