Samer A. Srour, MB, ChB, MS, Discusses Umbilical Cord Blood-Derived Natural Killer Cell Combination as a Potential Strategy for High-Risk Multiple Myeloma

Elotuzumab, lenalidomide, high-dose melphalan, as well as umbilical cord blood–derived natural killer cells and autologous stem cell transplant demonstrated tolerability and improved transplant outcomes for high-risk multiple myeloma.

Treatment with umbilical cord blood–derived natural killer cell plus the combination of elotuzumab (Empliciti), lenalidomide (Revlimid), and high-dose melphalan (Evomela) with autologous stem cell transplant (ASCT) resulted in improved transplant outcomes and hematologic response rates for patients with high-risk multiple myeloma, according to Samer A. Srour, MB, ChB, MS.

In a phase 2 trial (NCT01729091), in a population of 30 patients 73% had a very good partial response (VGPR) or better prior to ASCT, 40% achieved a complete response (CR) or stringent CR (sCR), and 43% were minimal residual disease (MRD) negative.1 Three months after transplant, 97% of patients had a VGPR, 76% had a sCR or CR, and 75% were MRD negative.

Srour, an assistant professor in the Department of Stem Cell Transplantation and Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center, and principal investigator of this study, spoke with CancerNetwork® regarding the findings from the which were presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, emphasizing the importance administering treatment in the right setting.

“We have to always think about how to use these good, safe treatments in the right setting, and this is the right platform in the transplant setting and the low tumor burden setting,” Srour said. “We have to move forward into a phase 2 or phase 3 randomized study to prove that these results are accurate in a larger setting. Hopefully, at some point, [this regimen will] get FDA registration approval.”

In the interview, Srour highlighted key data that read out of the study, the positive safety profile the combination, and the need to expand on this research further.

CancerNetwork®: Can you describe the process for utilizing the umbilical cord blood-derived natural killer cell combination therapy along with elotuzumab, lenalidomide, high-dose melphalan, and ASCT for this patient population?

Srour: We’ve been working with the umbilical cord-derived natural killer cells for over 10 years now. What was presented at ASCO this year is a product of 10 years of work. We know that natural killer cells have anti-tumor activity in addition to other benefits and they’re safe when we use them. The availability of these cells is limited to some donors who have to donate because the patients themselves have frequently dysfunctional natural killer cells. We run one of the largest cord blood centers in the country, and that’s where we started working on the cord-derived natural killer cells, and whether we can use this as a readily available resource for our patients. We have shown that expanding the natural killer cells from cord blood is feasible. We are able to generate a high number of these cells. They are purified natural killer cells that aren’t very contaminated by T cells.

Initial preclinical data showed some anti-tumor activity against myeloma from in vivo mouse models.2 When we took [patients] to the clinic, we wanted to make sure they have better activity because there were many studies, not just in myeloma but other cancers, showing that natural killer cells by themselves, although they have some tumor activity, are not good enough to make it to a clinically meaningful benefit. Initially, we added lenalidomide, a drug that can enhance [natural killer] cells to the cord blood-derived [natural killer] cells.

We showed some activity, but we were not happy [with the results seen with] lenalidomide and natural killer cells; we wanted it to be stronger. Then we added elotuzumab to this platform based on some preclinical data. We showed preclinically, that we have synergism, and increased anti-tumor activity when we add elotuzumab to lenalidomide and natural killer cells, particularly in high-risk resistant myeloma cell lines. That’s where we took it to the clinic as a phase 2 expansion [trial], and we used this platform. The results so far are impressive.

What did the efficacy findings present at this year's meeting include?

This expansion, phase 2 cohort which included in the final platform of elotuzumab, lenalidomide, and the cord blood–derived expanded natural killer cells [began] in early 2018, and we accrued the last patient in early 2021. [This took place] over 2 years, and despite COVID, we were able to accrue very well on this study. Now we have mature data after an immediate follow-up of 26 months for these 30 patients who all have high-risk multiple myeloma. Historically, we know the median survival is short—[about] less than 3 to 5 years—and with all the new treatments in myeloma, we were not able to overcome much of the resistance and much of the high-risk profile of these patients.

