Safety Run-In Cohort Supports Addition of Isatuximab to Chemotherapy Triplet in Myeloma

Katja Weisel, MD

Katja Weisel, MD

All 10 patients enrolled in the safety run-in cohort of the phase II, multicenter GMMG-CONCEPT trial had a response with the addition of isatuximab to the chemotherapy regimen carfilzomib (Kyprolis) and lenalidomide (Revlimid) plus dexamethasone (I-KRd). The quadruplet regimen also appeared well-tolerated in patients with treatment-naïve multiple myeloma (MM).

Six patients achieved a very good partial response (VGPR) and 4 a complete response (CR) following cycle 2 of treatment. After cycle 6, patients had a CR, 2 with a VGPR, and 1 with progressive disease.

Treatment-emergent adverse events (TEAEs) were reported in all 10 patients. The most common grade 3 or greater TEAEs were hematologic, including neutropenia, leukopenia, lymphopenia, anemia, and thrombocytopenia. Cerebral vascular disorders, self-limiting ventricular tachycardia, and diarrhea accounted for the most common grade 3 or greater nonhematologic TEAEs. Five serious toxicities occurred, including infections and incidents of cerebral ischemia and self-limiting ventricular tachycardia. However, cerebral events were not classified as treatment-related due to preexistingconditions.

Patients with newly diagnosed MM and high-risk disease defined as deletion 17p or t(4;14) or t(14;16) or >3 copies of +1q21 are currently being enrolled into the trial. To be included in the trial, all patients have to be International Staging System (ISS) stage 2 or 3. Patients could have previously received 1 cycle of any treatment. Patients are being stratified by transplant eligibility or ineligibility, in which arm A includes eligible and age ≤70 years and arm B includes ineligible or age >70 years. The primary end point of this trial is to achieve minimal residual disease (MRD)-negativity.

In an interview withTargeted Oncology, Katja Weisel, MD, Department of Hematology, Oncology and Stem Cell Transplantation, University Hospital Eppendorf, Hamburg, Germany, discussed the safety findings of the 4-drug chemotherapy regimen in the GMMG-CONCEPT trial, which were presented at the 17^thInternational Myeloma Workshop (IMW).

TARGETED ONCOLOGY: How do patients deal with the 3- versus 4-chemotherapy regimen? Is it generally accepted and tolerated?

Weisel:Currently, we see a trend toward the 4-drug regimen, and we have to ask the question of whether that is feasible and tolerable for our patients. What we see is that this is a very tolerable treatment strategy when we bring together the monoclonal antibodies, the proteasome inhibitors, the immunomodulating agents, and the dexamethasone. Those combination treatments are well-tolerated in young but also in elderly patients.

TARGETED ONCOLOGY: What was the rationale for evaluating this treatment regimen?

Weisel:I presented an investigator-initiated, academic trial, which is conducted in 20 centers in Germany. We treated only high-risk patients defined by cytogenetics risk and ISS stage. We treated those patients with isatuximab in combination with carfilzomib, lenalidomide, and dexamethasone for an extended induction treatment. Transplant eligible patients undergo high-dose methylation treatment and autologous stem cell transplantation. All patients receive consolidation and a 3-drug maintenance treatment. The primary goal, which is also the primary endpoint, is to achieve MRD-negativity. We measure this with FLOW in this high-risk patient population because we know high-risk patients have a much better prognosis regarding progression-free but also overall survival if MRD-negativity is reached.

TARGETED ONCOLOGY: What are the findings reported at IMW?

Weisel:We report, for the first time on this trial, the safety run-in phase that accounts for the first 10 patients included in the trial. What we saw is a favorable safety profile where there was no discontinuation due to AEs during induction treatment. All patients could be kept on the protocol. We have some hematologic toxicity; however, we had only 1 case of febrile neutropenia and overall 3 grade 3/4 non-hematologic toxicities, including 1 diarrhea, 1 ventricular tachycardia, and 1 cerebral bleeding, however that was due to a congenital aneurysm.

Overall, we saw that we have a very favorable toxicity profile. At first glimpse, we also looked at the efficacy, and we saw in the first 10 patients that all patients after 2 cycles of induction treatment were at least VGPR, and this was continuously deepened overtime. After induction, we had the majority of the patients in CR. For now, these are encouraging first data out of the trial.

TARGETED ONCOLOGY: What was your rationale for combining this particular agent with the 3-drug regimen?

Weisel:We learned from the trials, especially in relapsed MM, that the addition of the monoclonal CD38 antibody leads to a decent amount of MRD-negativity. Our rationale to add this antibody in the first-line treatment was to put the best drugs together to do everything that we can do to bring this high-risk patient population in an MRD-negativity disease state. We know that monoclonal antibodies, in general, are well-tolerated, so the risk-benefit assessment for us was in favor of the benefit.

TARGETED ONCOLOGY: How was this agent received in patients that have renal impairment?

Weisel:We included in the trial patients with an eGFR of 30 MPL ml/min. We also include patients that have moderate or are at the beginning of severe renal impairment. So far, we have no signal that it has more toxicity in renal-impaired patients. I, myself, am [investigating] relapsed patients and introducing daratumumab (Darzalex) in patients with severe renal impairment, also under the dialyzes. We see that the monoclonal antibodies can be very safely administered also underdialyzes.

TARGETED ONCOLOGY: What is the place for subcutaneous daratumumab versus intravenous (IV) daratumumab?

Weisel:We currently have a new development, so the monoclonal antibodies have the potential to be administered subcutaneously. This is currently available in clinical trials, at least, for daratumumab. I have had experience with that in clinical trials. It makes things easy because you can administer it in 10 minutes and the infusion-related reactions are less. However, we saw with an optimized strategy of IV treatment with accelerated IV application of monoclonal antibodies that the CD38 antibodies can be much more rapidly administered in the daily routine, even if you use IV like we did that at the beginning. I think in regard to convenience, it’s good to have the choice of both for the individual patient to see how to administer the antibody.

TARGETED ONCOLOGY: What are the next steps for the GMMG-CONCEPT?

Weisel:For our trial, we plan to include overall 153 patients. We currently have included 112. The next step will be an interim analysis of induction treatment, and we hope to present that next year at the conventions. We also do a large correlative study program looking at the immune profiling and immune signature of our patients. We hope we can get inside how the immune system may control the residual disease and may lead to further durability of MRD-negativity. We would like to elucidate more on the mechanisms behind keeping patients in deep remissions overtime.

Reference:

Weisel K, Asemissen AM, Schieferdecker A, et al. Isatuximab, carfilzomib, lenalidomide and dexamethasone (I-KRd) in front-line treatment of high-risk multiple myeloma: results of the safety run-in cohort in the phase II, multicenter GMMG-CONCEPT trial. Presented at: The 17th International Myeloma Workshop; Sept. 12-15, 2019; Boston. Abstract 362.