Nizar Bahlis, MD, Recaps Follow-Up Data on Combo Therapy for R/R Multiple Myeloma

After 3 years of follow-up, data from the phase 3 POLLUX trial evaluating daratumumab plus lenalidomide and dexamethasone for the treatment of patients with relapsed/refractory multiple myeloma were presented at the 60th ASH Annual Meeting & Exposition in San Diego, California.

Among the results, higher rates of deeper responses and delayed disease progression stood out, demonstrating the combination therapy’s long-term efficacy.

While at the conference, lead investigator Nizar Bahlis, MD, associate professor at Charboneau Cancer Research Institute at the University of Calgary, sat down with Rare Disease Report^®(RDR^®) to go over the trial’s highlights and explain what long-term use of the combination therapy means for patients.

[Editor’s note: Transcript is slightly modified for readability.]

RDR^®: What is the background behind this trial?

Bahlis: “The POLLUX trial was looking to explore the activity of daratumumab, the first-in-class CD38-targeted, IgGκ monoclonal antibody in combination with lenalidomide and dexamethasone, which was the standard therapy for multiple myeloma when the study was designed.

The study compared the outcome of patients with relapsed multiple myeloma receiving daratumumab in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone. The study demonstrated improved progression-free survival response rates in multiple myeloma.

At ASH 2018, I presented a follow-up of this trial to examine whether there is persistent or continued improvement in outcomes of these patients."

RDR^®: What were the hallmarks you observed in the data?

Bahlis: “The study was looking to demonstrate whether the improvement in progression-free survival continued over time or changed over time. At the follow-up now of 43/44 months, the median progression-free survival is 44.5 months for the daratumumab plus lenalidomide and dexamethasone arm compared to only 17.5 months for the lenalidomide and dexamethasone arm.

These results represent the best survival outcome for patients with relapsed multiple myeloma that we have ever used in this patient population. Importantly also, the study outcome demonstrated further improvement with the updated follow-up of the overall response rate as 93% of the patients have responded, 57% have achieved complete remission—which was an incredible result—and over 80% achieved very good partial remission as well.

In this study, we also explored the depth of response, in particular the minimal residual disease (MRD), meaning patients who achieved at least a 10^—5 MRD depth of response. In this study, we demonstrated that 30% of the patients in the daratumumab arm with MRD 10^—5 using the clonoSEQ technology [Adaptive Biotechnologies] for MRD measurements.

These are incredible results. Importantly, the study shows that more than half of these patients sustain the MRD negative states with a longer follow-up or sustain the MRD negative state beyond 12 months.

This is an unprecedented result for a multiple myeloma therapy, and it dramatically improves the outcomes of patients."

RDR^®: What makes this combination therapy unique in its function for patients with relapsed/refractory multiple myeloma?

Bahlis: “We’re really fortunate in multiple myeloma to have the combination of monoclonal antibodies with the class of immunomodulatory drugs in general. Like I said before, daratumumab is the first-in-class monoclonal antibody targeting CD-38. At the same time, immunomodulatory drugs have the advantage of activating the adaptive and innate immunity. So, we have a class of drugs activating adaptive and innate immunity, but at the same time, we have a monoclonal antibody targeting the myeloma cells.

One unique thing—and perhaps fortunate thing for us in multiple myeloma with daratumumab—is that it not only targets the myeloma cells by binding to CD-38 and the myeloma cells, but it also targets CD-38 and some of the immunosuppressive cells in the bone marrow environment. In particular, it binds myeloid suppressive cells and FACS, which express CD-38, inducing their cell death, but it also suppresses some of the inhibitory cells in the bone marrow environment, such as regulatory T cells and regulatory B-cells as well.

Again, we have the perfect storm type of environment with activating immunology drugs, antibodies binding to myeloma cells, and also suppressing the immunosuppressive cells in the bone marrow environment. Therefore, it’s not surprising to see the dramatic responses that we’ve seen."

RDR^®: What are the next steps with this data?

Bahlis: “We are still awaiting the overall response to make sure; the follow-up is still early. Nevertheless, we are seeing some signs of improvement in overall survival in favor of the daratumumab plus lenalidomide and dexamethasone arm. As of this update, there are 17 more deaths in the lenalidomide and dexamethasone arm, suggesting we will most likely see an improvement in overall survival.

Also, 1 important aspect of multiple myeloma is that whatever therapy you administer today, you want to be sure that it doesn’t impact your outcome in the next line of therapy, and that’s what we call the multiple myeloma progression-free survival 2, or PFS2.

Importantly, this study did demonstrate that despite the significant improvement with daratumumab in the initial PSF1, it did not impact the response of the patient in the next line of therapy. Therefore, the PSF2 was improved in the daratumumab arm."