Our final blog entry on the key clinical developments presented at the American Society of Hematology (ASH) annual meeting held in early December 2022 focuses on the prevalence of monoclonal gammopathy of undetermined significance (MGUS) and optimal treatment strategies for patients with smoldering multiple myeloma (SMM) at the highest risk of progressing to multiple myeloma.
Additionally, minimal residual disease (MRD) assessment in patients with multiple myeloma is moving beyond the bone marrow through use of mass spectrometry (MS) to assess M protein in the blood.
iStopMM Study and MGUS Insights
Myeloma precursor conditions remain an active area of research. Two large nationwide studies—the Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) study in Iceland and the Promise study in the US and Canada—aim to define clinical characteristics of MGUS and SMM via screening.
Focusing on MGUS prevalence and characteristics, iStopMM looked at 75,000 individuals—representing more than half of Icelanders ≥40 years. At ASH 2022, the iStopMM investigators reported on MGUS prevalence by age, sex, and immunoglobulin subtypes. MGUS was diagnosed in 3,358 individuals (about 4.5% prevalence for the entire group and 5% for people >50 years). The majority of individuals with MGUS (57%) had an IgG subtype (IgM 21%; IgA 12%). Of the individuals with MGUS, 43% were considered low risk and 0.3% high risk of progression based on the Mayo Clinic risk stratification model.
Ultimately, iStopMM is the largest population-based screening study conducted to date confirming a pattern of higher MGUS prevalence with increasing age and male sex. Interestingly, the individuals with IgA subtype progressed slower with age than did individuals with other subtypes.
Concerns have been raised about whether SARS-CoV-2 vaccine administration in patients with premalignant plasma cells (eg, those with MGUS) may trigger disease progression. iStopMM investigators looked at changes in serum M protein levels in individuals with MGUS who had received at least one SARS-CoV-2 vaccination (n=1,814). The most common vaccine used was the BNT162b2 (54.4% of MGUS individuals). The analysis showed no difference in the rate of M protein increase following vaccination compared to the observation period before vaccination (for both men and women). The investigators ultimately found no evidence of MGUS progression following SARS-CoV-2 vaccination, irrespective of the number of doses administered and the type of vaccine used.
Current guidelines suggest that individuals with MGUS do not require a bone marrow biopsy for testing, because most individuals never progress to SMM or myeloma.
To help clinicians identify patients for which they can confidently defer collecting a bone marrow sample, the iStopMM investigators used their dataset to help predict the risk of progressing to myeloma in individuals who had ≥10% bone marrow plasma cells. The validated model used results from standard MGUS work-up tests, including antibody isotype, M protein concentration, free light chain ratio, and total immunoglobulin concentrations. External validation of this model is awaited.
High-Risk SMM Interventions
The GEM-CESAR study is investigating an intensive treatment strategy (induction therapy and autologous stem cell transplantation [ASCT]) aimed at eliminating the risk of progression to myeloma in patients with high-risk SMM by inducing and maintaining MRD negativity (measured by next-generation flow [NGF] at 1 × 10-5 sensitivity).
In this study, 99 high-risk (31 with ultra–high-risk) transplant-eligible SMM patients (<70 years) were treated with six cycles of carfilzomib-lenalidomide-dexamethasone (KRd) followed by ASCT and two more cycles of KRd and maintenance therapy with lenalidomide (up to 2 years). At a median follow-up of 65.8 months, 70 patients had completed the scheduled treatment and 94% remained alive and progression-free. MRD negativity rates included 40% of patients after induction, 63% after ASCT, 68% after consolidation, and 52% after maintenance. Ultimately, the sustained MRD negativity rate 2 years after stopping maintenance (and 4 years after ASCT) was 25.6%. The rates using a sensitivity threshold of 1 × 10-6 were 27%, 43%, 57%, and 43%, after induction, ASCT, consolidation, and maintenance, respectively, and a sustained MRD negativity rate of 23%. Investigators concluded that a portion of high-risk SMM patients treated with curative intent maintain MRD negativity and that progression to myeloma is driven by MRD persistence and lack of sustained MRD negativity.
