Autologous stem cell transplant for multiple myeloma: Impact of melphalan dose on the transplant outcome.

We evaluated impact of melphalan dose on transplant outcomes for multiple myeloma. Between 1995 and 2019 459 consecutive patients received a transplant; 69(15%) received melphalan ≤150 mg/m2 (Mel 150 cohort) and 390 (85%) melphalan 200 mg/m2 (MEL 200 cohort). The primary outcome was overall survival (OS) from the date of transplant. Progression-free survival (PFS), engraftment, transplant response, and cumulative relapse at 2 years were secondary outcome measures. Patients in Mel 150 cohort had adverse clinical and laboratory parameters at base line. Transplant response was better for Mel 200 cohort (p < 0.024). Median OS at a median follow-up of 88 months was similar in the two cohorts; 100 Vs 102 months (Mel 200), p = 0.817. Median PFS (60.0 Vs 53 months, p = 0.746), relapse at two years (32.4% Vs 30.9%, p = 0.745) and grade 3-4 mucositis (p = 0.823) were similar. Initial treatment prepares patients better for subsequent similar transplant outcomes despite differences in baseline characteristics.

Graded Depth of Response and Neoplastic Plasma Cell Index as Indicators of Survival Outcomes in Patients With Multiple Myeloma Following Autologous Stem Cell Transplant.

OBJECTIVES: With a substantial number of patients with multiple myeloma (MM) experiencing disease relapse, the quest for more sensitive methods to assess deeper responses indicative of cure continues. METHODS: In this prospective analysis of 170 patients with MM at day 100 after autologous stem cell transplant, we evaluated the predictive value of conventional response, measurable residual disease (MRDTOTAL: the aberrant percentage of plasma cells [PC%] among total bone marrow cells), and neoplastic plasma cell index scores (NPCI: the aberrant PC% of total PCs). RESULTS: Significantly better progression-free survival (PFS) and overall survival (OS) were observed with deepening conventional response. Conventional response-based stratification within the MRD-positive and MRD-negative subgroups showed a significantly higher PFS (hazard ratio [HR], 3.11; P < .005) and OS (HR, 3.08; P = .01) in the conventional response-positive/MRD-positive group compared with the conventional response-negative/MRD-positive group. Using K-adaptive partitioning to find the optimum threshold for MRD, patients achieving less than 0.001% MRDTOTAL had superior PFS (MRDTOTAL 0.001% to <0.1%: HR, 6.66, P < .005; MRDTOTAL ≥0.1%: HR, 11.52, P < .005) and OS (MRDTOTAL 0.001% to <0.1%: HR, 5.3, P < .05; MRDTOTAL ≥0.1%: HR = 9.21, P < .005). The C index and Akaike information criterion metrics demonstrated the superior performance of the NPCI compared with MRDTOTAL in predicting treatment outcome. CONCLUSIONS: Progressive deepening of response, conventional as well as MRD, correlates with superior survival outcomes. The NPCI proved to be a superior determinant of survival and can be explored as a better statistic than MRD.

Multiple Myeloma: Impact of Time to Transplant on the Outcome.

BACKGROUND: Autologous stem cell transplant (ASCT) is a standard therapy for transplant eligible patients of multiple myeloma (MM). To evaluate impact of time to transplant on subsequent outcomes, we analyzed data on consecutive MM patients who received novel agents-based induction prior to transplant. METHODS: Between 2006 and 2019, 363 MM patients underwent ASCT. Patients' median age was 52 years, ranging from 20 to 72 years, 233 (64.2%) were males. Median interval from diagnosis to transplant was 11.5 months (range, 4-67.5); 201 (55.4%) patients underwent ASCT within 12 months (early) and 162 (44.6%) beyond 12 months since diagnosis (delayed ASCT). Primary objective was progression-free survival. Secondary objectives were-response rate to transplant, overall survival (OS), and transplant-related mortality (TRM). RESULTS: Post-ASCT complete response (CR) (77.1% vs. 64.8%; P < .025) and CR+ very good partial response rate (89% vs. 81.5%; P < .03) was higher for early ASCT cohort. Engraftment characteristics, regimen-related toxicities, and day +100 TRM (3.5% vs 3.7%; P = .564) were similar in 2 cohorts. Median OS for early versus late cohort from date of diagnosis is 127.0 (95% CI, 98.9-155.1) versus 104.5 months (95% CI, 79.3-129.6; P = .356) and from date of transplant is 119.0 (95% CI, 93.4-144.6) versus 89.5 months (95% CI, 57.4-121.6), P < .02. Median PFS is better for early transplant cohort; 69.5 (95% CI, 56.7-82.3) versus 50.0 months (95% CI, 35.6-64.4), P < .05, respectively. CONCLUSION: Early transplant for myeloma is associated with higher response rate and better progression-free survival.

High-dose chemotherapy followed by autologous stem cell transplant for multiple myeloma: Predictors of long-term outcome.

