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MULTIPLE MYELOMA, GAMMOPATHIES

Outcomes of triple class (proteasome inhibitor, IMiDs and monoclonal antibody) refractory patients with multiple myeloma

Leukemia volume 36, pages 873–876 (2022)Cite this article

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Multiple myeloma (MM) is a genetically heterogenous plasma cell malignancy that is characterized by the accrual of subclonal genetic changes as the disease advances [1]. These subclonal alterations contribute to the development of therapeutic resistance and despite the improvement in the overall survival (OS), MM remains incurable [2]. Proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) had been the backbone of therapeutic regimens in MM until recently [3]. Monoclonal antibodies (mAbs) against CD38 and SLAMF7 can improve outcomes for patients previously treated with PIs and IMiDs [4]. However, patients with diseases that are refractory to PIs, IMiDs, and mAbs have a poor prognosis and are commonly referred to as having a triple class refractory (TCR) disease [5]. Currently, there is no established standard of care for TCR MM with promising treatment options including selinexor, bispecific antibodies, and chimeric antigen receptor T(CAR-T) cell therapies [4, 6, 7]. In this study, we report the outcomes of patients with triple refractory MM and response to therapy post TCR status. Consecutive patients with MM diagnosed between 01/01/2013 and 12/31/2018 and seen at Mayo Clinic, Rochester, MN were included in this study. Refractoriness to therapy was defined as non-responsiveness (failure to achieve at least a minimal response) to therapy or progression on or within 60 days of discontinuation of therapy [8]. Patients meeting the definition for refractory disease for at least one PI, IMiD, and monoclonal antibody (daratumumab, isatuximab or elotuzumab) were considered to have TCR disease. The mSMART 3.0 (www.msmart.org) classification was used to characterize cytogenetic risk using interphase fluorescence in situ hybridization (FISH), with high-risk cytogenetic features including t(4;14), t(14;16), t(14;20), deletion 17p, TP53 mutation and 1q gain. Patients with FISH data available within 6 months of TCR date was utilized for comparison with baseline FISH cytogenetic data at diagnosis of MM. The international myeloma working group (IMWG) criteria were used for response assessment.

Between 01/01/2013 and 12/31/2018, out of 1773 patients with MM, a total of 249 patients (14%) were identified to have TCR MM. The median follow-up from diagnosis of MM till the date of the last follow-up was 6.8 years (95% CI: 6.3–7.3 years). The median follow-up from TCR MM till the last follow-up was 1.9 years (95% CI: 1.6–2.4). Characteristics of the cohort are depicted in Table 1. Cytogenetic data were available in 208 patients at diagnosis; 116 (56%) patients harbored high-risk cytogenetics. At TCR status, 110 (44%) patients had FISH data available; 95 patients (87%) had high-risk cytogenetics (Table 1). Among these 110 patients, 91 patients also had FISH data available from the time of diagnosis for comparison. Thirty-one percent (28/91) patients did not demonstrate any new cytogenetic abnormality at TCR status; 31% (28/91) had a new 1q duplication, 25% (23/91) had a new 17p deletion, 24% (22/91) had a new 8q24 deletion, 19 (21%) patients had a near tetraploid clone, 3% (3/91) patients had a new deletion 1p.

Table 1 a. Clinical characteristics at diagnosis and TCR status, b. Refractoriness to proteasome inhibitors, immunomodulatory imide drugs and monoclonal antibodies, c. First salvage treatment post triple refractory status.
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Authors and Affiliations

  1. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    Saurabh Zanwar, Prashant Kapoor, Angela Dispenzieri, Martha Q. Lacy, Morie A. Gertz, Francis K. Buadi, Suzanne R. Hayman, David Dingli, Taxiarchis Kourelis, Amie Fonder, Miriam Hobbs, Yi Hwa, Wilson Gonsalves, Rahma Warsame, Eli Muchtar, Nelson Leung, Robert A. Kyle, S. Vincent Rajkumar & Shaji Kumar

  2. Department of Medicine, Mayo Clinic, Rochester, MN, USA

    Saurabh Zanwar, Matthew Ho, Prashant Kapoor, Angela Dispenzieri, Martha Q. Lacy, Morie A. Gertz, Francis K. Buadi, Suzanne R. Hayman, David Dingli, Taxiarchis Kourelis, Wilson Gonsalves, Rahma Warsame, Eli Muchtar, Nelson Leung, Robert A. Kyle, S. Vincent Rajkumar & Shaji Kumar

  3. Division of Nephrology, Mayo Clinic, Rochester, MN, USA

    Nelson Leung

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Contributions

SZ, MH, and SK conceived the project, collected data, performed preliminary analysis, and wrote the first draft of the manuscript. PK, AD, MQL, MAG, FKB, SRH, DD, TK, AF, MH, YH, WG, RW, EM, NL, RAK, and SVR reviewed the manuscript draft, critically appraised the manuscript, and recommended modifications. All authors agreed with the final draft of the manuscript.

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Correspondence to Shaji Kumar.

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Zanwar, S., Ho, M., Kapoor, P. et al. Outcomes of triple class (proteasome inhibitor, IMiDs and monoclonal antibody) refractory patients with multiple myeloma. Leukemia 36, 873–876 (2022). https://doi.org/10.1038/s41375-021-01433-9

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