Another trial looked at a treatment strategy aimed at reducing the risk of progression and potentially eradicating the malignant clone in high-risk SMM used a four-drug treatment regimen. In this study (ASCENT), 87 patients were enrolled and 41 completed all scheduled treatment, which included a fixed-duration (2 years) of induction therapy with daratumumab-KRd (6 cycles), consolidation with daratumumab-KRd (6 cycles), and maintenance therapy with daratumumab-lenalidomide (12 cycles). After a median follow-up of 25.8 months, 38 patients remain on study. The overall response rate was 97% (≥VGPR 92%) and 84% achieved MRD negativity. The 3-year progression-free survival (PFS) rate was 89.9%.
Disease Monitoring in the Blood via Mass Spectrometry
A retrospective study from the Mayo Clinic examined M protein via Mass-Fix, a mass spectrometry–based blood test, in newly diagnosed myeloma patients and compared results with MRD assessment in the bone marrow. From a study population of 274 patients, 55% achieved Mass-Fix negativity, 43% achieved MRD negativity (in bone marrow), and 23% achieved both Mass-Fix and MRD negativity.
Patients who achieved Mass-Fix negativity had a better PFS than patients who did not (86.7% vs 70% P<0.001). Overall survival was similar in patients who achieved negativity via Mass-Fix or MRD and those who did not. Sustained Mass-Fix negativity of ≥6 and ≥12 months was achieved in 76% and 71% of patients, respectively. Sustained Mass-Fix negativity of ≥12 months was associated with longer PFS than was negativity <12 months (2-yr PFS 94.4% vs 80.2%; P=0.019). Median duration of Mass-Fix negativity was 27 months (range 25–30 months) and nearly half of patients who lost Mass-Fix negativity eventually had progressive disease. Investigators concluded that sustained Mass-Fix negativity is a potentially valuable tool for evaluation of prognosis and disease control and that loss of Mass-Fix negativity could be used to alert clinicians to the need for early treatment intervention.
In the phase 3 multicenter GMMG-MM5 trial, German investigators used mass spectrometry (MS) to detect and monitor M protein in peripheral blood samples of newly diagnosed, transplant-eligible myeloma patients. Blood samples were tested via quantitative immunoprecipitation mass spectrometry (QIP-MS) at baseline, after induction therapy, prior to maintenance therapy, and after 1 year of maintenance therapy. Results showed that MS negativity rates increased from 6% post induction to 31% and 44% prior to and 1 year after maintenance therapy. MS negativity was associated with improved PFS at all time points. The best outcomes were observed for patients with no high-risk cytogenetics, such as del17p, t(4;14), t(14;16), or gain 1q and MS negativity (median PFS 4.8 years). Poor outcomes were observed for patients with high-risk FISH and MS positivity (median PFS 1.9 years). Sustained MS negativity was associated with improved PFS compared to sustained MS positivity.
The use of blood-based MRD measurement with MS was assessed in GEM2014MAIN, a phase 3 randomized trial investigating lenalidomide-dex (Rd) vs ixazomib-lenalidomide-dex (IRd) maintenance therapy after ASCT in newly diagnosed myeloma patients. After 2 years of maintenance therapy, bone marrow and peripheral blood samples from 156 patients were analyzed by NGF (3 × 10-6 sensitivity) or QIP-MS. Residual disease was detected in 29% of patients by NGF and 24% of patients by QIP-MS—a concordance of 85%. MRD positivity by either method was associated with shorter PFS at 5 years compared to patients with MRD negativity (57% vs 89% via NGF; 62% vs 86% via QIP-MS). Investigators suggest that QIP-MS MRD assessment could be used to define the optimal time point for bone marrow–based MRD assessment.
For further analysis of the clinical data presented at ASH, check our additional blog posts here and here.
Support for this activity has been provided through donations from Amgen and Karyopharm; grants from Bristol Myers Squibb and Genentech, a member of the Roche Group; and sponsorships from AbbVie, GSK, and Sanofi US.
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