Background & objectives: Survival of patients with multiple myeloma (MM) has improved in the past two decades following use of novel agents and autologous stem cell transplantation. To determine predictors of long-term outcome, data of MM patients who underwent autologous stem cell transplantation (ASCT) at a tertiary care centre in north India were retrospectively analyzed. Methods: Between 1995 and 2016, 349 MM patients underwent ASCT. Patients' median age was 52 yr, ranging from 29 to 68 yr, 68.2 per cent were males. Thirty three per cent patients had international staging system (ISS) Stage III and 68.5 per cent had received novel agents-based induction. High-dose melphalan (200 mg/m2) was used for conditioning; patients with renal insufficiency (estimated glomerular filtration rate <40 ml/min) received melphalan 140-150 mg/m2. Results: Post-transplant, 317 of 349 (90.8%) patients responded; complete [complete response (CR)] -213 (61%)], very good partial response (VGPR) -62 (17.8%) and PR in 42 (12%)]. Induction with novel agents, pre-transplant chemosensitive disease, transplant in first remission and serum albumin (≥3.5 g/dl) were predictors of significant response. At a median follow up of 73 months, median overall survival (OS) was 90 months [95% confidence interval (CI) 70.8-109.2], and progression-free survival (PFS) was 41 months (95% CI 33.0-49.0). On multivariate analysis, achievement of CR post-transplant, transplant in first remission, ISS Stages I and II (vs. III), absence of extramedullary disease and serum albumin ≥3.5 g/dl were predictors of prolonged OS. For PFS, achievement of post-transplant CR and transplant in first remission were predictors of superior outcome. Interpretation & conclusions: Treatment with novel agents, achievement of complete remission post-transplant, ISS Stages I and II, absence of extramedullary disease and transplant in first remission were predictors of long-term survival for patients with MM.

Clinical impact of chromothriptic complex chromosomal rearrangements in newly diagnosed multiple myeloma.

Complex Chromosomal Rearrangements (CCRs) are increasingly being reported as genetic risk factors of clinical significance in cancer owing to their identification using high resolution whole genome profiling technologies. This study employed high resolution CGH + SNP microarrays for whole genome copy number variations (CNV) profiling and identified CCRs in 11/107(10%) newly diagnosed Multiple Myeloma (MM) patients. Six patients exhibited Chromothripsis (CTH) among seven chromosomes that were confirmed with automated CTLPscanner web tool and; five cases displayed chromoplexy (CPL) which involved multiple chromosomes. Presence of chromothripsis in chromosome 17 in three out of six patients indicate a link between TP53 aberrations and incidence of CTH. Multivariable Cox regression model demonstrated a significant association of CTH with poor PFS (HR = 3.09, p = 0.010) and OS (HR = 3.31, p = 0.024) which suggests that CTH is an additional independent prognostic marker in multiple myeloma. Addition of CTH in risk stratification models in clinical setting in multiple myeloma may help in upfront identification of high risk patients for suitable customized therapy.

Nucleic acid based risk assessment and staging for clinical practice in multiple myeloma.

The recently introduced Revised International Staging System (R-ISS) for multiple myeloma (MM) integrates albumin, ß2 microglobulin, lactate dehydrogenase (LDH) with high-risk cytogenetic aberrations (CA), i.e., t(4;14) and t(14;16) and del17p using fluorescent in situ hybridization (FISH). We evaluated utility of nucleic acid-based tests of multiplex ligation-based probe amplification (MLPA) and quantitative real-time polymerase chain reaction (qRT-PCR) to define the CA and the R-ISS categories as per this approach were evaluated for their ability to predict outcome in terms of response, progression-free (PFS), and overall survival (OS). In this study (n = 180), 17 (9.4%), 118 (65.6%), and 45 (25%) patients were assigned to R-ISS1, R-ISS2, and R-ISS3 categories with statistically significant differences in median PFS (p = 0.02) and OS (p < 0.001).On univariate analysis, serum creatinine, LDH, 17p deletion, chromosome 1q gain, and response after first induction therapy were associated with statistically significant differences (p < 0.05) in PFS and in addition, age> 65 years and use of triplet therapy with OS. On multivariate analysis, only serum creatinine, LDH, and response after first induction therapy retained significance for predicting PFS and in addition, use of triplet therapy retained significance for the OS. The proposed nucleic acid-based algorithm using qRT-PCR and MLPA for R-ISS is resource-effective in terms of small quantities of sample required; feasibility of batch processing and reduced overall cost for the total number of regions evaluated and retained the prognostic significance of R-ISS, making it suitable for clinical practice for molecular characterization of MM.

Prevalence of Monoclonal Gammopathy of Undetermined Significance in India-A Hospital-based Study.

