The Clinical Characteristics and Outcomes of Multiple Myeloma Patients With Oligo or Non-Secretory Relapse-A Retrospective Cohort Study.

Introduction

Multiple Myeloma (MM) is a malignancy of plasma cells whose clinical presentation may include anemia, hypercalcemia, renal insufficiency, and lytic bone lesions [ 1 ]. The presence of monoclonal antibodies in the serum and/or urine, secreted by the malignant plasma cells, is the hallmark of MM. Infrequently, monoclonal protein (M‐protein) and the involved free light chain (iFLC) are either not detected (non‐secretory) or are below the threshold considered as measurable disease according to IMWG criteria [ 2 ], termed oligo‐secretory MM (OSM). The incidence of OSM at presentation was estimated at 1%–3% [ 3 ], and in another study OSM constituted 10% of all newly diagnosed MM patients [ 4 ], however, the data on the frequency of OSM at time of relapse are scarce. MM patients are monitored for monoclonal antibody levels to detect disease relapse. OSM patients present a clinical challenge due to the difficulty of detecting relapses and assessing response to treatment in the absence of a measurable monoclonal protein.

It is of interest to understand the frequency of OSR, and whether and to what extent a potential delay in relapse diagnosis affects the disease burden and extent of organ damage at the time relapse is finally recognized, compared to secretory myeloma patients, and whether this impacts outcomes.

The mechanism that disrupts the cell's ability to produce or secrete antibodies remains poorly understood. A study from 1976 suggested that the antibodies are synthesized and secreted with structurally abnormal chains that are then quickly degraded [ 5 ]. It has been shown that a frameshift mutation in nucleotides encoding the constant region of the kappa light chain prevents secretion outside the cell in a patient with non‐secretory myeloma [ 6 ]. That patient had t(11; 14)(q13; q32) rearrangement. A study published in 2002 found that 11 out of 14 non‐secretory patients had the t(11; 14) [ 7 ]. The authors postulated that this gave the cells a more “lymphoplasmacytic morphology” with a lower secreting capacity than MM cells without the translocation.

Data about the incidence, clinical characteristics, and outcomes of OSR are lacking. Moreover, OSM patients are usually excluded from clinical trials since most trials require measurable disease to facilitate assessment of response to therapy. We describe this population's clinical characteristics and outcomes, assess factors predictive of OSR, and estimate the incidence of oligo‐secretory relapse MM patients.

Methods

We conducted a retrospective study of all consecutive MM patients who were diagnosed with MM at Mayo Clinic, Rochester, Minnesota (Mayo Clinic Cohort), and at Tel Aviv Sourasky Medical Center (TASMC cohort), Israel, since 1990 and who were treated for a disease relapse between 01/2016 and 07/2022. Patients presenting with oligo‐secretory disease at diagnosis were excluded.

The definition of oligo‐secretory MM)OSM(includes all three following criteria: M‐protein < 1 gr/dL, U‐PEP < 200 mg/24 h, and iFLC < 10 mg/dL. IMWG criteria defined relapse in the absence of measurable disease in serum or urine [ 2 ]: new or increasing lesion(s) or increase in bone marrow or circulating plasma cells (PCs). The index OSR was defined as the relapse number (i.e., first relapse, second relapse, etc.) of the patient's first OSR. Since the definition of secretory relapses in patients with IgA is challenging [ 8 ], we defined an OSR in IgA patients as a relapse with IgA levels < 1000 mg/dL.

For every oligo–secretory–relapsed (OSR) patient, we matched one secretory‐relapsed (SR) patient treated in the same center. The matching was done by the relapse index number of the relapse and by the year that the relapse occurred (note that accordingly, by definition, the OSR cohort and the controlled had the same number of prior lines of therapy). The OSR cohort included all consecutive MM patients with measurable disease at diagnosis that developed an OSR. The SR Cohort included the matched cohort.

The study was approved by both centers' Institutional Review Board (IRB). For risk stratification, we used the international staging system (ISS) and fluorescence in situ hybridization (FISH) in CD38‐positive sorted plasma cells. High‐risk FISH was defined according to IMWG risk stratification criteria and included del 17p, t(4; 14), t(14; 16), t(14; 20), and Gain 1q.

OS was defined from day OSR to death from any cause. PFS was defined as the time from the day of OSR to reinitiating therapy or death.

