A bit of good news this week for the myeloma community: a recent breakthrough in myeloma research was made by a group of Spanish researchers. 
 
Headed by Dr. Bruno Paiva (University of Navarra—Pamplona, Spain), a group of Spanish researchers from Cima Universidad de Navarra and the Spanish Myeloma Group (GEM-PETHEMA) developed an open-access calculator using data from flow cytometry that identifies an MGUS-like pattern in the bone marrow plasma cells, thus helping achieve much better outcomes in identifying patients with multiple myeloma and light-chain (AL) amyloidosis. 

According to the study, “Definition and Clinical Significance of the Monoclonal Gammopathy of Undetermined Significance–Like Phenotype in Patients With Monoclonal Gammopathies,” published in the Journal of Clinical Oncology, “an algorithm to identify patients having MGUS-like phenotype was developed on the basis of the percentages of total bone marrow (BM) plasma cells (PC) and of clonal PC within the BM PC compartment, determined at diagnosis using flow cytometry in 548 patients with MGUS and 2,011 patients with active multiple myeloma. The clinical significance of the algorithm was tested and validated in 488 patients with smoldering multiple myeloma, 3,870 patients with active multiple myeloma, and 211 patients with AL amyloidosis.”

This important observation and the development of a clinical tool have several implications for the myeloma community.

Discovery of the MGUS-Like Pattern

Monoclonal Gammopathy of Undetermined Significance (MGUS) is a precursor state of myeloma. MGUS is typically stable, without the indication of active disease.  The rate of potential progression to active myeloma is only one percent every year. The plasma cells in MGUS have  particular immune features which can be identified by flow cytometry.
 
The Spanish research team was able to show that assessing the number and pattern of these types of cells in the bone marrow of patients with active myeloma yields much better outcomes for myeloma patients following treatment, including lengths of remission and overall survival (OS). 
 
Based on the study, this subset of myeloma patients had excellent outcomes, with the following results for each category:

• “Patients with smoldering multiple myeloma with MGUS-like phenotype showed significantly lower rates of disease progression (4.5 percent and zero percent at 2 years in two independent series). There were no statistically significant differences in time to progression between treatment versus observation in these patients.”
• “In active newly diagnosed multiple myeloma, MGUS-like phenotype retained independent prognostic value in multivariate analyses of progression-free survival (PFS; hazard ratio [HR], 0.49; P = .001) and overall survival (OS; HR, 0.56; P =.039), together with International Staging System, lactate dehydrogenase, cytogenetic risk, transplant eligibility, and complete remission status.” 
• “Transplant-eligible patients with active multiple myeloma with MGUS-like phenotype showed PFS and OS rates at 5 years of 79 percent and 96 percent, respectively. In this subgroup, there were no differences in PFS and OS according to complete remission and measurable residual disease status.”
•  “Application of the algorithm in two independent series of patients with AL predicted for different survival.” 

This subset of patients had excellent outcomes even though residual disease was present. It’s IMPORTANT to note that these patients were NOT MRD negative.



Significance of MGUS-Like Pattern



In recent studies attempting to achieve best outcomes or cure with new treatment protocols, three groups of patients have emerged:

1. MRD Negative


In the CESAR Trial, where KRd (carfilzomib, lenalidomide, dexamethasone) plus autologous stem cell transplant were used as treatment for patients with high-risk smoldering multiple myeloma, and the ASCENT Trial, where Dara-KRd (daratumumab, carfilzomib, lenalidomide, and dexamethasone) was used as treatment for patients with high-risk SMM, up to 84 percent of patients in the ASCENT Trial achieved MRD negative status at the 10^-5 level. These patients mostly continue to do well and are in remission at 3-6 years.
 
Over time, if MRD negativity is sustained, these patients are to be considered as potentially cured in the conventional sense but will need confirmation through detailed follow-up testing.



2. MRD Positive


In a variety of treatment trials, an important subset of patients has been noted to do well with stable disease despite having obvious residual disease. 
 
The Spanish study indicates that such patients with good outcomes can be identified as having an MGUS-like immune pattern or phenotype. This means that such patients can be observed without immediate need for additional therapy and could ultimately fall into a category of functional cure  or the prolonged absence of active disease. Longer-term outcomes for such patients remain to be determined.
 

3. MRD Positive Relapse/Progressive Disease


In sharp contrast to the MGUS-like subgroup are myeloma patients with residual disease which is active and producing relapse. For this group, new therapy is required. It is extremely helpful to distinguish patients with MRD Positive Relapse/Progressive Disease from the MGUS-like group.



The Bottom Line



The Spanish research team has made a breakthrough in developing this open-access MGUS-like Calculator and being able to identify patients with myeloma as well as amyloidosis who have this type of better prognosis based upon a more benign immune profile. 
 
The fact that this subgroup of patients does well without the need for ongoing treatments is especially important. Making this tool broadly available is very helpful for the myeloma community.