MagnetisMM-1 Shows Promise of Elranatamab in Relapsed/Refractory Myeloma

Moshe Y. Levy, MD

Elranatamab (PF-06863135) demonstrated a manageable safety profile in patients with relapsed or refractory multiple myeloma treated in the phase 1 MagnetisMM-1 trial (NCT03269136), and the agent showed promising early activity as a monotherapy and in combination with pomalidomide (Pomalyst).

In the monotherapy cohort, 30 patients with relapsed/refractory multiple myeloma received elranatamab by subcutaneous injection. To evaluate the safety of the agent, 6 dosing groups were included. In total, 6 patients received elranatamab at 80 μg/kg, 4 received a dose of 215 μg/kg, another 4 patients were treated with 360 μg/kg of elranatamab, 6 received 600 μg/kg, and another 6 received the highest dose level, 1000 μg/kg.

Objective responses to elranatamab were observed at dose levels of 215 μg/kg or higher. The objective response rate (ORR) in these patients was 70.0% with stringent complete responses (sCR) or CR in 30.0%. The recommended phase 2 dose was determined to be 1000 μg/kg, and in the population of patients treated at this dose level, the ORR was 83.3%.

The safety analysis showed no dose-limiting toxicities. The most common treatment-emergent adverse events (TEAEs) of any grade were lymphopenia (86.7%), anemia (76.7%), and cytokine release syndrome (CRS, 73.3%). Notably, CRS events were grade 1/2 only and only lasted for a median duration of 3,0 days (range, 1-10). Treatment to resolve CRS included tocilizumab (Actemra) in 9 patients and steroids in 3 patients.

In the combination arm, 8 out of 9 patients with relapsed/refractory multiple myeloma were treated. The confirmed ORR in this arm was 78%, which included 1 sCR, 2 very good partial responses, and 4 partial responses.

Safety findings from patients treated with elranatamab plus pomalidomide showed that the most common TEAEs of any grade were CRS (78%), fatigue (79%), neutropenia (78%), and diarrhea (67%).

Overall, the phase 1 results support the continued development of elranatamab for the treatment of patients with multiple myeloma.

In an interview with Targeted Oncology™, Moshe Yair Levy, MD, director of Hematologic Malignancies Research at Texas Oncology-Baylor Charles A. Sammons Cancer Center, discussed the role of elranatamab myeloma treatment and the data from MagnetisMM-1, which he recently presented in a poster during the 2021 Society of Hematologic Oncology Annual Meeting.

TARGETED ONCOLOGY™: What are the key unmet medical needs for patients with relapsed or refractory multiple myeloma?

Levy: The unmet needs in relapsed/refractory multiple myeloma have certainly changed throughout time. We currently have so many more options for relapsed/refractory myeloma and can achieve very high response rates and very deep responses even in previously treated myeloma. But eventually, we do run out of effective therapies. So, when we're out of effective therapies, these patients no longer have favorable outcomes. Currently, the high unmet need is in what we call the penta-refractory population. These are people who have disease that has progressed on 2 proteasome inhibitors, bortezomib [Velcade], and carfilzomib [Kyprolis], the 2 IMIDs pomalidomide and lenalidomide [Revlimid], as well as and a CD-38 monoclonal which is usually going to be daratumumab [Darzalex], but it certainly could be as isatuximab [Sarclisa] as well.

So, we know that these patients tend to have very rapid progression and a very protracted median overall survival of less than 6 months. So outside of cellular therapies, all the other therapies that we have provide very low response rates, and usually not very deep and long responses. So thankfully, now we do have cellular therapy, which is addressing this unmet need. We had approval of our first BCMA-directed CAR T product, which had very high rates of response and much longer responses than we have previously seen in this patient population. We also have these by specific targeted antibodies such as elranatamab.

Can you describe the uniqueness of elranatamab? What is its mechanism of action?

This the by specific monoclonal antibody that will be able to bind both CD-3 as well as B cell maturation antigen. Therefore, it's able to get the immune system to come in and to destroy these BCMA-expressing cells. And as we know, the BCMA has near ubiquitous expression in multiple myeloma, and not as much on normal cells, which is what makes it a very good target in the treatment of multiple myeloma.

Can you go into detail on what led to the exploration of this drug for the treatment of R/R multiple myeloma?

As I mentioned, patients who are penta-refractory or penta-exposed have a high unmet need because they tend to do quite poorly. The cellular therapies tend to have much higher response rates as well as deeper and longer responses than we've seen with our non-cellular therapies in this patient population. So, this is an off-the-shelf therapy, which means that we're not doing ex vivo manipulation of autologous cells. This is a therapy that can be just taken off the shelf and administered immediately. This is particularly important now, as we've seen that there have been some supply line disruptions due to the pandemic. Folks who are usually eligible for CAR T-cell therapy or even for these bispecific therapies tend to be heavily pretreated and have rapidly progressive disease. So, an off-the-shelf therapy allows them to be treated immediately, as opposed to the cell collection.

Can you discuss the results of the MagnetisMM-1 study?

The results with both monotherapy as well as combination therapy did demonstrate very high response rates. These were heavily pretreated patients with high-risk of disease, and another unique aspect of this study is they also allowed for previous BCMA-directed therapy. Some of these patients had already received either an antibody-drug conjugate targeting BCMA or even CAR T-cell therapy targeting BCMA. This is rather unique because most of our BCMA-directed studies have excluded patients who had received these prior therapies.Despite the fact that these were heavily pretreated patients, we still saw very high response rates.

We know now that the dose that we're trying to achieve is greater than 215 micrograms per kilogram. We were able to assign a standard dose instead of weight-based dosing and what we saw was that the overall response rate was quite high. So, at this recommended phase 2 dosing, which was 1000 mics per kilo, the confirmed overall response rate was 83%.

Furthermore, the median duration of response has not yet been reached, showing that these responses appear to be quite durable. Many of the responses were complete or stringent, complete responses, and there were also high rates of MRD negativity. All the patients who achieved either a CR or a stringent CR did achieve MRD negativity, as measured by the International Myeloma Working Group criteria at a sensitivity of 1 times 10 to the minus 5.

What should other oncologists take away from this study?

This study shows that you can actually use antibody therapy to achieve very high rates of response with durability in a very heavily pretreated patient population with multiple myeloma.

_Reference:

_{Levy MY, Bahlis NJ, Raje NS, et al. MagnetisMM-1: A study of elranatamab (PF-06863135), a B-cell maturation antigen (BCMA)-targeted, CD3-engaging bispecific antibody, for patients with relapsed or refractory multiple myeloma (MM). Presented at: 2020 Society of Hematologic Oncology Virtual Annual Meeting; September 9-12; virtual. Abstract MM-379.}