Categorical variables were described as frequency and percentage. Continuous variables distribution was evaluated using histogram and Q‐Q plot and reported as mean and standard deviation or as median and interquartile range. The patients and disease characteristics of the OSR cohort were compared to those of the SR cohort. The Chi‐Square and Fisher's exact tests were used to compare categorical variables, while the independent samples t ‐test and Mann‐Whitney test were applied to compare continuous variables. The reverse censoring method was used to describe the length of follow‐up. Kaplan‐Meier curves were used to describe the OS and PFS probabilities during the study period and to estimate the median survival time. The log‐rank test was applied to compare between groups. All statistical tests were two‐sided, and p < 0.05 was considered as statistically significant. Statistical analysis was performed using SPSS software (IBM SPSS Statistics for Windows, version 29.0.2, IBM Corp., Armonk, NY, USA, 2023).

Results

Between January 2016 and July 2022, we identified 86 who had an OSR, 38 at Mayo Clinic and 48 at TASMC.

Incidence of OSR

At TASMC, a total of 289 patients presented with secretory relapse and progressed; 48 (16.6%) had an OSR. The incidence of OSR was similar in the 1st–2nd relapse (14%, 36 of 258 pts who experienced 1st–2nd relapse) compared to 3rd or subsequent relapse (10%, 12/120 pts). The incidence of OSR could not be assessed among the Mayo Clinic cohort since the denominator could not be estimated, since many patients were non‐evaluable due to missing levels of myeloma monoclonal proteins in the database at the 60‐day period prior to relapse.

Patient Characteristics

The baseline characteristics for all 86 patients are listed in Table 1 . The mean age was 60.9 (range 33–80.8), and 44 (50.6%) were men. 14 patients (16.2%) had high‐risk cytogenetic features. Fifty‐nine patients (68.9%) received bortezomib‐based induction, 43 patients (50%) underwent autologous stem cell transplantation (ASCT), and none received daratumumab frontline (Table 2 ). At index relapse, 40 patients (47.1%) received daratumumab, and 12 patients (14.1%) underwent radiation therapy ( p = 0.01). Patients' characteristics at the time of index relapse are listed in Table 3 . The defining criteria for treatment initiation are listed in Table 4 and include new lytic lesions in 65 patients (75.6%), a new plasmacytoma in 22 patients (25.6%), an increase in an existing lesion in 25 patients (29.1%), hypercalcemia in one patient (1.2%), and creatinine rise > 2 in two patients (2.4%).

The matched cohort consisted of 86 patients, and their baseline characteristics are listed in Table 1 . When comparing the two cohorts' baseline characteristics (Table 1 ), the OSR group was younger ( p = 0.001), and the involved light chain levels at diagnosis were lower ( p < 0.001). All other baseline characteristics did not differ between the two cohorts. The groups did not differ in the induction treatment administered at frontline as well. However, 12 patients (14.1%) of the OSR cohort and only two (2.4%) in the SR cohort received radiation ( p = 0.01). In terms of patients' characteristics at the time of relapse (Table 3 ), the OSR patients had lower creatinine levels ( p = 0.002), higher platelet levels ( p = 0.028), higher hemoglobin levels ( p = 0.004), and lower median BMPC ( p = 0.002). When comparing the defining criteria for relapse to the SR group, more patients in the OSR were treated due to a new lesion ( p < 0.001), a new plasmacytoma ( p < 0.001), an increase in a lesion ( p < 0.001), whereas, as expected, more patients in the SR cohort were treated due to a rise in the M protein and involved light chain ( p < 0.001).

Outcome

The median OS of the OSR group since OSR was 4.01 years (95% CI 1.625–6.395), and the median OS of the SR control group was 3.25 years (95% CI 2.255–4.245) ( p = 0.4). The median TTNT of the OSR group was 2.56 years (95% CI 0.461–4.65), and the median TTNT of the SR control group was 1.64 years (95% CI 0.406–2.874) ( p = 0.144) (Figures 1 and 2 , respectively).

Twenty‐eight patients (32.6%) had a SR following an OSR. The median time from the OSR to the secretory relapse was 8.95 months (IQR 5.05–21.56). The median OSR index was 2 (IQR 1–3), with 12 patients (42.9%) having a secretory relapse when the OSR index was 1. The relapse criteria of the SR after OSR group was a new bone lesion in 22 patients (78.6%), an increase in lesion size in 7 patients (25%), a plasmacytoma in 8 patients (28.6%), elevation in the M spike in 2 patients (7.1%), an increase in the BMPC > 10% in 2 patients (7.7%), and a decrease in hemoglobin > 2 g/dL in 4 patients (14.8%). Total is > 100% since relapse was seen by more than one criterion in patients. None of the patients had an increase in creatinine at the secretory relapse, an increase in dFLC > 10 mg/dL, or hypercalcemia.

