Om Dutt Sharma

Complete response after autologous stem cell transplant in multiple myeloma.

We evaluated long‐term outcome of patients achieving complete response (CR) after autologous stem cell transplantation (ASCT) for multiple myeloma. Between April 1990 and June 2012 191 patients underwent ASCT. The median age was 53 years (range, 26–68 years), 135 were men. Pretransplant, patients received induction therapy with VAD (vincristine, doxorubicin, dexamethasone; n = 77), novel agents (n = 92), or alkylating agent‐based, n = 22); 43% received more than one line of induction regimen. Response to transplant was defined as per EBMT criteria. The median follow‐up for the entire group was 85 months (range, 6–232.5 months). Following transplant 109 (57.1%) patients achieved CR. Median progression‐free survival (PFS) for patients with CR was higher compared to those with VGPR and PR, (107 vs. 18 vs. 18 months, P < 0.001). Number of lines of therapy pretransplant (one or two vs. more than two lines of therapy (P < 0.001), and absolute lymphocyte count of ≤3000/cmm were predictors of superior PFS. Median overall survival (OS) for patients with CR was higher, (204 months), compared to those with VGPR (71.5 months, P < 0.001) and PR (51.5 months, P < 0.001), respectively. On Cox regression analysis, patients who received one line of induction therapy pretransplant (hazard ratio, HR 2.154, P < 0.001) and those with absolute lymphocyte count of ≤3000/mm3 (HR 0.132, P < 0.001) had superior PFS. For overall survival, induction treatment up to one line (HR 2.403, P < 0.004) and Hb > 7.1 G/dL at diagnosis (HR 4.756, P < 0.01) were associated with superior outcome. On landmark analysis at 12 months, PFS and OS continued to remain superior for patients attaining CR. Achievement of CR post transplant is associated with longer OS and PFS. Among complete responders, those who receive one line of induction therapy pretransplant have superior outcome.

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.

Minimal residual disease evaluation in autologous stem cell transplantation recipients with multiple myeloma

The use of novel agents for the treatment of multiple myeloma (MM) has enabled attainment of deeper responses and the information that progression-free survival (PFS) and overall survival (OS) correlate with the depth of response has further created a need for the development of sensitive laboratory assays for the detection of minimal residual disease (MRD).[1,2] The serum protein electrophoresis (SPEP) has been in use for more than 30 years and although, still a gold standard for the diagnostic work-up, it has limited role in MRD detection due to its low sensitivity, false positivity due to presence of oligoclonal bands during the phases of bone marrow regeneration after chemotherapy or autologous stem cell transplantation (ASCT) and inability to monitor light-chain and nonsecretory MM.[3–5] The serum-free light-chain assay (SFLC) was initially propagated for the diagnosis and monitoring of nonsecretory and light-chain MM, but a recent study in patients with detectable M band has revealed its ability to predict a better PFS and OS for those who attained normal SFLC ratio (SFLCR) after treatment.[6] The same is reflected in the international response criteria for MM where the patients with normalization of SFLCR are accorded the status of being in stringent CR (sCR).[7] Multiparametric flow cytometry (MFC) has limited role at the diagnostic front in MM, but a number of studies have shown its prognostic utility in detecting MRD.[1,5,8,9] However, hemodilution of the bone marrow aspirate and the patchy nature of myeloma disease are major limitations resulting in false-negative MRD result using MFC.[10,11] Assessments of adequacy of the bone marrow aspirate on morphological assessment or the presence of normal plasma cells (PC) on MFC or estimating neoplastic plasma cell index are some of the remedial measures suggested to offset the false negativity of MFC in MRD detection in MM.[10,11] However, till date, there is no consensus on the method that is best suited for MRD detection in MM. We report, here, a comparison of the conventional CR (negative SPEP and IFX plus <5% PCs in BM) with sCR (CR plus normal SFLC ratio [SFLCR]) and iCR by MFC in MM patients undergoing ASCT and discuss the discrepant results. In this prospective observational study, 71 consecutive patients of MM who received ASCT after conditioning with high-dose melphalan were evaluated for residual disease using conventional laboratory methods of serum and urine protein electrophoresis plus immunofixation, SFLCR and MFC. The MFC was performed using a fivecolor a panel of antibodies: CD138 FITC, CD38 PE-Cy5, CD45 PE-Cy7, CD56 PE and CD19 PE-CF594 (BD Biosciences). A minimum of 500,000 events were acquired on a flow cytometer (FC-500, Beckman Coulter) and the data were analyzed using FCS-Express software version 4.0 (Denovo Software). Plasma cells were gated as events with bright expression of CD38, CD138 and dim expression of CD45. Minimal residual disease was defined as positive if a discrete population of phenotypically aberrant PC defined as >50 CD19-CD56þ events was identified in the 500,000-event free file (0.01% limit of detection). All the investigations were done as part of pretransplant work-up and at Dþ 100 post-transplant and at Dþ 180 except MFC which was done at first two time points only. Disease response was assessed as per International Myeloma Working Group (IMWG) response criteria for multiple myeloma;[7,11] stringent complete response (sCR) was defined as bone marrow PC <5% with negative serum and urine protein electrophoresis with

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

Micro‐Abstract A cross‐sectional hospital‐based study was undertaken during a 3‐month period to ascertain the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in North India. Of the 3429 patients evaluated, MGUS was detected in 49 (1.43%) and multiple myeloma (MM) in 6 (0.17%). To the best of our knowledge, the present study is the first systematic study of the prevalence of MGUS in an Indian population. Our results highlight the relatively low incidence of MGUS in Indians compared with that in white and black populations. The incidental detection of MM in our study points to the need for creating awareness regarding myeloma‐related symptoms in appropriate age groups. 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.