Serum B-Cell Maturation Antigen Reflects Disease Status in a Patient Who Developed Nonsecretory Multiple Myeloma: A Case Report.

Introduction: Multiple myeloma (MM) is an incurable bone marrow (BM)-based cancer involving clonal plasma cells. Most patients show elevated levels of serum monoclonal protein (sMP) and kappa or lambda serum free light chains (sFLCs) at diagnosis. However, around 1-2% of patients, termed nonsecretory, do not produce these biomarkers. As the disease progresses, more patients may become unevaluable using conventional markers, requiring invasive and expensive procedures like BM biopsies and positron emission tomography-computed tomography (PET-CT) scans for assessment and highlighting the need for alternative methods to monitor disease progression. Case Presentation: We present a case report of an MM patient who developed nonsecretory disease during his second line of treatment when he complained of new rib pain; progressive disease was then confirmed on a PET-CT scan. The patient showed an increase in his serum B-cell maturation antigen (sBCMA) levels whereas his conventional myeloma markers did not detect disease activity (sMP remained undetectable and involved sFLC level was normal). After starting a new treatment regimen, his rib pain disappeared, PET-CT scan improved, and sBCMA levels decreased. Upon relapse, he developed increased rib pain with a rising sBCMA level; his conventional myeloma markers did not detect disease activity. After changing to a new regimen, his rib pain improved, and this was accompanied by a decrease in his sBCMA levels. Conclusion: Thus, this case exemplifies the potential for sBCMA to provide a non-invasive method for monitoring MM patients who develop nonsecretory disease.

The incidence of translocation t(11;14) among patients with multiple myeloma in a single clinic.

OBJECTIVES: Data regarding bone marrow (BM) sampling and cytogenetic testing rates for identification of translocation (11q13;14q32) and their changes over time in a multiple myeloma (MM) population are limited. We analyzed these metrics at a clinic specializing in the treatment of MM. METHODS: A total of 760 BM aspirate samples from 351 patients were collected between August 2004 and October 2021. We analyzed BM sampling statistics, cytogenetic testing frequency, and the incidence rates for the t(11;14) translocation in a single clinic specializing in the treatment of MM. RESULTS: We report that most (54.4%) patients had only 1 aspirate collected; the main reason (64.6%) for BM collection was to confirm disease progression. Less than half (47.5%) of BM samples collected for evaluation of MM disease had cytogenetic testing, but the rates have markedly increased in recent years. Our data demonstrated an incidence rate of 19.3% for t(11;14). CONCLUSIONS: This report suggests that some patients may need to retest for this genetic aberration due to the possibility of false negatives and the potential benefit of identifying the t(11;14) marker for patients who may be candidates for a highly effective targeted therapy consisting of the BCL-2 inhibitor venetoclax.

Clinical Outcomes and Serum B-Cell Maturation Antigen Levels in a Real-World Unselected Population of Newly Diagnosed Multiple Myeloma Patients.

BACKGROUND: Progression-free survival (PFS) and overall survival (OS) of newly diagnosed multiple myeloma (MM) patients have been widely published in the clinical trials setting, but data published from real-world settings are limited. OBJECTIVE: We determined the survival and factors that predict outcomes among 161 unselected, newly diagnosed MM patients whose frontline therapy was started at a single clinic specializing in the treatment of this B-cell malignancy. PATIENTS AND METHODS: None of these patients underwent an autologous stem cell transplantation as part of their initial therapy and the population had a high proportion (35%) of cytogenetic high-risk patients. RESULTS: With a median follow-up of 42.7 months, the cohort had a median PFS of 22.8 months and a median OS of 136.2 months. The 1-, 3-, and 5-year survival rates were 97.5%, 85.3%, and 76.2%, respectively. These results are considerably better than those reported from patients enrolled in clinical trials and those from countries with national registries. Age <65 years predicted for a longer OS (p = 0.0004). Baseline serum B-cell maturation antigen (sBCMA) levels were also assessed and showed median and mean levels of 320.3 ng/mL and 551.1 ng/mL, respectively. Furthermore, patients with baseline sBCMA levels in the lowest quartile (≤136.2 ng/mL) showed a longer PFS (p = 0.0262). CONCLUSION: These results provide clinicians with a real-world understanding of the survival of unselected, newly diagnosed patients initiating therapy in a clinic specializing in the care of MM patients.

Efficacy of isatuximab in combination with steroids for the treatment of relapsed/refractory multiple myeloma patients exhibiting only biochemical progression-A single center retrospective study.

