Treatment of Intermediate Risk Smoldering Myeloma

Presentation

This patient, a 59-year-old female with IgA kappa smoldering multiple myeloma (SMM), had a long history of degenerative back pain and upon further work-up, she was noted to have a monoclonal paraprotein of 1.6 g/dL. PET/CT showed no lytic disease nor did the MRI of her spine and pelvis. The bone marrow biopsy demonstrated clonal plasma cells of 22%, flow cytometry was positive with FISH detecting t(4;14) and cytogenetics without any abnormalities. The free light chain (FLC) ratio was 6.07. No end organ damage was noted, nor were there any CRAB features. With an FLC ratio of 6.07, M spike of 1.6, plasma cells at 22%, a t4:14 mutation, and IgA subtype, the patient was placed within the low-intermediate risk group (risk score 7), giving her a 25% 2-year risk of progression to symptomatic MM. Per current criteria, with 1 positive score from the current treatment algorithm (bone marrow greater than 20), the patient was placed in the intermediate risk category.¹

Risk stratification of smoldering multiple myeloma (SMM)¹

The patient was screened for the iberdomide vs. iberdomide and dexamethasone clinical trial, randomized to arm B with monotherapy iberdomide. Her comorbidities included baseline grade 1 peripheral neuropathy to both feet, back pain, and hypertension that was well controlled on medication.

Treatment

The patient chose to participate on the iberdomide clinical trial, receiving therapy for a total of 24 cycles as per protocol. She had stem cell mobilization following cycle 4 of therapy and then continued the trial with no dose reductions. Her iberdomide dose was a 1.3 mg capsule on days 1-21 on a 28-day cycle. She tolerated the treatment well with no worsening of her baseline neuropathy and mild grade 1 fatigue that worsened in the third week of treatment and improved on her off week. The patient achieved a serum complete response (sCR) with low detectable minimal residual disease (MRD) at completion of the 24th cycle. She then moved to the observation phase with visits every 3 months and currently has no signs of progression. With initiation of the trial, she also started an antiviral with valacyclovir and, since she had no prior history of a thromboembolic event, she took a daily 81 mg aspirin. 

Discussion

All patients with symptomatic multiple myeloma (MM) evolve from a monoclonal gammopathy of undetermined significance (MGUS). SMM is found between MGUS and MM so it is important to make the clinical distinction since SMM has a higher risk to progression. ¹ Previously, observation was the standard of care for a patient with SMM though clinical trials demonstrate a benefit for a risk-stratified approach.² Two recent trials with lenalidomide in high risk SMM demonstrated that early intervention delays progression and the development of end-organ damage.^3-5 This has led to further trials looking at SMM and the benefit of early intervention for intermediate or high risk smoldering patients. The patient went on a trial with iberdomide vs. iberdomide and dexamethasone. Iberdomide (CC-220) is a cereblon E3 ligase modulator with much higher binding to cereblon than the immunomodulatory drugs lenalidomide and pomalidomide and is in the novel cereblon E3 ligase modulatory drugs (CELMoDs) category. Iberdomide has been used in clinical trials for relapsed refractory MM and newly diagnosed MM. It is also used in high risk smoldering trials as the one this patient participated in. So far, there is a favorable toxicity profile with iberdomide though more investigational trials are needed.^6-8

It is important to remember that we only treat SMM in the context of a clinical trial and only those with intermediate or high-risk disease. The goal is to intervene early to delay or prevent development of end-organ progression. Risk stratification is used to differentiate between MGUS and SMM.

For our patient, a clinical trial made sense. She achieved an sCR with low MRD positivity. She tolerated the iberdomide very well and now continues in observation and is able to participate in her normal activities. The advanced practice provider and clinical pharmacist play a critical role in identifying potential trial patients and discussing and managing the adverse events.

References

1. Rajkumar SV, Kumar S, Lonial S, Mateos MV. Smoldering multiple myeloma current treatment algorithms. Blood Cancer J. 2022;12(9):129. Published 2022 Sep 5. doi:10.1038/s41408-022-00719-0
2. Mateos MV, Kumar S, Dimopoulos MA, et al. International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM). Blood Cancer J. 2020;10(10):102. Published 2020 Oct 16. doi:10.1038/s41408-020-00366-3
3. Lonial S, Jacobus S, Fonseca R, et al. Randomized Trial of Lenalidomide Versus Observation in Smoldering Multiple Myeloma. J Clin Oncol. 2020;38(11):1126-1137. doi:10.1200/JCO.19.01740
4. Mateos MV, Weisel K, De Stefano V, et al. LocoMMotion: a prospective, non-interventional, multinational study of real-life current standards of care in patients with relapsed and/or refractory multiple myeloma. Leukemia. 2022;36(5):1371-1376. doi:10.1038/s41375-022-01531-2
5. Mateos MV, Hernández MT, Giraldo P, et al. Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol. 2016;17(8):1127-1136. doi:10.1016/S1470-2045(16)30124-3
6. Bjorklund CC, Kang J, Amatangelo M, et al. Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide- and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN. Leukemia. 2020;34(4):1197-1201. doi:10.1038/s41375-019-0620-8
7. Ackley J, Ochoa MA, Ghoshal D, Roy K, Lonial S, Boise LH. Keeping Myeloma in Check: The Past, Present and Future of Immunotherapy in Multiple Myeloma. Cancers (Basel). 2021;13(19):4787. Published 2021 Sep 24. doi:10.3390/cancers13194787
8. Lonial S, Popat R, Hulin C, et al. Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial. Lancet Haematol. 2022;9(11):e822-e832. doi:10.1016/S2352-3026(22)00290-3