Precursor Conditions Unlock Potential for Early Interventions in Multiple Myeloma

Multiple myeloma arises from precursor conditions, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma. Since MGUS was first described more than 40 years ago, its definition and implications have continued to evolve. Data presented at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition underscored the growing focus on improving screening, advancing methods of detection, and improving our understanding of the genomic, genetic, and epigenetic factors that govern progression and therapeutic resistance.

No routine screening process is established for multiple myeloma or other blood cancers among the general population, despite the availability of a simple blood test with better sensitivity and specificity of detection for monoclonal protein than intrusive and potentially nonsensitive studies such as mammograms and colonoscopies. The argument for many years has been that early detection offers no benefit because of low rates of progression and unclear survival advantages. However, this argument is not valid with recent data that demonstrate early interceptions have a significant beneficial effect on survival.

The prevalence of MGUS is approximately 3% to 5% among Americans older than 50 years.¹ However, these statistics are based on a predominantly White population, use old technologies of serum protein electrophoresis, and do not account for at-risk individuals (based on race or family history). MGUS and multiple myeloma exhibit one of the largest racial disparities of all cancer types.

Compared with White Americans, Black Americans have a 2- to 3-fold higher MGUS prevalence.² A growing body of evidence suggests that heritable factors may influence this racial disparity, with results of several studies demonstrating that a family history of multiple myeloma or a related plasma cell dyscrasia is a strong risk factor for MGUS and multiple myeloma.³

Two studies, presented at 2021 ASH, demonstrated the utility of screening and whom it will provide benefit: the iStopMM study (NCT03327597) in Iceland and the PROMISE study (NCT03689595) in the US (TABLE^4-6).

iStopMM Clinical Trial

iStopMM is the first population-based, unbiased screening study for MGUS that includes a randomized trial component to assess follow-up strategies.⁴ All Icelandic residents born before 1976 (age ≥ 40 years) were eligible to participate, and blood samples were collected alongside blood sampling in the Icelandic health care system. A total of 75,422 participants provided a serum sample for screening, of which 3725 (4.9%) had MGUS.

MGUS prevalence was dependent on age, with 2.3%, 6.2%, and 12.9% of diagnoses occurring in age groups 40 to 59 years, 60 to 79 years, and 80 to 103 years, respectively. With a median follow-up of 3 years, data from the randomized control trial evaluating follow-up strategies revealed that active screening identified a significantly higher number of individuals with any lymphoproliferative disorder, specifically smoldering Waldenström macroglobulinemia, smoldering myeloma, and multiple myeloma.5 Interestingly, of the 1279 patients randomized to intensive follow-up, bone marrow sampling from 970 participants revealed smoldering myeloma in 105 (10.8%) individuals. The prevalence of smoldering myeloma was 0.53% in the population of participants 40 years and older. Thus, the iStopMM study demonstrated the value of screening for early detection and intervention, although evidence of the effect on survival outcomes is yet to be determined.

Promise Study

Investigators of the PROMISE study only screened individuals in high-risk populations, namely Black Americans and those with a first- or second-degree relative with a blood cancer.⁶ The study population included 7600 screened patients using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) as well as serum protein electrophoresis and immunofixation. The overall prevalence of MGUS, as detected by MALDI-TOF MS, was 10%. Screening identified monoclonal gammopathies (MGs) in 40% of high-risk individuals 50 years and older, with 13% having high-concentration MGs (MS-MGUS); a lower-concentration fraction of MGs was further defined as monoclonal gammopathy of indeterminate potential (MGIP).

Significantly worse overall survival was reported among those with MGs and, more specifically, among those with MS-MGUS or high-MGIP. Moreover, MGs were associated with developing blood cancers, cardiovascular diseases, and autoimmune disorders. In addition, screening did not demonstrate a significant effect on health-related quality of life or anxiety because of cancer worry across the pre- and postscreening interval. These results indicate that older adults in these populations could benefit from regular, high-sensitivity screening to identify MGs and to consider further investigation into their risk for MM and other comorbidities.

Beyond Screening

In addition to screening, another increased focus has been on improved, less-invasive methods of detection and surveillance in multiple myeloma. Minimal residual disease (MRD) assessments are a highly sensitive tool for assessing depth of response, risk stratification, and treatment of patients. Achieving MRD negativity is associated with improved progression-free survival (PFS), regardless of high-risk disease features.

Bone marrow–based MRD assessments are limited by their invasive nature, heterogeneity of marrow involvement, and cost of the available assays. Mass spectrometry (MS) is being evaluated by investigators as a more sensitive method of measuring paraproteinemia and has recently been approved by the International Myeloma Working Group (IMWG) for use in lieu of immunofixation. Giles et al assessed the prognostic effect of detectable residual monoclonal free light chains by MALDI-TOF MS in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM).⁷ They found that MS positivity was associated with shorter PFS than MS negativity, regardless of response attained as defined by IMWG criteria. This held true in patients with MRD negativity on maintenance therapy, with results demonstrating that those who were MRD negative and MS positive had a shorter time to progression (TTP) than those who were MRD negative and MS negative. Thus, MS provides an alternative to invasive bone marrow testing and may provide additional sensitivity for residual disease detection and prognosis.

Similarly, evaluating circulating tumor cells (CTCs) by next-generation flow has been found to hold prognostic value.⁸ Garcés et al evaluated CTCs in patients with smoldering myeloma and NDMM, finding CTCs were detected in 248 of 316 (78%) patients with smoldering myeloma and in 597 of 650 (92%) patients with NDMM. Untreated patients with smoldering myeloma (n = 230) with high CTC levels (≥ .02%) exhibited ultrahigh risk of transformation vs those with low and undetectable CTCs (median TTP, 11 months vs not reached, respectively; P < .0001).

