| Abstract|| |
Light chain myeloma (LCM) has a reported worldwide incidence of approximately 15%–20% among all multiple myeloma (MM) patients. Few western studies have shown strong correlation of LCM with anemia, higher International Staging System scores, proclivity to renal failure, elevated lactate dehydrogenase levels, raised serum-free light chain ratio, higher frequency of extramedullary plasmacytomas, and poorer overall survival, attributable probably to lack of differentiation and skeletal destruction. The primary aim of this retrospective observational study was to define the clinical and hematological characteristics as well as prognostic outcome of Indian LCM patients in comparison with the IgG and IgA subtypes. Patients were defined according to the International Myeloma Working Group diagnostic criteria 2016 and staged as per the International Staging System. Out of 104 patients of newly diagnosed MM in which results of serum immunofixation (IFE) were available, 65 were of IgG isotype (62.5%), 15 had IgA (14.4%), and 24 had light chain myelomas (LCMs) (23.1%). It was observed that LCM patients significantly correlated with hypercalcemia and higher serum-free light chain ratios, whereas IgA patients were strongly associated with anemia and lower serum albumin levels. However, no difference was found among the three subgroups in terms of serum lactate dehydrogenase levels, proclivity to renal failure, presence of lytic bone lesions, prognostic scoring, pretransplant chemosensitivity, and progession-free survival (1 year). Thus, it may be concluded that Indian LCM patients have significantly different clinico-hematological profile in comparison with other published studies worldwide. Also, their prognostic outcomes are not worse when compared with patients of other protein isotypes, probably due to standardized treatment regimens applied.
Keywords: Electrophoresis, immunofixation, multiple myeloma, plasmacytoma
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Singh N, Agrawal N, Sekhri R, Mehta A, Kumar D, Vishwakarma G, Ahmed R, Bhurani D. Light chain myeloma: A brief report from India. Indian J Pathol Microbiol 2019;62:441-4
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Singh N, Agrawal N, Sekhri R, Mehta A, Kumar D, Vishwakarma G, Ahmed R, Bhurani D. Light chain myeloma: A brief report from India. Indian J Pathol Microbiol [serial online] 2019 [cited 2020 Sep 26];62:441-4. Available from: http://www.ijpmonline.org/text.asp?2019/62/3/441/263479
Multiple myeloma (MM) is a biologically complex and clinically heterogeneous disease. The most common type of M protein found in MM is IgG followed by IgA and light chains only. LCM has a reported worldwide incidence of approximately 15%–20% among all MM patients and is more commonly of the lambda subtype., Few published studies have shown strong correlation of LCM with anemia, higher ISS scores, proclivity to renal failure, elevated lactate dehydrogenase (LDH) levels, raised serum-free light chain (SFLC) ratio, higher frequency of extramedullary plasmacytomas, and poorer overall survival (OS), attributable probably to lack of differentiation and skeletal destruction.,,, Although enough data are found in literature pertaining to this issue, Indian data are not readily available to assess disease burden and its therapeutic implications with respect to serum protein subtyping; although some Indian studies have touched upon the clinical profile of myeloma patients in general as well as in posttransplant settings.,,, Keeping this in mind, we evaluated the clinical and hematological characteristics as well as prognostic outcome of Indian LCM patients in comparison with the IgG and IgA isotypes as defined on serum immunofixation and serum-free light chain assay.
This retrospective study involved all the newly diagnosed multiple myeloma (NDMM) patients who presented to the Hematology OPD during the period from September 2013 to August 2016 at our tertiary care center. Patients with NDMM who received treatment and in whom 1-year follow-up data were available were included in this study. Patients with monoclonal gammopathy of uncertain significance, coexisting malignancies, nonsecretory myeloma, solitary plasmacytoma of bone, relapsed/refractory, and previously treated cases of MM were excluded from the study. Informed consent from the patient and ethical clearance was taken from the institutional review board. Patients were evaluated on the basis of proper history, clinical examination, laboratory, and imaging investigations including CRAB features, such as anemia, hypercalcemia, renal insufficiency and lytic bone lesions, bone marrow examination, serum protein electrophoresis and immunofixation, SFLC ratio, Positron Emission Tomography (PET)-scan, and skeletal survey. All patients were defined in accordance with the International Myeloma Working Group (IMWG) diagnostic criteria 2016 and staged as per the International Staging System (ISS). Information about cytogenetics/FISH studies required for revised-ISS scoring was available only in 50 patients. Enrichment of plasma cells was performed using CD138-positive selection beads (Stem Cell Technologies, Canada). Patients were allocated to receive one of the bortezomib-based regimens followed by autologous stem cell transplantation (ASCT) as per patient eligibility. BLD-21comprised of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of every 21-day cycle, 40 mg dexamethasone/day on days 1, 8, and 15 along with 25 mg/day of lenalidomide for 14 days per cycle. Alternative regimens included BTD using 100 mg of thalidomide on days 1–28 in place of lenalidomide or BCD using cyclophosphamide 300 mg/m2/day on days 1, 8, 15, and 22 of every cycle along with bortezomib and dexamethasone, respectively, given in selective patients. All the patients were evaluated for response status (CR/VGPR/PR) after completion of four cycles of therapy as well as progression-free survival (PFS) at 1 year and OS in accordance with the IMWG uniform response criteria 2016 for the assessment of treatment outcomes. Statistical analysis was done using SPSS software version 23.0 and data were presented in mean (standard deviation), median (range), and frequency (percentage). Association between categorical variables was tested by the Fisher's exact test. Comparison of quantitative variables between groups of patients was carried out by the nonparametric Mann–Whitney U-test and Wilcoxon rank-sum test as applicable. Continuous variables with normal distribution were tested using two-independent samples t-test. Significance of PFS at 1 year was calculated using log-rank test. P value <0.05 was considered as statistically significant.
