Minimal Residual Disease in Multiple Myeloma

Hello, I’m Kathleen Colson. Welcome to the Multiple Myeloma Center for Nurses. This video will explore minimal residual disease, including what it is, how to test for it, and why the results are important for patient management.

Multiple myeloma is a B-cell malignancy.^1,2 Dysfunctional plasma cells, called myeloma cells, are a result of genetic changes in plasma cells when they are formed in the bone marrow.^2,3

Over time, myeloma cells undergo random and treatment-associated changes that impact the characteristics of the myeloma cell population at each relapse.⁴ As multiple myeloma cells multiply, single cells accumulate random genetic mutations.⁴ This gives rise to a series of subclonal populations that all compete with each other for resources, which leads to disease progression or therapy resistance. This is referred to as intra-clonal heterogeneity. The clones can be more or less sensitive to a specific type of treatment.^4,5

If clones are more resistant to treatment, that puts the patient at an increased risk for relapse.⁵ The drugs used to treat myeloma also cause a selective pressure by killing cancer clones that are sensitive to them while leaving the clones that are more resistant.⁴ This allows the resistant clones to expand, ultimately leading to disease progression.⁴ Treatment therefore contributes to the evolution of clones resistant to therapy and may impact the length of remission or time to relapse.^4,6 Minor subclones are subpopulations of cells that descend from a clone but then diverge by accumulating other changes. Minor subclones can emerge upon disease relapse.⁷ As a result, when myeloma relapse does occur, the clone types present are often more diverse than in the original population that was present at diagnosis, and the dominant clone is usually different from the original primary clone.^5,7

The occurrence of relapsed disease at any time in the journey means that some myeloma cells escaped the previous line of therapy.⁴ Myeloma cells coexist in the marrow with normal plasma cells.^1,2 Even when a patient has achieved a complete response to treatment and is in remission, a small number of myeloma cells can still be present. This is called minimal residual disease or MRD, which refers to the small number of myeloma cells left in the body after treatment.^8,9 When a patient tests positive for MRD, it means that there are residual cancer cells in the body after treatment.⁸

When MRD is detected, this is known as MRD positivity.⁸ When a patient tests negative, no residual cancer cells are found. When no MRD is detected, this is known as MRD negativity.⁸ The deeper the response, the fewer residual cells that can be detected and the more likely the patient will be MRD negative.⁹

Since different clones have different sensitivity to treatment, using combination drug regimens—with each drug having a different mechanism of action—has the potential to reduce the number of residual cells.⁴

The goal of combination therapy is to leverage the different selective pressure of each treatment on the myeloma cells and reduce tumor burden, which may provide a better chance of longer remission by preventing some subclones from growing and causing early relapse.⁴

Residual cells are a major cause of relapse in myeloma, but they often go undetected by standard means to detect myeloma such as assessing the number of plasma cells in bone marrow, or measuring serum monoclonal protein, or looking for new lesions with PET scans.¹⁰

MRD testing is done to¹⁰:

• Determine whether treatment has eradicated the myeloma or whether traces remain
• Monitor patient remission status
• Detect recurrence of the myeloma
• Choose the treatment that will best meet the clinical needs of the patient

MRD negativity may be associated with longer remission and survival times.⁸ In one study, patients who achieved a complete response after frontline therapy and were MRD-negative showed a significantly longer median time to tumor progression of 131 months vs 35 months for patients who were MRD-positive.¹¹ In patients who achieved a very good partial response or a complete response after frontline therapy, median time to progression and overall survival of MRD-negative patients were also longer than for MRD-positive patients.¹¹

MRD measurements may also inform the need for consolidation and maintenance strategies, help evaluate the comparative efficacy of various therapies, and identify patients who need additional or different treatment.¹¹ MRD detection may contribute to the design of patient-specific treatment approaches such as de-escalation of therapy for MRD-negative patients, or continuous or escalation of treatment for MRD-positive patients, which is consistent with the current standard of care in other hematological malignancies.¹¹

MRD may potentially serve as a surrogate endpoint in clinical trials and help accelerate drug development.^12,13 An increasing number of clinical trials are using MRD rates as a primary or secondary endpoint.^12,13 In the future, more MRD-guided treatment decisions may be made.^12,13

According to the International Myeloma Working Group, or IMWG, a complete response or CR refers to negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow.^14,15

In an attempt to refine the understanding of depth of response, the uniform response criteria were updated and expanded by the IMWG to introduce the definitions of stringent complete response, or sCR; immunophenotypic CR; and molecular CR^14,15:

• Stringent CR is a CR plus normal free light chain ratio and absence of clonal plasma cells by immunohistochemistry or two- to four-color flow cytometry; two consecutive assessments of laboratory parameters are needed¹⁵
• Immunophenotypic CR is a sCR plus absence of phenotypically aberrant plasma cells in bone marrow, with a minimum of 1 million total bone marrow cells analyzed by multiparametric flow cytometry (with greater than 4 colors)¹⁵
• Molecular CR is a CR plus negative allele-specific oligonucleotide polymerase chain reaction (sensitivity of 10^-5)¹⁵