Outcomes of Patients That Became Secretory After OSR

Twenty‐eight patients had a SR after their OSR versus 56 patients who remained oligo‐secretory (Table S1 ). There was no predictive factor for SR after OSR. The ORR to treatment of the secretory relapse was 55% (sCR in 2 patients, CR in 2 patients, VGPR in 5 patients, PR in 3 patients, SD in 4 patients), 6 patients had PD, and data was missing for 6 patients. Table S2 compares the relapse criteria of these two cohorts. The median OS of the SR after OSR group was 3.35 years (95% CI 1.541–5.159), and the median OS of the group that remained oligo‐secretory was 5.8 years (95% CI 2.072–9.528) ( p = 0.336). The median TTNT of the SR after OSR group was 1.683 years (95% CI 0.341–0.919), and the median TTNT of the group that remained oligo‐secretory was 4.58 years (95% CI not reached‐not reached) ( p < 0.001) (Figure S1 and Figure 3 , respectively).

Discussion

Oligo‐secretory and non‐secretory MM present a clinical challenge due to the difficulty of detecting relapse and confirming response to treatment. These patients are excluded from most clinical trials, which typically require the presence of measurable disease in blood or urine, to facilitate rapid and quantitative assessment of their disease burden in response to study treatment. While approximately 10% of NDMM have oligo‐secretory disease, we found that an additional ∼17% of patients who presented with secretory MM will later develop an OSR, together, accounting for a significant proportion of myeloma patients. In our study, the OSR cohort was younger and had lower involved light chain levels at presentation than the SR cohort, suggesting that some of the cellular pathways leading to lack of immunoglobulin secretion were already present at diagnosis. In terms of treatment, we could not find any regimen that increases the risk of OSR. However, none of the patients in our cohort were treated with daratumumab upfront or were treated with bispecific antibodies or CAR‐T at any stage. The OSR patients were radiated more frequently than SR patients: 12 patients (14.1%) of the OSR cohort and only two (2.4%) in the SR cohort received radiation. This reflects the high proportion of OSR patients whose relapse was not recognized until the development of a new plasmacytoma or increase in the size of a lytic lesion. In contrast, SR patients were recognized biochemically by a rise in the level of their immunoglobulin protein marker and therapeutic intervention was administered long before new bone lesions could develop. Awareness that lower light chain levels at diagnosis predicts OSR can help clinicians be mindful and pursue imaging, allowing for early detection of relapses before irreversible organ damage occurs. Recently published data suggests that soluble B‐cell maturation antigen (sBCMA) is a useful tool for monitoring responses in patients with OSM and early relapse detection. In 115 newly diagnosed MM patients, sBCMA correlated strongly with %BMPC, paraprotein level, and involved free light‐chain levels. Longitudinal changes in sBCMA were consistent with disease status in 17 OSR cases [ 9 ].

The defining criteria for treatment initiation in OSR in our cohort include lytic bone lesions in 75.6%, a new plasmacytoma in 25.6%, an increase in a lesion in 29.1%, hypercalcemia in 1.2%, and creatinine rise > 2 in 2.4%. As expected, when comparing these characteristics to the SR cohort, the criteria for relapse in the OSR cohort were more frequently a new bone lesion, new plasmacytoma, and increased size of the lesions. At the time of relapse, the OSR cohort had lower creatinine, attributed to the fact that measurable light chains are necessary for the development of cast nephropathy. We found the OSR cohort to have lower BMPC infiltration, reflecting the lower disease burden. Our data is supported by a report of 100 patients with OSM at diagnosis that showed that compared to patients with secretory MM, OSR patients were younger and had less frequent renal dysfunction. In this report, the OSM cohort patients were less anemic and had less extensive bone marrow infiltration, similar to our results [ 10 ]. We found that the OSR group had higher platelet counts. These findings can be explained by the fact that more patients in the OSR cohort relapsed with a lytic lesion, a plasmacytoma, or an increase in lesion size, without extensive bone marrow involvement (i.e., macrofocal disease). All this can point to potential biological differences, necessitating further investigation to identify genetic or microenvironmental differences between these MM subtypes.

The median OS of the OSR group was 4.04 years, and the median TTNT was 2.56 years. It is questionable to what extent a delay in relapse diagnosis affects outcomes of OSR compared to SR. The median OS and TTNT did not differ between the two groups. However, the fact that OSR patients present more frequently with new lesions, an increase in the size of existing lesions, and new plasmacytomas can negatively impact the quality of life (QOL) due to fractures and pain and emphasize the importance of regular imaging surveillance. The findings that oligo‐secretory disease did not emerge as a prognostic factor for shorter survival are also supported by a study focusing on oligo‐secretory myeloma at diagnosis [ 10 ].

