Today at IMW, there were a number of different topics discussed such as immunotherapy (specifically, the chimeric antigen receptor [CAR] T-cell therapies and bispecific antibodies), smoldering multiple myeloma (SMM), and COVID-19. Let’s dig in…
CAR T-Cell Therapies
All of the studies presented today provided updates to data previously presented at meetings earlier this year and late last year. Updates from trials such as these give a sense of the durability of these treatments with longer follow-up.
Abecma (idecabtagene vicleucel)
Abecma is a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy and the first CAR T-cell therapy to be approved for patients with multiple myeloma. Abecma is a personalized therapy where a patient’s own T cells are collected, altered so that they can recognize BCMA on the surface of myeloma cells, and are infused back into the patient, where they kill the myeloma cells. You can learn more about Abecma here.
Dr. Larry Anderson from The University of Texas Southwestern Medical Center presented updated data from the KarMMa phase 2 trial which investigated Abecma at different cell doses in 128 patients with triple-class refractory myeloma (that is, they received treatment with—and did not respond satisfactorily to—the three main classes of drugs currently used to treat myeloma: proteasome inhibitors [for example Velcade], immunomodulatory drugs [for example, Revlimid], and anti-CD38 monoclonal antibodies [for example, Darzalex). In the long-term follow up data presented by Dr. Anderson, Abecma treatment resulted in:
- Responses in 73% of patients (33% achieved a complete response) regardless of the number of prior lines of therapy
- Responses improved at higher doses:
- 81% of patients responded
- 39% achieved a complete response
- Responses observed in all patient sub-groups:
- High tumor burden, 71%
- Extramedullary disease, 70%
- Revised International Staging System III disease, 48%
- Response lasted a median of 10.9 months (8.6 months for patients achieving a complete response and 21.5 months for patients who achieved a complete response or better)
- In patients who received higher doses, median duration was 11.3 months
- Median time until disease progression in patients who achieved a complete response or better was 22.4 months
- Median overall survival was 24.8 months
- Low blood cell (neutrophil) counts in 91% of patients
- Cytokine release syndrome in 84% of patients
- Neurotoxicity in 18% of patients
These results are consistent with previous reports and show that Abecma continues to demonstrate durable responses in a heavily pretreated patient population. Several clinical trials of Abecma are ongoing.
Ciltacabtagene autoleucel (cilta-cel)
Cilta-cel is a CAR T-cell therapy that targets BCMA similar to Abecma; however, cilta-cel is engineered to bind to two sites on the BCMA protein. Trials of cilta-cel in various patient populations are ongoing and at this meeting updates from two different trials of cilta-cel were reported.
The first trial, called CARTITUDE-1, is a phase 1/2 trial investigating the use of cilta-cel in 97 patients who had received a median of six prior lines of therapy. The results reported by Dr. Sundar Jagannath at the Mount Sinai Hospital showed:
- 98% of patients responded (80% achieved a stringent complete response)
- Median duration of response was 21.8 months
- Of the 61 patients evaluable for MRD measurement, 92% achieved MRD negativity
- Median time until disease progression was 22.8 months
- Common side effects included low white blood cell, platelet, and red blood cell counts
- Cytokine release syndrome occurred in 95% of patients and neurotoxicity in 21%
The second trial, a phase 2 trial called CARTITUDE-2, was conducted in patients with progressive multiple myeloma and presented by Dr. Adam Cohen from the University of Pennsylvania. In this trial, patients had a median number of three or fewer prior lines of therapy—this is a patient population that is less heavily pretreated than the other studies described today. Twenty patients received a single infusion of cilta-cel. Results showed:
- 95% of patients responded to cilta-cel treatment (75% achieved a stringent complete response or better)
- The median duration of response was not yet reached
- All four patients who could be assessed for MRD were MRD negative
- Common side effects included low white blood cell, platelet, and red blood cell counts
- 85% of patients experienced cytokine release syndrome and 20% experienced neurotoxicity
- One death occurred and was deemed due to COVID-19
Cilta-cel will continue to be investigated in other populations of myeloma patients, in earlier-line settings, and as outpatient treatment. Excitement for this drug is starting to grow because the US FDA has granted cilta-cel a priority review for the treatment for relapsed/refractory multiple myeloma. We anticipate that this therapy may be approved by the end of this year!
