Rajkumar, S. Vincent

Despite successful treatment of the clonal plasma cell implicated in its pathogenesis, patients with AL amyloidosis (AL) experience significant morbidity related to underlying amyloid mediated organ dysfunction. While normalization of the serum free light chain measurements [normal ratio of involved and uninvolved free light chains (nFLCr)] is the goal of therapy and centerpiece of hematologic response criteria, achieving (or not achieving) meaningful organ response (OR) is clinically significant for its implications on long‐term symptomatology as well as overall survival (OS), and remains the ultimate goal of treatment. Expectations for organ recovery following successful therapy leading to nFLCr in AL remain poorly described. We evaluated the timeframe and predictive factors for OR, and long‐term outcome, in 313 AL patients who achieved nFLCr following therapy initiation. OR was seen in 80% of surviving AL patients within 1‐year of nFLCr. Patients achieving early OR within 1 year of nFLCr had superior OS compared with those who despite obtaining nFLCr did not achieve early OR. We further evaluated factors predicting OR and OS among patients achieving nFLCr. Higher values of dFLC (involved–uninvolved) at diagnosis predict OR, and early OR predicts improved OS following successful hematologic therapy in AL. Am. J. Hematol. 90:181–186, 2015. © 2014 Wiley Periodicals, Inc.

Abstract Objective To determine the prognosis of patients with non‐secretory myeloma. Methods We studied 124 patients diagnosed with multiple myeloma who had no monoclonal protein detected on serum and urine immunofixation at diagnosis and on all subsequent follow‐up testing (non‐secretory myeloma). The overall survival ( OS ) of patients with non‐secretory myeloma was compared with 6953 patients with typical myeloma seen during the same time period in whom a monoclonal protein was detected at the time of diagnosis. Results One hundred and twenty‐four patients met criteria for non‐secretory multiple myeloma. The median follow‐up was 102 months (range, 1–204 months). The median progression‐free survival with initial therapy was 28.6 months, and the median OS was 49.3 months. There was a significant improvement in OS since 2001; median survival 43.8 months (prior to 2001) vs. 99.2 months (2001–2012), P < 0.001. OS was superior in patients with a normal baseline FLC ratio ( n = 10) compared to patients with an abnormal ratio ( n = 19), medians not reached in both groups. Prior to 2001, OS was similar in non‐secretory myeloma ( n = 86) and secretory myeloma ( n = 4011), median 3.6 vs. 3.5 yr, respectively, P = 0.63. However, among patients diagnosed between 2001 and 2012, OS was superior in non‐secretory myeloma ( n = 36) compared to secretory myeloma ( n = 2942), median 8.3 vs. 5.4 yr, respectively, P = 0.03. Conclusions Non‐secretory myeloma is an uncommon subtype of multiple myeloma. In the last decade, there has been an improvement in the survival of non‐secretory myeloma and appears superior to secretory myeloma.

AbstractBackgroundData regarding multiple myeloma (MM) that develops after kidney transplantation (KTx) are scarce. The outcomes of these patients were evaluated in a retrospective study.MethodsPatients with newly diagnosed MM after KTx were selected. Patients with a diagnosis of MM or those who received treatment for monoclonal gammopathy of renal significance (MGRS) prior to KTx were excluded.ResultsBetween 2001 and 2012, seven patients developed MM after KTx. Reasons for ESRD included ADPKD (1), C1q nephropathy (1), MPGN (2), hypertensive nephrosclerosis (2), and chronic interstitial nephritis (1). Before KTx, only four patients had monoclonal protein studies, four had monoclonal gammopathy of undermined significance (MGUS), and two of them had clonal plasma cells in bone marrow. Median follow‐up after MM was 70 months (range 19–100). Median survival was 80 months. Median time from KTx to MM was 72 months (range 3–204 months). The Kidney allograft failed in four patients due to monoclonal protein‐related renal disease. Five patients received chemotherapy: bortezomib (n = 3), lenalidomide (n = 2), melphalan (n = 1), thalidomide (n = 1), pomalidomide (n = 1), and high‐dose dexamethasone (n = 1). Three patients received ASCT.ConclusionMultiple myeloma after KTx is rare. Most patients who develop MM had MGUS prior to KTx. There is significant renal involvement in these patients. Survival is not worse when compared to MM without KTx. Further work is needed to identify the best treatment options for these patients.

Disease overview: Multiple myeloma accounts for approximately 10% of hematologic malignancies. Diagnosis: The diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end‐organ damage. If end‐organ damage is not present, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma. Risk stratification: In the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high‐risk myeloma. Patients with t(4;14) translocation are considered intermediate‐risk. All others are considered as standard‐risk. Risk‐adapted intial therapy: Standard‐risk patients can be treated with lenalidomide plus low‐dose dexamethasone (Rd), or a bortezomib‐containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate‐risk and high‐risk patients require a bortezomib‐based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients who are not candidates for transplant, initial therapy is given for approximately 12 to 18 months. Maintenance therapy: After initial therapy, lenalidomide maintenance is considered for standard risk patients who are not in very good partial response or better, while maintenance with a bortezomib‐based regimen should be considered in patients with intermediate or high risk myeloma. Management of refractory disease: Patients with indolent relapse can be treated first with 2‐drug or 3‐drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. Am. J. Hematol. 89:998–1009, 2014. © 2014 Wiley Periodicals, Inc.

