Lucio N. Gordan, MD, Discusses New Guidelines in 1q21+ Abnormalities in Multiple Myeloma

Recently updated guidelines from the National Comprehensive Cancer Network (NCCN) in multiple myeloma specifically discuss disease staging and risk stratification and advise clinicians on how to address 1q21+ abnormalities. The guidelines follow the Second Revision of the International Staging System (R2-ISS), which appeared in the Journal of Clinical Oncology (JCO), the official publication of the American Society of Clinical Oncology.¹

To learn more about this update and to gain understanding of the importance of theseabnormalities in multiple myeloma, Evidence-Based Oncology (EBO) spoke with Lucio N. Gordan, MD, president and managing physician of Florida Cancer Specialists & Research Institute. A version of this interview first appeared on Managed Care Cast, a podcast of The American Journal of Managed Care®.

EBO: Can you explain to us what 1q21+ abnormalities are in multiple myeloma and why this is important?

Gordan: We have learned that 1q21+ abnormalities are relatively common in multiple myeloma—about 30% to 40% of the patients have such an abnormality. It’s defined as having greater than gain upgraded, 3 copies or amplification of 4 copies or more. I think it’s important because by itself, 1q21+ is not necessarily a super high-risk prognostic factor, but in aggregate with other elements, it’s very important.

EBO: So, precisely what do these abnormalities mean in terms of the care for the patients, and how do they affect patient outcomes? What’s the increased risk relative to the overall multiple myeloma population?

Gordan: The Second Revision of the International Staging System, R2-ISS, adds 1q21 gain/amplification as a prognostic risk factor; it assigns 0.5 points. This means that it’s well recognized as a risk factor in terms of increased risk of progression of multiple myeloma. We also know that in patients who have relapsed disease, they show gain of chromosomal abnormalities. So, it’s important for us physicians to be aware of this finding to make sure that our FSH (follicle-stimulating hormone) panels include 1q21 gain/amplification, so we can properly risk stratify the patients for treatment. The FSH panel is a relatively common test, and all of us should be ordering FSH panel in multiple myeloma.

EBO: You mentioned the NCCN guideline update. The update was released on September 22, 2023, to incorporate recommendations from the JCO article of late 2022.¹ Can you go into a little more detail about what the guideline update says?

Gordan: The R2-ISS study was published in JCO in 2022, and it incorporated different prognostic factors including the “old” ISS [lactate dehydrogenase] t(4;14) del(17p) chromosome and the 1q21 gain/amplification. The R2-ISS is risk stratified from low- to high-risk disease based on these factors that I mentioned; (for) the median overall survival, the R2-ISS goes from 110 months for low risk all the way down to 38 months in high risk. As far as progression-free survival, it goes from 70 months for low risk all the way down to 20 months or so in high risk.

So, it means that R2-ISS is an easy, simplified, reproducible, modern way of doing risk stratification of patients with multiple myeloma. And it does include for the first time the 1q21 gain or amplification. So that’s important. The new NCCN guidelines do incorporate the R2-ISS risk stratification, and they also give light to 1q21 abnormalities, which weren’t as evident in the past iterations of NCCN.²

EBO: So basically, in the past, there was some awareness of the 1q21 gain/amplification, but it wasn’t spelled out as clearly. Maybe some physicians would be aware, but some physicians might not be aware—but now, it’s clearly stated in the guidelines. Do you expect there to be greater awareness? And with more widespread awareness, will there be more widespread testing for this in the future?

Gordan: I hope so. Certainly, I’d love to see uptake of this information by practicing hematologist/oncologists across the country as quickly as possible. It’s not as easy to get translation of science into the practice. We all know that takes longer than we would hope for, but I think with NCCN guidelines being so important, the fact that they are making this evident does help translate this into real-world practice.

EBO: What are the therapeutic challenges with addressing the 1q21 abnormalities? Do you have specific procure therapeutics that you look to when a patient has this abnormality?