OBJECTIVES: Isatuximab is approved for treatment of relapsed/refractory multiple myeloma (RRMM) with dexamethasone and carfilzomib or pomalidomide. Patients receiving these three-drug regimens have exhibited more Grade ≥ 3 adverse events (AEs) compared to the two-drug class combination of isatuximab and steroids alone. Thus, this single-center retrospective study investigated the efficacy of isatuximab with dexamethasone and methylprednisolone (ISAdm) for RRMM patients showing only biochemical progression (BP) of their disease. METHODS: Twenty-four RRMM patients exhibiting only BP were administered isatuximab at 10 mg/kg with dexamethasone once weekly for cycle 1 of a 28-day cycle, followed by every other week for each cycle thereafter. Starting in cycle 2, oral methylprednisolone was added every other day stopping 48 h before and starting 48 h after each dexamethasone infusion. RESULTS: Overall response rate and clinical benefit rate were 63% and 79%, respectively. Progression free survival was 12.9 months. There were only 5 AEs of Grade ≥ 3 which included lymphocytopenia (13%), leukopenia (4%), and neutropenia (4%). No Grade ≥ 3 AE related to respiratory infection, anemia, or thrombocytopenia were reported. CONCLUSION: This study shows that the two-drug class combination of ISAdm is an effective and well tolerated treatment option for RRMM patients exhibiting only BP.

Loss of anti-spike antibodies following mRNA vaccination for COVID-19 among patients with multiple myeloma.

BACKGROUND: Multiple myeloma (MM) patients have variable responses to mRNA vaccination to COVID-19. Little is known regarding their vaccine-induced antibody levels over time. METHODS: We monitored spike IgG antibody levels over 24 weeks among a subset of 18 MM patients who showed a full response after two mRNA vaccinations. RESULTS: MM patients had a more rapid decline in antibody levels as compared to eight healthy controls, with power law half-lives of 72 days (vs. 107 days) and exponential half-lives of 37 days (vs. 51 days). The patients with longer SARS-CoV-2 antibody half-lives were more likely to have undetectable monoclonal protein than those with shorter half-lives, suggesting better disease control may correlate with longer duration of vaccine-induced antibodies. Regardless, by 16 weeks post-second dose of mRNA vaccination, the majority of patients had antibody levels below 250 binding arbitrary units per milliliter, which would be unlikely to contribute to preventing COVID-19. CONCLUSIONS: Thus, even MM patients who respond adequately to vaccination are likely to require more frequent booster doses than the general population.

Third dose of an mRNA COVID-19 vaccine for patients with multiple myeloma.

We have reported that IgG antibody responses following two mRNA COVID-19 vaccinations are impaired among patients with multiple myeloma (MM). In the current study, sixty-seven patients with MM were tested for anti-spike IgG antibodies 0-60 days prior to their first vaccination, 14-28 days following the second dose, and both before and 14-28 days after their third dose of the mRNA-1273 or BNT162b2 vaccines. After the first two doses, most patients' (93 %) antibody levels declined to ineffective levels (<250 BAU/mL) prior to their third dose (D3). D3 elicited responses in 84 % of patients (61 % full response and 22 % partial response). The third vaccination increased antibody levels (average = 370.4 BAU/mL; range, 1.0-8977.3 BAU/mL) relative to just prior to D3 (average = 25.0 BAU/mL; range, 1.0-683.8 BAU/mL) and achieved higher levels than peak levels after the first two doses (average = 144.8 BAU/mL; range, 1.0-4,284.1 BAU/mL). D3 response positively correlated with mRNA-1273, a > 10-fold change from baseline for the two-dose series, switching from BNT162b2 to mRNA-1273 for D3, and treatment with elotuzumab and an immunomodulatory agent. Lower antibody levels prior to D3, poorer overall response to first two doses, and ruxolitinib or anti-CD38 monoclonal antibody treatment negatively correlated with D3 response. Our results show encouraging activity of the third vaccine, even among patients who failed to respond to the first two vaccinations. The finding of specific factors that predict COVID-19 antibody levels will help advise patients and healthcare professionals on the likelihood of responses to further vaccinations.

Response to mRNA vaccination for COVID-19 among patients with multiple myeloma.