Ultrasensitive molecular tests can detect the presence (called MRD positive) or absence (called MRD negative) of myeloma cells from bone marrow aspirates.^9,10

These tests include:

• Flow cytometry, which evaluates individual cells by checking for the presence or absence of certain protein markers on the cell surface⁸
• Polymerase chain reaction, abbreviated PCR, which identifies malignant cells based on characteristic genetic abnormalities such as mutations or chromosomal changes⁸
• Next-generation sequencing, which examines stretches of DNA or RNA to detect mutations and other genetic abnormalities⁸
• Imaging modalities such as magnetic resonance imaging and PET with computed tomography are used to assess extramedullary disease, which is disease outside the bone marrow^8,16

MRD testing can be used to⁸:

• Show how well the cancer has responded to treatment
• Confirm and monitor remissions
• Find cancer recurrence sooner than other tests
• Identify patients who may be at higher risk of relapse
• Identify patients who may need to restart treatment
• Identify patients who may benefit from other treatments, such as stem cell transplantation or combination therapy

MRD is an important predictor of progression-free survival in newly diagnosed and relapsed/refractory multiple myeloma patients. MRD assessment in the clinical practice setting likely has the same predictive power as that seen in clinical trials. Depth of response and MRD dynamics may drive clinical decision making, potentially improving outcome of patients with myeloma.¹⁷

This concludes the Minimal Residual Disease Video. Be sure to explore this site for more informational videos and educational resources!

References

1. American Cancer Society. Learn about cancer. What is multiple myeloma? Accessed July 8, 2021. https://www.cancer.org/content/dam/CRC/PDF/Public/8738.00.pdf

2. Farlex Medical Dictionary. Multiple myeloma. Accessed October 5, 2021. http://medical-dictionary.thefreedictionary.com/multiple+myeloma

3. Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Understanding multiple myeloma
pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer. 2007;7(8):585-598. doi:10.1038/nrc2189

4. Brioli A, Melchor L, Cavo M, Morgan GJ. The impact of intra-clonal heterogeneity on the treatment of multiple myeloma. Brit J Haematol. 2014;165:441-454. doi:10.1111/bjh.12805

5. Bianchi G, Ghobrial IM. Biological and clinical implications of clonal heterogeneity and clonal evolution in multiple myeloma. Curr Cancer Ther Rev. 2014;10(2):70-79. doi:10.2174/157339471002141124121404

6. Fakhri B. Clonal evolution in multiple myeloma. Clin Lymphoma Myeloma Leuk. 2016; 16(S1):S130-S134.10.1016/j.clml.2016.02.025

7. Magrangeas F, Avet-Loiseau H, Gouraud W, et al. Minor clone provides a reservoir for relapse in multiple myeloma. Leukemia. 2013;27(2):473-481. doi:10.1038/leu.2012.226

8. Minimal Residual Disease (MRD). Leukemia & Lymphoma Society. April 2019. Accessed October 5, 2021. https://www.lls.org/sites/default/files/National/USA/Pdf/Publications/FS35_MRD_Final_2019.pdf

9. Kostolopoulos IV, Ntanasis-Stathopoulos I, Gavriatopoulo M, Tsitsilonis OE, Terpos E. Minimal residual disease in multiple myeloma: current landscape and future applications with immunotherapeutic approaches. Front Oncol. 2020;10:860. doi: 10.3389/fonc.2020.00860

10. What is MRD testing? Myeloma Crowd. April 22, 2019. Accessed October 5, 2021. https://www.myelomacrowd.org/what-is-mrd-testing/

11. Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method for
minimal residual disease detection in multiple myeloma. Blood. 2014;123(20):3073-3079. doi:10.1182/
blood-2014-01-550020

12. Takamatsu H. Clinical value of measurable residual disease testing for multiple myeloma and implementation in Japan. Int J Hematol. 2020;111:519-529. doi:10.1007/s12185-020-02828-7

13. Burgos L, Puig N, Cedena MT, et al. Measurable residual disease in multiple myeloma: ready for clinical practice? J Hematol Oncol. 2020;13:82. doi:10.1186/s13045-020-00911-4

14. Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17:e328-e346.

15. Palumbo A, Rajkumar SV, San Miguel JF, et al. International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol. 2014;32(6):587-600. doi:10.1200/JCO.2013.48.7934

16. Devarakonda S, Jethava Y. Minimal residual disease in multiple myeloma: are we there yet? Int J Hematol Oncol. 2020;9(4):IJH29. doi:10.2217/ijh-2020-0018

17. Martinez-Lopez J, Wong SW, Shah N, et al. Clinical value of measurable residual disease testing for
assessing depth, duration, and direction of response in multiple myeloma. Blood Adv. 2020;4(14):3295-
3301. doi:10.1182/bloodadvances.2020003234