It is incredible to see such responses in patients who have been exposed to many prior therapies with only one injection of either of these two different CAR T-cell therapies!
Bispecific Antibodies
Bispecific antibodies or bispecific T-cell engagers are a different type of T-cell–directed therapy than CAR T-cells. Bispecific antibodies are made from two different antibodies that have been fused together, so that one piece binds to myeloma cells and another piece binds to cells of the immune system. Most bispecific antibodies target BCMA on myeloma cells and bind to a protein called CD3 that is found on T-cells. The T-cell, once attached to the myeloma cell, releases a type of poison that kills the myeloma cell. Additionally, the targets on myeloma cells are evolving beyond BCMA and we will discuss a bispecific antibody that targets the GPRC5D protein. Bispecific antibody treatment is not yet approved for use in patients with multiple myeloma, but the results of trials of two of these agents were discussed in today’s session.
Elarantamab
The MagnetisMM-1 trial is a phase 1 trial investigating the safety and efficacy of elranatamab as a single agent. Thirty patients who had been exposed to a median of 8 prior treatments (87% were triple-class refractory, 97% had received anti-CD38 therapy, and 23% had received prior BCMA-targeted antibody Blenrep or CAR T-cell therapy) received elranatamab subcutaneously (that is, under the skin) at varying doses. Investigators from Canada and the US reported:
- Common side effects included low white blood cell, platelet, and red blood cell counts
- All patients experienced cytokine release syndrome and 20% neurotoxicity
- At the four highest doses administered, 70% of patients responded to treatment (83% responded at the highest dose which is the recommended phase 2 dose)
- All patients with a complete response or better achieved MRD negativity
- 75% of patients who had prior BCMA-targeted therapy responded
Talquetamab
This bispecific antibody is different because it binds to a protein called GPRC5D rather than BCMA on myeloma cells. Updated results from the phase 1 trial were presented. Thirty relapsed/refractory myeloma patients with a median of 5 prior lines of therapy had been treated at the recommended phase 2 dose of talquetamab injected subcutaneously and the results showed:
- Common side effects included low white and red blood cell counts, infections, and taste disorder
- 77% of patients experienced skin-related side effects
- Cytokine release syndrome occurred in 73% of patients and 7% neurotoxicity
- 70% of patients responded to treatment—even patients with triple-class refractory or penta-refractory myeloma
The results from both trials support the further clinical development of these bispecific antibodies and we look forward to following the clinical progress of this new class of immunotherapy for myeloma patients, particularly those who continue to relapse.
For a quick refresher and visually captivating look at immunotherapy that includes CAR T cells and bispecific antibodies, check out our High Impact Topic Video here.
Smoldering Multiple Myeloma
Patients with active multiple myeloma typically have a preceding phase of disease referred to as either monoclonal gammopathy of undetermined significance (MGUS) or SMM (also called asymptomatic myeloma); collectively known as precursor conditions. Some SMM patients develop active myeloma much faster than others (ie, they are at higher risk of progression); identifying and treating these individuals earlier could potentially delay or event prevent that progression from occurring. Today at IMW, two presentations focused on strategies to improve the identification of patients at risk of progressing to active myeloma.
In the first presentation, researchers assessed two current clinical models that help identify the individuals with SMM who are most likely to progress to myeloma: (1) Mayo 2018 and (2) IMWG 2020.
- Both models use a 2-20-20 rule that measures three risk factors associated with progression to active myeloma: M protein levels, free light chain ratio, and the number of plasma cells in the bone marrow.
- The only difference is that the IMWG incorporates the presence of cytogenetic abnormalities as part of the assessment.
In their analysis, the investigators from the Mayo Clinic assessed risk in 704 SMM patients annually using both models to determine how well they can predict progression over time considering that the risk of progression to active myeloma decreases over time. The results showed that both models can reliably provide prognostic information about the risk of progression for patients with SMM up to 4 years post initial diagnosis. Also, patients who migrate to a higher risk category over time have an increased risk of progression suggesting that these patients be carefully monitored and may be candidates for early treatment intervention.