An evaluation from Dutta et al of CTCs in patients with MGUS or smoldering myeloma corroborates these findings. The results demonstrated that higher CTC counts correlated with increased disease risk and that genomic profiling of CTCs was congruent with bone marrow multiple myeloma cell expression, capturing 100% of clinically annotated bone marrow fluorescence in situ hybridization (FISH) copy number variation (CNV) events as well as expanding yield by identifying CNVs and MYC rearrangements not observed by FISH.⁹ Notably, patients with smoldering myeloma and at least 0.02% CTCs enrolled in the GEM-CESAR trial (NCT02415413) have not reached a median TTP. Thus, early intervention abrogated the poor prognosis of high CTC levels.

The value of early treatment in precursor conditions has been shown previously, such as in the phase 2/3 ECOG trial of lenalidomide (Revlimid) vs observation in patients with intermediate-risk and high-risk smoldering myeloma, in which treatment significantly delays progression to symptomatic multiple myeloma and the development of end-organ damage without negatively affecting quality of life.¹⁰ With the goal of developing deeper remissions and potential for cure, several ongoing studies are evaluating the efficacy of combination therapies in MGUS and/ or smoldering myeloma including the following:

• the B-PRISM study (NCT04775550) of daratumumab (Darzalex), bortezomib (Velcade), lenalidomide, and dexamethasone in patients with high-risk smoldering myeloma¹¹;
• a phase 2 trial (NCT02916771) of ixazomib (Ninlaro), lenalidomide and dexamethasone in high-risk smoldering myeloma¹²;
• a phase 2 study (NCT03236428) of daratumumab in patients with high-risk MGUS and low-risk smoldering myeloma¹³; and
• the GEM-CESAR trial of carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd), induction, followed by autologous stem cell transplantation, KRd consolidation, and Rd maintenance in patients with high-risk smoldering myeloma.¹⁴

Early findings have shown combination therapies employed in precursor settings are effective and well tolerated, with patients achieving high rates of deep, MRD-negative responses, and prevent progression to overt multiple myeloma. However, survival advantages remain to be seen.

References

1. Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354(13):1362-1369. doi:10.1056/NEJMoa054494
2. Benjamin M, Reddy S, Brawley OW. Myeloma and race: a review of the literature. Cancer Metastasis Rev. 2003;22(1):87-93. doi:10.1023/a:1022268103136
3. Vachon CM, Kyle RA, Therneau TM, et al. Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance. Blood. 2009;114(4):785-790. doi:10.1182/blood-2008-12-192575
4. Rögnvaldsson S, Love TJ, Thorsteinsdottir S, et al. Iceland screens, treats, or prevents multiple myeloma (iStopMM): a population-based screening study for monoclonal gammopathy of undetermined significance and randomized controlled trial of follow-up strategies. Blood Cancer J. 2021;11(5):94. doi:10.1038/s41408-021-00480-w
5. Thorsteinsdottir S, Gislason GK, Aspelund T, et al. Prevalence of smoldering multiple myeloma: results from the Iceland screens, treats, or prevents multiple myeloma (iStopMM) study. Blood. 2021;138(suppl 1):151. doi:10.1182/blood-2021-148617
6. El-Khoury H, Alberge JB, Barr H, et all. High prevalence of monoclonal gammopathy in a population at risk: the first results of the Promise study. Blood. 2021;138(suppl 1):152. doi:10.1182/blood-2021-149868 
7. Giles HV, Drayson MT, Wright N, et al. Residual monoclonal free light chain positivity by mass spectrometry identifies patients at increased risk of early relapse following first-line anti-myeloma treatment. Blood. 2021;138(suppl 1):820. doi:10.1182/blood-2021-150479
8. Garcés JJ, Puig N, Termini R, et al. Circulating tumor cells (CTCs) in smoldering and active multiple myeloma (MM): mechanism of egression, clinical significance and therapeutic endpoints. Blood. 2021;138(suppl 1):76. doi:10.1182/blood-2021-146535
9. Dutta AK, Lightbody AD, Lin Z, et al. Non-invasive liquid biopsy to quantify and molecularly characterize circulating multiple myeloma cells in the assessment of precursor disease pathology. Blood. 2021;138(suppl 1):78. doi:10.1182/blood-2021-150622 
10. 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
11. Nadeem O, Redd RA, Prescott J, et al. B-PRISM (Precision Intervention Smoldering Myeloma): aphase II trial of combination of daratumumab, bortezomib, lenalidomide and dexamethasone in high-risk smoldering multiple myeloma. Blood. 2021;138(suppl 1):4782. doi:10.1182/blood-2021-148023 
12. Nadeem O, Redd RA, Prescott J, et al. A phase II trial of the combination of ixazomib, lenalidomide, and dexamethasone in high-risk smoldering multiple myeloma. Blood. 2021;138(suppl 1):2749. doi:10.1182/blood-2021-149787 
13. Nadeem O, Redd RA, Koontz MZ, et al. A phase II study of daratumumab in patients with high-risk MGUS and low-risk smoldering multiple myeloma. Blood. 2021;138(suppl 1):1649. doi:10.1182/blood-2021-149797
14. Mateos MV, Martinez-Lopez J, Otero PR, et al. Curative strategy (GEM-CESAR) for high-risk smoldering myeloma (SMM): carfilzomib, lenalidomide and dexamethasone (KRd) as induction followed by HDT-ASCT, consolidation with Krd and maintenance with Rd. Blood. 2019;134(suppl 1):781. doi:10.1182/blood-2019-125204