The primary end point was day 100 post-transplant VGPR or better, and MRD negativity at day 100 after transplant. We gave this regimen in the context of the transplant. Patients took elotuzumab, then lenalidomide, and then we gave them high-dose melphalan, [followed by] the natural killer cells. After that, we gave them back their autologous stem cells, and then they were engrafted as any other [patients with] myeloma. They engrafted on time within 10 to 11 days from the transplant. We looked at the best response at 3 months after transplant before getting any other treatments. We found out that the VGPR or better was 97%. We don’t see that in the high-risk [patients with] myeloma. The MRD negativity rate was 75%. [This is rarely] seen in [patients with] high-risk myeloma even after transplant.

The primary endpoint was very impressive for us. We waited over 2 years to show [whether] this MRD-negativity rate and the VGPR [rate] translate to better progression-free survival [PFS] and overall survival [OS]. We found out that the 2-year PFS was 83%, which is historically around 60% or less, and then the OS was 97%. Only 1 patient died from COVID-19 infection.

These [findings] were impressive for us. This is a new regimen but it’s being used in a new era where there are many other treatments, so maybe the outcomes are better because of other confounders. Therefore, we looked around the same time period of 2018 to 2021, and we chose a control of [patients with] high-risk myeloma who were treated with us at MD Anderson. We looked at the data to compare our study patients to these control patients who were treated homogeneously in the same way, but without the [natural killer] cells, elotuzumab, [and] lenalidomide. We found statistically significant improvement in our study patients compared [with] the control. In the control arm, the 2-year, PFS was only 60%, and the 2-year OS was only 83%. That’s compared [with an] 83% PFS rate in our study and 97% OS rate; it is statistically significant.

We hope to move forward. We’re having serious discussions with different parties to move forward in a more multicenter phase 2 or 3 randomized study because these results are the first we’ve seen in [patients with] high-risk myeloma. [They were] impressive clinically meaningful improvements in the outcomes, not just numerical improvements.

Were there any concerns with regard to safety in this regimen?

I was personally very impressed on how safe this regimen was. We didn’t see any unexpected serious adverse effects [AEs]. This regimen was used in the context of transplant, so patients already had high-dose chemotherapy and were admitted to the hospital for that reason. They received the natural killer cells during that process. [There were] cytopenias, transfusions, and fevers or febrile neutropenia, which we see in transplantation. There were no unexpected AEs that you see with these cell therapies normally. That has been shown with other studies that natural killer cells—non-engineered natural killer cells and even the engineered natural killer cells—have a [better] toxicity profile than T cells or the CAR T cells.

How do you foresee this research impacting treatment?

This will be a new reviving step for the use of the natural killer cells in the feel of myeloma because we’ve been using [natural killer] cells for over a decade and not just at MD Anderson but in many other areas of the world and the United States. Every now and then we lose some hope that natural killer cells can still be utilized in the management of our [patients with] cancer. This study will revive the hope that the natural killer cells can be used. We just have to use them in the right setting. What we have done in our study at MD Anderson—the most novel part of it, not just the combination platform—is use it in the right setting. We used it in the transplant setting where the patients received some induction therapy, and they have a low tumor burden. The natural killer cells have a nicely immunosuppressed environment from the conditioning melphalan, and with low tumor burden, the natural killer cells, when you give them in that setting, are able to do what they’re supposed to do.

References

  1. Srour SA, Mehta RS, Shah N, et al. Phase II study of umbilical cord blood–derived natural killer (CB-NK) cells with elotuzumab, lenalidomide, and high-dose melphalan followed by autologous stem cell transplantation (ASCT) for patients with high-risk multiple myeloma (HRMM). J Clin Oncol. 2022; 40(suppl_16):8009-8009. doi: 10.1200/JCO.2022.40.16_suppl.8009
  2. Shah N, Martin-Antonio B, Yang H, et al. Antigen presenting cell-mediated expansion of human umbilical cord blood yields log-scale expansion of natural killer cells with anti-myeloma activity. PLoS One. Published Oct 18, 2013. doi:10.1371/journal.pone.0076781