Multiple myeloma (MM) patients are at higher risk for severe COVID-19. Their mRNA vaccination response against SARS-CoV-2 is unknown. Thus, we analyzed responses to mRNA vaccination against COVID-19 among these patients. Using an ELISA-based assay that detects IgG antibodies to SARS-CoV-2 spike protein, we determined serum antibody levels prior to immunization and 12-21 and 14-21 days following the first and second vaccinations, respectively, with mRNA-1273 (Moderna) or BNT162b2 (Pfizer/BioNTech) among 103 MM patients (96 and 7 with active and smoldering disease, respectively). We stratified patients into clinically relevant responders (>250 IU/mL), partial responders (50-250 IU/mL, which was above pre-COVID-19 background), and nonresponders (<50 IU/mL). Smoldering MM patients responded better than those with active disease. Only 45% of active MM patients developed an adequate response, while 22% had a partial response. Lower spike antibody levels were associated with older age, impaired renal function, low lymphocyte counts, reduced uninvolved immunoglobulin levels, > second line of treatment, and among those not in complete remission. Patients who received mRNA-1273 vaccine had higher anti-spike antibody levels than those who were vaccinated with BNT162b2. Thus, most MM patients have impaired responses to mRNA vaccination against COVID-19, and specific clinical and myeloma-related characteristics predict vaccine responsiveness.

Baseline serum B-cell maturation antigen levels predict time to disease progression for patients with smoldering multiple myeloma.

Multiple myeloma (MM) patients with smoldering (S) disease are defined by a lack of CRAB/SLiM criteria but may transform into disease requiring treatment. The International Myeloma Working Group risk stratification model for SMM uses serum M-protein, serum-free light chain ratio, and bone marrow plasma cell percentage. We investigated whether baseline serum B-cell maturation antigen (sBCMA) levels are predictive of disease progression among 65 patients with SMM. A receiver operating characteristic curve was used to establish a definition for high-risk baseline sBCMA. Mantel Byar analysis was used to examine whether high-risk sBCMA was correlated with shorter time to transformation, and a time-dependent cox proportional hazard was used to determine whether it is independent of other risk factors. A z test for proportions was used to compare the percentage of patients that progressed among high-risk versus low-risk sBCMA patients. A baseline sBCMA level ≥137.5 mg/ml was found to be the optimal cutoff between high- and low-risk SMM patients. Patients with high-risk sBCMA levels had a shorter time to transformation (P = .000332). sBCMA was also higher at the time of transformation than baseline levels (P = .0116). sBCMA was the only variable found to be significantly predictive of time to transformation and additionally was found to be independent of other risk factors. In this study, we have shown for the first time that sBCMA levels predict transformation of SMM to active disease and that these levels increase at the time of transformation. These results are consistent with other studies showing that active MM patients undergoing therapy with higher baseline sBCMA levels are more likely to progress early and its levels increase at the time of disease progression.

Normalization of serum B-cell maturation antigen levels predicts overall survival among multiple myeloma patients starting treatment.

Serum B-cell maturation antigen (sBCMA) is a novel biomarker for B-cell malignancies. A normal reference range (<82·59 ng/ml) has been recently established but the impact of achieving normal levels to outcomes for patients receiving treatment for B-cell malignancies has not been studied. We first found that among multiple myeloma (MM) patients starting a new treatment, those who begin treatment within normal sBCMA limits (<82·59 ng/ml) have improved progression-free survival (PFS; P = 0·0398) and overall survival (OS; P = 0·0217) than those who do not. Furthermore, among patients who begin treatment with elevated (≥82·59 ng/ml) sBCMA levels, we assessed the relationship of a decrease in sBCMA to the normal range to OS and found that those who normalize sBCMA demonstrated improved OS (P = 0·0078). Normalizing patients also experienced a markedly improved overall response rate (P < 0·0001). Moreover, all patients who achieved complete remission (CR) showed normalization of sBCMA, and time to normalization (median 0·9 months) was faster than time to CR (5·0 months; P = 0·0036) for these patients. These results suggest that normalization of sBCMA may be an accurate predictor of OS for MM patients during treatment and predict for a higher likelihood of response.

Estimating a normal reference range for serum B-cell maturation antigen levels for multiple myeloma patients.

The serum B-cell maturation antigen (sBCMA) has been identified as a novel serum biomarker for patients with multiple myeloma. However, no study has yet established a reference range for sBCMA levels. Its levels were determined in 196 healthy subjects and showed a right-tailed distribution with a median value of 37·51 ng/ml with a standard deviation of 22·54 ng/ml (range 18·78-180·39 ng/ml). Partitioning of subgroup reference ranges was considered but determined to be irrelevant. A non-parametric method using the median ± 2 standard deviations suggests using a universal reference interval of <82·59 ng/ml.