In the second presentation, European clinicians investigated the value of measuring myeloma cells from the blood every six months in 150 SMM patients as a predictor of disease progression. The investigators also looked at the profile of the immune cells collected from the blood of these same patients. The results showed:
- Patients with low levels of myeloma cells in the blood (≤73 cells/μL) had a lower risk of progression than patients with high levels (>0.73 cells/μL) (15% vs 67% progressed at 2 years); median time to progression for patients with high levels was 17.5 months
- Certain T cell subsets from the blood samples were associated with a shorter time to progression and a higher risk of transformation to active myeloma
These data are interesting in that a new, minimally invasive measure in the blood may have the potential to replace measurement of plasma cells from bone marrow biopsy samples—potentially changing the 2-20-20 model to a 2-20-0.7 model—to assess risk in SMM patients. We will continue to monitor for the latest developments!
For more information on multiple myeloma precursor conditions, please view our High Impact Topic video here or our latest online Expert Session here.
COVID-19
Coronavirus disease 2019—better known as COVID-19—is an illness caused by a type of virus called a coronavirus. There are many types of coronavirus, including some that cause the common cold. The coronavirus that causes COVID-19 was first identified in 2019. Based on what is currently known, the people at highest risk of getting severely ill from COVID-19 are older adults and people who have serious underlying medical conditions such as cancer. A session at today’s IMW—appropriately titled a “Hot Topics in Myeloma”—focused on COVID-19: how myeloma patients are affected by it and how they have fared with the available vaccines.
Vaccination Response
Clinicians at the Massachusetts General Hospital and the Dana-Farber Cancer Institute presented their data on whether myeloma patients are able to mount a sufficient response to any of the three available COVID-19 vaccines: mRNA vaccines (Pfizer and Moderna) or adenovirus vaccine (J&J). Ninety-one myeloma patients had been vaccinated and included in this analysis. The results showed:
- 91% of patients had a spike protein antibody response
- Spike protein antibody responses based on individual vaccines occurred in:
- 74% with Moderna vaccine
- 51% with Pfizer vaccine
- 20% with J&J vaccine
- 56% of patients achieved a spike protein antibody response greater than 100 U/mL (only 45% of patients with progressive disease achieved this level)
The investigators conclude that myeloma patients have an impaired response following COVID-19 vaccination and that being in remission is associated with an improved spike protein antibody response. Also, the Moderna vaccine elicited a higher antibody response than the other vaccines.
From the clinicians at the Icahn School of Medicine at Mount Sinai, they report their experience with the mRNA vaccines (both the Pfizer and Moderna vaccines) response in myeloma patients. Two doses of either mRNA vaccine was administered to 320 myeloma patients. The results showed:
- 3% of patients had a spike-binding antibody response over 10 days after the second vaccine dose
- In a control group of age-matched healthcare workers, the antibody levels were significantly higher
- Myeloma patients on active treatment had lower antibody levels compared with patients not on therapy
- 8% of patients failed to develop a detectable spike-binding antibody response and of those patients: 58.5% were on an anti-CD38 antibody, 31.7% were on an anti-BCMA bispecific antibody, and 9.8% were on CAR T-cell therapy (more than 3 months after the therapy)
- Anti-CD38-containing therapy and BCMA-targeted treatments ae associated with not developing detectable antibodies
- Patients who had prior COVID-19 infection had antibody responses 10-fold higher than patients without prior COVID-19 infection
As with the study from Massachusetts General Hospital, the data from Mount Sinai suggest that myeloma patients mount a suboptimal response after vaccination. Furthermore, two similar studies were presented today, one conducted in the United Kingdom and one in Germany, also concluded that the response to vaccination is lower in patients with myeloma especially after the first dose.
It will be interesting to learn what guidance will be made for myeloma patients with the new information gathered.
For basic information about COVID-19 and viral infections, please click here and here. Additionally, the MMRF has many resources on COVID-19 in multiple myeloma patients and can be found on our website here.
Be sure to hear what myeloma experts Dr. Irene Ghobrial and Dr. Cesar Rodriguez have to say about the day’s presentations here.
Stay tuned for more one more update from IMW 2021!…