A surprising finding of this study was the relatively high rate of SR after the OSR. In most patients with OSR, subsequent relapses remained oligo‐secretory; However, a third of the OSR cohort had a secretory relapse after the OSR, with a median time of 8.95 months to the SR. In 42.9% of these relapses, the OSR index was 1. None of these patients had an increase in creatinine levels at the secretory relapse. We did not find any predictive factor for SR after OSR. The ORR to treatment of the secretory relapse was 55% (sCR in 2 patients, CR in 2 patients, VGPR in 5 patients, PR in 3 patients). The OS of this cohort was 3.35 years, not statistically different from the cohort that remained oligo‐secretory. However, the median TTNT was 1.68 years and was significantly shorter than the group that remained oligo‐secretory. The incidence of secretory relapse after OSR has never been described before. One possible explanation is that the switch from OSR to SR reflects reemergence of a previous secretory clone or the expansion of a secretory subclone under therapeutic pressure; this may be related to increased therapy resistance and, thus, shorter TTNT. Alternatively, this can reflect early treatment in centers with access to advanced imaging, triggering treatment based on biochemical progression only. Thus, theoretically, some of the cases classified as OSR would have evolved to SR if treatment had not been initiated. We suggest that data on SR post‐OSR is robust enough to support continuous monitoring of light chains after the OSR, as a subsequent SR is not a rare event.

The limitations of our study are its retrospective nature and the number of patients. We could not provide data on irreversible target organ damage, such as fractures or irreversible rise in creatinine. Another significant limitation in the SR after the OSR cohort is that these patients were treated at centers with access to advanced bone imaging, allowing for early relapse detection. If the treating physician waited longer, the monoclonal proteins might have reappeared. We did not have the exact number of OSR patients treated for relapsed MM at Mayo Clinic, so the calculation of the prevalence of OSR was limited to the TASMC cohort. This arises from the fact that the Mayo Clinic is a referral center, and for many patients, treatment is changed locally. To include a patient, we required lab results, including M‐protein and FLC, available within 60 days preceding the change of therapy date. If these data were not available, the patient was excluded. Another important limitation of this study is that it did not include patients treated with bispecifics and CART, which, to our clinical mpression, increase the risk of OSR.

Conclusions

OSR happens rather early (median OSR index was 2), and these patients are characterized by younger age and lower levels of light chain secretion at presentation. Despite the diagnostic challenge in the absence of monoclonal proteins, the outcomes of OSR (OS, PFS, ORR) are similar to those of the SR control group. The natural history of oligosecretory myeloma patients is similar standard secretory MM pts. Moreover, A third of the OSR patients had a subsequent secretory relapse, and these patients had a poorer prognosis. As a non‐negligible proportion of MM have oligo‐secretory disease at diagnosis (∼10%) or develop an OSR during their subsequent disease course (17%), we suggest that efforts should be made to include OSR patients in clinical trials, as there is a need to obtain treatment response and prognosis data in oligo‐secretory patients. Furthermore, we believe that refined and validated response assessment criteria are urgently needed. Approaches such as positron–emission tomography‐computed tomography (PET/CT), multiparametric flow cytometry, and biomarker response evaluations can help with such assessments in patients with oligo‐secretory myeloma in the future.

Author Contributions

I.V., and Y.C. designed the study, analyzed the data, wrote the first draft, and approved the final version of the manuscript. T.Z.B. analyzed the data. I.C., G.F., N.M., and R.S., Collected the data and critically revised the manuscript and approved the final version of the manuscript. T.S., S.T., E.L., S.L., I.A. P.R., A.D., and M.A.G. critically revised the manuscript and approved the final version of the manuscript. All authors have reviewed the manuscript, agree with its contents, and consent to its submission to BCJ.

Funding

The authors have nothing to report.

Conflicts of Interest

Dr. Gertz reports: DSMB AbbVie, DSMB Celgene, Akcea Honoraria and consulting, i3Health educational materials, Prothena consulting, Research to Practice Honoraria, Alnylym consulting, Ambry Genetics honorarium, Amgen honorarium, Janssen Honorarium, Celgene Honorarium, Stock Options Aurora Bio, Ionis Advisory Board, Karyopharm Honorarium, Pfizer honorarium to institution, Sanofi honorarium.

Supporting information

Figure S1: The baseline characteristics: SR vs. OSR after OSR.

Table S1: Criteria used to define SR post OSR.

Table S2: Overall survival.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

Supplementary Materials

Figure S1: The baseline characteristics: SR vs. OSR after OSR.

Table S1: Criteria used to define SR post OSR.

Table S2: Overall survival.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.