BACKGROUND: We sought to determine the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in a hospital-based cohort in India. PATIENTS AND METHODS: From March 2015 to May 2015, 3429 patients (age range, 40-88 years) were enrolled in the present study. Of the 3429 enrolled patients, 2354 (68.6%) were men and 1075 (31.4%) were women. Serum samples were collected from all patients and analyzed using serum protein electrophoresis (SPEP). The positive SPEP samples were subjected to immunofixation. The patients with positive results for both SPEP and immunofixation were registered in the oncology department and investigated further for plasma cell dyscrasias. RESULTS: Of the 3429 study patients, 49 (1.43%) were found to have MGUS, and multiple myeloma was diagnosed in another 6 (0.17%). The prevalence rate of MGUS in patients aged 40 to 49, 50 to 59, 60 to 69, and 70 to 80 years was 0.83%, 1%, 2.62%, and 1.75%, respectively. Of the 49 MGUS patients, 5 (10.2%) were in the high-intermediate risk category using the Mayo Clinic criteria for risk stratification. At 30 months of follow-up, 1 patient in the high-intermediate category had developed multiple myeloma. CONCLUSION: To the best of our knowledge, the present study is the first systematic study on the prevalence of MGUS in an Indian population. The overall prevalence of MGUS was 1.43% in the evaluated Indian cohort, lower than that reported for white and black populations. The incidental detection of 6 subjects with multiple myeloma of 3429 screened subjects in our study was high compared with the reported incidence of multiple myeloma in India of only 1.9 per 100,000 persons. This finding indicates the need to create awareness about myeloma-related symptoms and screening studies in appropriate age groups, at least in the hospital-based setting.

Flow Cytometry in Diagnosis of Myelomatous Pleural Effusion: A Case Report.

Plasma cell myeloma is a multifocal plasma cell neoplasm associated with increased monoclonal protein in serum and/or urine. Pleural effusions in patients with myeloma are uncommon (6 %). However, effusions due to direct infiltration of the pleura by plasma cells (myelomatous pleural effusion) are extremely rare (<1 %) and usually seen with IgA myeloma. The diagnosis of such cases requires pleural fluid cytology, electrophoresis or pleural biopsy. We present a case of myelomatous pleural effusion diagnosed using flow cytometry immunophenotyping in addition to the pleural fluid cytology. A 45 year old female was diagnosed as plasma cell myeloma (IgG kappa) in 2007. She received multiple lines of therapy during the course of her treatment including thalidomide, dexamethasone, lenalidomide, bortezomib, and doxorubicin based regimens. However, the patient had progressive extramedullary disease and developed pleural effusion in 2014. Cytological examination of the pleural fluid showed degenerative changes. Few preserved areas showed mononuclear cells including morphologically abnormal plasma cells. Immunophenotyping of these cells by flow cytometry revealed a pattern indicating neoplastic plasma cells. There was expression of CD38, CD138, and CD56, with absence of CD19, CD10 and CD45. This confirmed the diagnosis of myelomatous pleural effusion. Subsequently, the patient was offered a dexamethasone, cyclophosphamide, etoposide and cisplatin based regimen but, she declined further treatment and succumbed to her disease 3 months later. Myelomatous pleural effusion is a rare complication of plasma cell myeloma. Flow cytometry can be used as an adjunctive technique in its diagnosis particularly in cases with equivocal cytology and electrophoresis findings.

Synergistic effect of vascular endothelial growth factor and angiopoietin-2 on progression free survival in multiple myeloma.

Bone marrow neoangiogenesis plays an important role in multiple myeloma (MM) and depends on the interplay of angiogenic cytokines. We investigated the levels of angiogenic cytokines such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiopoietin (Ang)-1, Ang-2 and hypoxia inducible factor-1 alpha (HiF-1α) in MM patients and their association with treatment outcome. Serum levels and mRNA expression of VEGF, Ang-2, Ang-1, bFGF and HiF-1α were evaluated in 71 MM patients using enzyme-linked immunosorbent assay and reverse transcriptase polymerase chain reaction. In multivariate Cox regression analysis, serum levels of VEGF≥756 pg/ml (HR 2.2, 95% CI 1.02-4.91; p=0.045) and relative mRNA expression levels of Ang-2≥0.93 (HR 21.0, 95% CI 6.27-70.45; p<0.001) were predictive of inferior progression free survival (PFS) and patients with concomitant increase in VEGF and Ang-2 had poor outcome compared to the rest of the patients (HR 32.6, 95% CI 7.20-148.36; p<0.001). These results suggest that VEGF and Ang-2 act in synergy and their expression levels at presentation are predictive of PFS in MM.

Economical choices in setting up a diagnostic myeloma laboratory.

In setting up a diagnostic myeloma laboratory the popular, highly automated and otherwise excellent choices of equipment and laboratory practices, so exorbitantly raise costs that the sustainability, even in large government hospitals in third world countries may become difficult. Based on our experience in a regional cancer center in India, we offer here, guidelines for carrying out high resolution electrophoresis, densitometry, immunofixation and urine concentration. We show that by simply employing well established techniques and doing them properly, one can get results of excellent quality at minimum cost and minimum dependence on costly imports.