ASH 2023: How Extramedullary and High-Risk Myeloma Patients Are Responding to Immunotherapy

Bispecific antibody and CAR-T therapies have emerged as encouraging treatment options for patients with relapsed/refractory myeloma.  

Extensive research is being done on their effectiveness and durability with individuals who have received more than four previous lines of treatment.

However, how are high-risk myeloma patients, such as those with extramedullary myeloma reacting to these exciting new therapies? Less research is being done with patients who have extramedullary disease.

Myeloma drugs are great at targeting the bone marrow. However, as myeloma progresses, myeloma cells can lose their adhesion to the bone marrow and travel outside to other parts of the body, becoming extramedullary (or outside the bone marrow disease). 

This usually happens after individuals have relapsed several times, which by clinical definition is high risk disease, although there are rare cases of newly diagnosed myeloma being identified as extramedullary This diagnosis creates a more difficult treatment landscape.  

At the recent American Society of Hematology meeting, Charan Vegivinti, MD, shared the results of a systematic review and meta-analysis to compare the efficacy of bispecific antibody treatment vs. CAR T for extramedullary disease and high-risk cytogenetics.   

This is an exciting analysis, as specific medical data on the effectiveness of immunotherapy treatments for patients with extramedullary disease and high-risk genetics is usually overlooked and not reported on as often as it should be.

Study Method

In this study, researchers conducted a systematic literature search to identify clinical trials that investigated the use of bispecific antibodies and CAR T therapies when treating relapsed/refractory patients.  

• Sources included: PubMed, Cochrane, ASH 2022 and ASCO 2023 
• Abstracts used the search terms: bispecific antibodies AND multiple myeloma, CAR T cell therapy AND multiple myeloma.  

The bispecific search utilized 15 studies from the following sources:

• PubMed 263 studies found; 7 were clinical trials, and 5 were included
• 6 ASH, 3 ASCO, and 1 IMS abstract

The CAR-T search yielded 27 studies from the following sources:

• PubMed found 84 and Cochrane 20 studies. After screening, 21 were included
• 6 ASCO abstracts were also included in the final analysis

A statistical analysis was completed with tools to assess for statistical differences.   

Study Results

Bispecific Antibodies

Overall Response Rate (ORR) was reported across 15 studies, covering a study population of 1083 patients. Researchers pooled the statistics from these studies together to give an accurate reflection of how likely extramedullary and high-risk myeloma patients are to respond to the bispecific antibody treatment. 

Overall Response Rates (ORR) for Specific Conditions:

• For patients with extramedullary disease (EMD), the response rate in 5 studies involving 134 patients was greater than 48%.
• For those with high-risk disease (HRCA), the response rate in 6 studies with 144 patients was 63%.

Overall Response Rate for the Entire Group:

• When looking at all patients (combining both extramedullary and high-risk disease), the overall response rate (ORR) was 66%. This means that, on average, about two-thirds of the patients responded positively to the treatment.
• The 95% Confidence Interval (CI) for this result is between 59% and 73%. The confidence interval gives a range within which we can be reasonably confident the true response rate lies.

Subgroup Analysis: 

• When they looked at different targets, there was a statistically significant difference in the response rates among the entire myeloma population. This means that the treatment had varying levels of effectiveness depending on the target of the specific bispecific antibody therapy. However, when they looked at only extramedullary and high-risk myeloma, there were no longer any significant statistical differences based on the therapy's target. 
• That being said, a study testing the combination of teclistamab and talquetamab showed the highest overall response rate for patients with extramedullary disease compared to other single-agent bispecific antibodies. Dr. Yael Cohen and colleagues conducted this study.

In simpler terms, bispecific antibody treatment has been proven to be generally effective overall, with about two-thirds of patients responding well. The response rates were also specific to the type of disease, with extramedullary disease showing a response rate greater than 48% and high-risk disease showing a response rate of 63%.

CAR T-Cell Therapy

Overall Response Rate (ORR) was reported across 27 studies, covering a study population of 1469 patients. Researchers pooled the statistics from these studies together to give an accurate reflection of how likely extramedullary and high-risk myeloma patients are to respond to CAR T-cell therapy treatment. 

Overall Response Rates (ORR) for Specific Conditions:

• For patients with extramedullary disease (EMD), the response rate in 14 studies involving 172 patients was reported. When pooled, stats showed that 77% responded positively to the treatment. Because these are cross-study results, this statistic has a confidence interval (CI) between 68% and 87%.
• For those with high-risk cytogenetic abnormalities (HRCA), the response rate in 11 studies with 268 patients was reported. Interestingly, 77% also responded positively to the treatment in this subgroup. These stats have a confidence interval (CI) between 69% and 86%.

Overall Response Rate for the Entire Group:

• When looking at the entire population overall for these pooled CAR-T studies, the overall response rate (ORR) was 86%. This means that, on average, about 86% of patients responded positively to the treatment.
• The 95% Confidence Interval (CI) for this result is between 82% and 90%. The confidence interval gives a range within which we can be reasonably confident the true response rate lies.

Publication Bias: 

• The funnel plot, a tool to assess publication bias, showed a possible bias for overall response rate for CAR T cell therapy. The p-value of 0.021 indicates there might be a publication bias, meaning the results could be influenced by what studies get published.

In simpler terms, the treatment showed a high overall response rate of 86% across all patients. The response rates for specific conditions, such as extramedullary disease and high-risk cytogenetic abnormalities, were both 77%. However, there's a suggestion of potential publication bias in studies related to CAR T cell therapy, indicating caution in interpreting these results due to a possible influence of which studies are published.

Bispecific Antibodies vs. CAR T-Cell Therapy 

Considering both the possible publication bias and the confidence intervals of the pooled statistics, the overall response rate for both the extramedullary and high-risk cytogenetics groups was found to be higher with CAR T-cell therapy than with bispecific antibody therapy. 

Conclusion

This systematic review found both bispecific and CAR T therapy to be effective treatment options for relapsed myeloma patients. However, overall survival in the whole cohort, extramedullary disease cohort and high risk cytogenetic cohort were identified to be superior with CAR-T therapy.  

The study indicates the difficulty in directly comparing pooled estimates to two different therapies and found no significant difference in extramedullary disease and high-risk cytogenetics between the different types of bispecific antibody treatments. 

Progression-free survival has not been reported in the majority of clinical trials and thus was not included in this report.  

Better and more clinical, published reporting of extra-medullary responses is needed to measure the full impact of these treatment options on these patient subgroups and to guide the development of strategies.

As a myeloma patient you can use this study to guide your questions and conversation with your specialist as you are making treatment decisions, especially if deciding between CAR-T or bispecific antibody treatments. 

Learn more about both bispecific antibody and CAR T treatments in HealthTree University’s Know Your Therapy course.

ASH 2023 Resources

Would you like to watch ASH 2023 myeloma research interviews from the investigators themselves? Click "ASH 2023" here: HealthTree University Conference Coverage

To read other ASH 2023 articles, click here: HealthTree 2023 ASH Articles