Abstract The plasma cell malignancy Multiple Myeloma (MM) is a rare but deadly form of cancer with 5 year survival rates of ∼30%. Epidemiological studies have suggested that MM exacts an especially heavy burden on African American (AA) patients. We examined a multi-ethnic cohort of MM tumors to assess potential differences in the frequency of molecular events in tumors derived from either African American (AA) or European American (EA) patients. The frequency of 14q32 translocation breakpoints at the IgH locus was compared among a series of data from 115 AA MM patients from three studies and EA MM from the Eastern Cooperative Oncology Group (ECOG). In addition, we analyzed matching genome-wide copy number and transcriptional data among 45 AA MM tumors and 196 EA MM tumors to determine differences in the frequency of molecular events in tumors from these populations. No differences were found for specific translocation subtypes; however, we detected a statistically significant difference in the overall frequency of IgH translocations between the two groups, which occurred more frequently in EA patients (52% vs. 40%; p = 0.032). When assessing genomic copy number events previously shown to be associated with poor outcome in MM, frequencies of alterations were not significant after correcting for multiple testing. Furthermore, there was not a significant difference in the association of high-risk disease using expression profiling. Our study represents the first comprehensive assessment of the frequency and distribution of molecular alterations in MM tumors from both AA and EA patients and could help shed light on possible biological features associated with population differences in incidence and outcome in MM. Citation Format: Angela S. Baker, Esteban Braggio, Susana Jacobus, Sungwon Jung, Dirk Larson, Terry Therneau, Angela Dispenzieri, Scott A. Van Wier, Gregory Ahmann, Joan Levy, Louise Perkins, Seungchan Kim, Kim Henderson, David Vesole, S. Vincent Rajkumar, Dianne F. Jelinek, John Carpten, Rafael Fonseca. Characterization of myeloma tumors from a multi-ethnic cohort using cytogenetics and genomic analysis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2021. doi:10.1158/1538-7445.AM2013-2021

Summary The presence of clonal circulating plasma cells (c PC s) remains a marker of high‐risk disease in newly diagnosed multiple myeloma (MM) patients. However, its prognostic utility in MM patients with previously treated disease is unknown. We studied 647 consecutive patients with previously treated MM seen at the Mayo Clinic, Rochester who had their peripheral blood evaluated for c PC s by multi‐parameter flow cytometry. Of these patients, 145 had actively relapsing disease while the remaining 502 had disease that was in a plateau and included 68 patients in complete remission (CR) and 434 patients with stable disease. Patients with actively relapsing disease were more likely to have clonal c PC s than those in a plateau ( P < 0·001). None of the patients in CR had any clonal c PC s detected. Among patients whose disease was in a plateau, the presence of clonal c PC s predicted for a worse median survival (22 months vs. not reached; P = 0·004). Among actively relapsing patients, the presence of ≥100 c PC s predicted for a worse survival after flow cytometry analysis (12 months vs. 33 months; P < 0·001). Future studies are needed to determine the role of these findings in developing a risk‐adapted treatment approach in MM patients with actively relapsing disease.

Key Points Survival of patients with primary plasma cell leukemia has improved in recent years, but is still inferior to those patients with multiple myeloma. This survival benefit appears to be mainly in patients older than 65 years of age.

AbstractImmunoglobulin light chain (AL) Amyloidosis is a condition whereby misfolded proteins generated by plasma cells deposit in tissues causing organ dysfunction. Chemotherapy and autologous stem cell transplant when eligible are standard treatment options. Several studies report long‐term outcomes of patients post‐transplant. However, there is a paucity of literature describing outcomes of relapsed patients post‐transplant. We performed a retrospective study to assess outcomes and therapies employed upon relapse after transplant. Between 1996 and 2009, 410 patients received transplant at the Mayo Clinic as first‐line therapy. Of those patients, 42 (10%) died within 3 months of transplant, 64 (16%) died without documented relapse, 158 (38%) were alive without documented progression, and 146 (36%) had documented progression. Those 146 patients are the subject of our study, and their median time to hematologic relapse/progression was 23.6 months (95%CI 18.3, 26.3 months). Their median overall survival and 5‐yrs overall survival from post‐transplant relapse/progression was 51.7 months (95%CI 34.1–62.3) and 39%, respectively. The most common first regimen for treatment after relapse was lenalidomide or thalidomide. In conclusion, our study indicates that patients with AL amyloidosis fare well post‐transplant relapse/progression. Additionally, it provides a yardstick to design clinical trials to determine best treatment options.

Purpose To provide an update on recent advances in the management of patients with multiple myeloma who are not eligible for autologous stem-cell transplantation. Methods A comprehensive review of the literature on diagnostic criteria is provided, and treatment options and management of adverse events are summarized. Results Patients with symptomatic disease and organ damage (ie, hypercalcemia, renal failure, anemia, or bone lesions) require immediate treatment. The International Staging System and chromosomal abnormalities identify high- and standard-risk patients. Proteasome inhibitors, immunomodulatory drugs, corticosteroids, and alkylating agents are the most active agents. The presence of concomitant diseases, frailty, or disability should be assessed and, if present, treated with reduced-dose approaches. Bone disease, renal damage, hematologic toxicities, infections, thromboembolism, and peripheral neuropathy are the most frequent disabling events requiring prompt and active supportive care. Conclusion These recommendations will help clinicians ensure the most appropriate care for patients with myeloma in everyday clinical practice.