Gordan: It’s a great question. So, the previous studies, the ICARIA-MM study [NCT02990338] in multiple myeloma³ and the IKEMA study⁴ [NCT03275285], did have subgroup analyses, comparing isatuximab plus pomalidomide and dexamethasone, vs pomalidomide and dexamethasone by themselves; these subgroup analyses showed the patients who got isatuximab had significant superior overall survival and progression-free survival.⁵

The ICARIA-MM study and the IKEMA [subgroup analyses] have been published; there was a subgroup analysis for patients with multiple myeloma in the refractory setting, who had 1q21 gain/amplification. And in this study, patients were analyzed getting isatuximab plus pomalidomide, and dexamethasone vs pomalidomide and dexamethasone. The other study was carfilzomib-dexamethasone, with or without isatuximab.5 And the bottom line is that progression-free survival and overall survival were improved with the addition of an anti-CD8 antibody, in this case isatuximab. So that’s a good, quote, unquote, piece of data that we have that allows us to choose the best therapies for a patient with a specific signature.

EBO: What’s the best way to get the word out into clinical practice about these results and get the better uptake? You mentioned that sometimes it takes a long time for the information to get out—for example, what would be the process at Florida Cancer Specialists (FCS), where you have about 100 sites of care?

Gordan: Yes, we have nearly 100 sites, almost 600 providers. It’s a very large enterprise. Our pharmacy and therapeutics team connects every 2 weeks, and we do upgrades of new information and issue releases in a very timely fashion. After September 2023, with the NCCN information on myeloma, the providers have already received an alert about what has happened in this space. We try to be as proactive as we can. And I think opportunities like I’m receiving [here] to speak to other oncologists/hematologists in the country allow propagation of knowledge as quickly as possible.

At FCS, we’re interested in doing real-world evidence studies, including all the data points we have going back more than a decade in terms of all the specifics about the patient demographics, genetics, genomics, so that we can measure retrospectively and prospectively what happens when we incorporate new information from genomic standpoint, for instance, and what happens when we match the best therapy for the patient. With that development, we will try to bring more papers and abstracts to the world of medical oncology/hematology, in the United States and elsewhere, about how we’re trying to educate [our team] as quickly as possible.

EBO: Are there any payer barriers related to this guideline that should be addressed?

Gordan: I don’t think so. I haven’t had any pushback, as far as FSH panel in multiple myeloma and as far as therapeutic selection. Once it’s in the NCCN guidelines, it becomes not easy but easier to get patients through the process and through claims, educated and paid for. So, from my standpoint, the short answer is no. The challenge is just sharing the knowledge about what’s happening, not only in the world of myeloma but also in the other cancers and hematological disorders; it’s hard to keep up with everything, as you know.

EBO: Is there anything else that you’d like to share?

Gordan: Multiple myeloma is an incredibly complex disease process and/or multiple diseases. We need to stay abreast of the latest and the best information that we can, and we are taking a very serious approach at FCS as far as educating our providers, to again mesh the best treatment plan or clinical research protocol to the patient’s molecular and personal signature of disease. It’s an exciting time to be a practicing medical oncologist/hematologist.

References

1. D’Agostino M, Cairns DA, Lahuerta JJ, et al. Second Revision of the International Staging System (R2-ISS) for overall survival in multiple myeloma: a European Myeloma Network (EMN) report within the HARMONY Project. J Clin Oncol. 2022;40(29):3406-3418. doi:10.1200/JCO.21.02614
2. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 2.2024. Accessed November 16, 2023. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf
3. Richardson PG, Harrison SJ, Bringhen S, et al. Isatuximab for relapsed/refractory multiple myeloma: review of key subgroup analyses from the phase III ICARIA-MM study. Future Oncol. 2021;17(34):4797-4812. doi:10.2217/fon-2021-0568
4. Capra M, Martin T, Moreau P, et al. Isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma: IKEMA subgroup analysis by number of prior lines of treatment. Blood. 2022;140(suppl 1):7138-7140. doi:10.1182/blood-2022-162731
5. Martin T, Richardson PG, Facon T, et al. Primary outcomes by 1q21+ status for isatuximab-treated patients with relapsed/refractory multiple myeloma: subgroup analyses from ICARIA-MM and IKEMA. Haematologica. 2022;107(10):2485-2491. doi:10.3324/haematol.2022.280660