Out of 104 patients of newly diagnosed MM in which results of serum immunofixation (IFE) were available, 65 were of IgG isotype (62.5%), 15 had IgA (14.4%), and 24 had LCMs (23.1%). Possibility of IgD/IgE myeloma was ruled out by IFE before a final diagnosis of LCM was made. Three patients had concomitant amyloidosis, whereas two had plasma cell leukemia. Only six patients overall had extramedullary plasmacytomas (5.8%) involving sites, such as lymph nodes, soft tissue of scalp, paravertebral region, nasopharyngeal wall, and orbit as evidenced on magnetic resonance imaging or PET-scan with no predilection for any protein subgroup. On statistical analysis, LCM patients correlated well with hypercalcemia (P = 0.047) and higher SFLC ratios (0.03). IgA isotype was strongly associated with anemia (P = 0.017) and lower serum albumin levels (P = 0.001) [Table 1]. However, no difference was found among the three subgroups in terms of serum LDH levels, bone marrow plasma cell percentage, serum beta-2-microglobulin levels, proclivity to renal failure, or presence of lytic bone lesions. ISS-III score was observed in 32.7%, 25%, and 28.6% of IgG, IgA, and LCM patients, respectively. [Figure 1] shows the prevalence of various cytogenetic abnormalities detected by FISH studies in myeloma patients. However, no predilection for any of the protein subgroups was observed. Response less than PR (stable and progressive disease) was seen in 24.1%, 10%, and 25% of IgG, IgA, and LCM patients, respectively, although the difference was not statistically significant. Also, PFS (1 year) or OS was not significantly different in the three subgroups irrespective of transplant status [Table 2]. About 20/34 (30.7%), 04/15 (26.6%), and 07/24 (29.1%) of patients with IgG, IgA, and LCM subgroups, respectively, underwent ASCT with high dose melphalan conditioning in CR/VGPR.
|Table 1: Baseline characteristics of newly diagnosed multiple myeloma patients with respect to serum protein subtyping (n=104)|
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|Table 2: Prognostic scoring and response to chemotherapeutic regimens in newly diagnosed multiple myeloma patients on the basis of serum protein subtyping|
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Within the LCM subgroup, 13 (13/24 = 54.2%) and 11 (11/24 = 45.8%) were of lambda and kappa subtypes, respectively. Furthermore, the lambda subtype was associated with higher median beta-2-microglobulin levels (P = 0.023) than the kappa subtype. But, there was no significant difference between the kappa and lambda subtypes with respect to anemia, serum LDH, hypercalcemia, bone marrow plasma cell percentage, renal failure, ISS scores, or chemosensitivity.
LCM is the subtype of MM characterized by the production of only light chains and is known to be frequently associated with anemia, renal failure, and poorer prognosis. Diagnosis should be made promptly in patients with no detectable M protein on serum protein electrophoresis to avoid irreversible renal damage. Bortezomib, a reversible proteasome inhibitor, has shown significant activity in myeloma patients and is safely administered to patients with renal failure, even those under dialysis. In this study, the overall frequency of the three subgroups corroborates well with the published literature, with LCM constituting 23.1% of all NDMM cases and being more commonly of lambda subtype. However, our observations are strikingly different from that of Ríos-Tamayo et al. who found a statistically significant correlation of light chain only subtype with proclivity to renal failure, higher ISS scores, elevated LDH levels, raised SFLC ratio, and lower median PFS. Moreover, only six (6/104 = 5.8%) of our patients showed the presence of extramedullary plasmacytomas (EMPs) unlike the study by Zhang et al., where they observed a much higher (33.3%) incidence of EMP among their LCM subset of patients. In terms of serum LDH levels, our finding corroborates well with that of Chim et al. who showed strong association of elevated LDH with ISS III but not serum protein isotype and Complete Response (CR) rates to induction. Our observations are similar to that of Sasaki et al. who also found strong association of LCM with younger age, hypercalcemia, and no difference in terms of serum LDH levels and bone marrow plasma cell percentage, but unlike our findings, their LCM patients correlated strongly with anemia, renal failure, higher beta-2 microglobulin levels, and higher pretransplant CR rates to induction. Moreover, they also concluded that M-protein isotype does not affect PFS or OS, similar to our study. Kumar et al. showed that PFS and overall response to treatment in post-ASCT patients do not get affected by the results of protein subtyping similar to our study., The major limitations of the present study are the small sample size and shorter follow-up data.
It may, thus, be concluded that the Indian LCM patients have significantly different clinico-hematological profile in comparison with other published studies. Moreover, their prognostic outcomes do not differ significantly in comparison with patients of other protein subtypes when treated with standardized bortezomib-based regimens unlike the observations of few other published studies worldwide.
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Department of Pathology, Rajiv Gandhi Cancer Institute and Research Center, Rohini, New Delhi
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2]