Howard R. Terebelo

Secondary primary malignancies in multiple myeloma: an old NEMESIS revisited.

The treatment of myeloma has undergone extraordinary improvements in the past half century. These advances have been accompanied by a concern for secondary primary malignancies (SPMs). It has been known for decades that extended therapy with alkylating chemotherapy agents, such as melphalan, carries an increased risk of therapy-related myelodysplastic syndrome and/or acute myeloid leukemia (t-MDS/AML), with a cumulative risk as high as 10–15%. High-dose chemotherapy with autologous stem cell support became widely accepted for myeloma in the 1990s. Despite the use of high doses of melphalan, the risk of t-MDS/AML with this procedure is estimated to be less than 5%, with much of this risk attributable to pretransplant therapy. Recently, lenalidomide has come under scrutiny for its possible association with SPMs. It is too soon to declare a causal relationship at this time, but there appears to be an increased number of SPMs in reports from several studies using lenalidomide maintenance. Current studies should be amended and future studies planned to better define the risk of SPMs and the risk factors and mechanisms for its development. Patients should be educated regarding this potential concern but the current use of lenalidomide should not generally be altered until further data are available.

Connect MM registry: The importance of establishing baseline disease characteristics

BACKGROUND Connect MM is the first and largest observational, noninterventional, prospective registry of patients newly diagnosed with multiple myeloma (NDMM) in the United States. It collects longitudinal data on patients within clinical practice including patients in clinical trials. PATIENTS AND METHODS Of the 1513 patients enrolled, 1493 were protocol-eligible. RESULTS Median age was 67 years, 81.9% (1223/1493) were Caucasian, and 57.2% (854/1493) were male. Of these patients, 26.5% (232/877) were International Staging System stage I, 34.9% (306/877) stage II, and 38.7% (339/877) stage III. Eastern Cooperative Oncology Group performance status of 0/1/2 were reported in 96.6% (1017/1053). Clonal plasma cells > 10% were found in 91.6% (1282/1399) of patients and M-component in 98.8% (1343/1359). Hypercalcemia was present in 7.3% (108/1481) of patients, serum creatinine > 2 mg/dL in 18.3% (271/1484), anemia in 45.1% (673/1493), and bone involvement in 76.7% (1143/1490). Of the 15 National Comprehensive Cancer Network (NCCN) recommended diagnostic tests, a median of 12 were performed. Lactate dehydrogenase assessment, serum free light chain ratio, and immunofixation were reported in 38.4% (574/1493), 62.1% (927/1493), and 66% (985/1493) of patients, respectively. Quantitative immunoglobulin, β-2 microglobulin, and protein electrophoresis (serum or urine) were reported in 72.3% (1080/1493), 74.1% (1107/1493), and 78.0% (1164/1493) of patients, respectively. Bone marrow biopsy was reported in 92.2% (1376/1493), but conventional cytogenetic and fluorescence in situ hybridization analysis were reported in only 63.2% (944/1493) and 59.8% (893/1493) of patients, respectively. A high-risk cytogenetic profile (according to International Myeloma Working Group [IMWG] criteria) was found in 16.9% (253/1493). CONCLUSION This analysis provides insight into the demographic and disease characteristics of NDMM patients in a range of clinical practices. Creating solid records of baseline patient disease characteristics using suggested NCCN diagnostic work-up and IMWG criteria provides a foundation for monitoring disease progression and response to treatment.

Trisomy 15, Sex Chromosome Loss, and Hematological Malignancy

We report 6 patients with myelodysplasia who, on routine cytogenetic studies, demonstrated trisomy 15. Four of these also had sex chromosome loss. A review of the literature revealed 6 other cases of trisomy 15 with sex chromosome loss and 22 cases of trisomy 15 as the sole chromosomal abnormality. All cases had hematologic malignancy or myelodysplasia. Trisomy 15 is uncommon but tends to be associated with myelodysplasia in older subjects, and with sex chromosome loss in about one third of cases.

Connect MM® – the Multiple Myeloma Disease Registry: incidence of second primary malignancies in patients treated with lenalidomide

Advances in treatment have extended the survival of patients with multiple myeloma (MM),[1] but this increased survival time also increases the potential for developing second primary malignancies ...

Phantom Limb Pain as a Manifestation of Paclitaxel Neurotoxicity

Paclitaxel is a chemotherapeutic agent with activity directed against several malignancies. It has multiple adverse effects including neurotoxicity. We describe 2 patients with prior amputation who experienced phantom limb pain (PLP) after receiving paclitaxel therapy. A third patient experienced disabling neurotoxicity in the extremity of a prior ulnar nerve and tendon transposition after receiving paclitaxel. This unique syndrome should be identified as a direct causal effect of paclitaxel. In this report, we review the pathophysiology of PLP and treatment options. Physicians should be aware that PLP can occur after initiation of paclitaxel.

Occurrences of opportunistic infections in chronic myelogenous leukemia patients treated with imatinib mesylate.

Tyrosine kinase inhibition has revolutionized the treatment of hronic myelogenous leukemia (CML). Currently approved agents n this class include imatinib, dasatinib, and nilotinib. Imatinib is reversible tyrosine kinase inhibitor which preferentially binds o the adenosine triphosphate (ATP)-binding site of the Abelon kinase (c-ABL). This action blocks signal transduction of the CR-ABL fusion protein and effectively induces hematologic and ytogenetic remissions in CML. It is known that imatinib affects any branches of the immune system includingmonocyte-derived endritic cells, monocytes, and T cells [1–4]. Whether these ffects result in an increased susceptibility to infection in humans emains unknown. An increased rate of opportunistic infections asobservedwithchronic imatinib treatment inanimal studies [5]. lso, bacterial, fungal, and viral infections with suspected causalty to imatinib have been reported in clinic trials. We report on wo cases of opportunistic infection in immunocompetent patients eceiving imatinib.

Recognition of early mortality in multiple myeloma by a prediction matrix

Early mortality (EM; death ≤ 6 months from diagnosis) has been reported in several newly diagnosed multiple myeloma (NDMM) trials. Before the era of novel agents, the incidence was 10%‐14%. Causes of death included infections/pneumonia, renal failure, refractory disease, and cardiac events. Staging systems, such as the revised International Staging System (r‐ISS), and prognostic factors including cytogenetics, lactate dehydrogenase levels, and myeloma‐specific factors, are useful to assess overall prognosis; however, they cannot predict EM. We evaluated patients treated with novel agents in the Connect MM® Registry and identified risk factors of the EM cohort. Eligible patients were enrolled in the registry within 60 days of diagnosis. Univariate and multivariate analyses were conducted to evaluate associations between baseline characteristics and EM. Prediction matrices for EM were constructed from a logistic model. Between September 2009 and December 2011, 1493 patients were enrolled in the registry and had adequate follow‐up. Of these patients, 102 (6.8%) had EM and 1391 (93.2%) survived for > 180 days. Baseline factors significantly associated with increased EM risk included age > 75 years, higher Eastern Cooperative Oncology Group performance status, lower EQ‐5D mobility score, higher ISS stage, lower platelet count, and prior hypertension. Renal insufficiency trended toward increased EM risk. These risk factors were incorporated into a prediction matrix for EM. The EM prediction matrix uses differential weighting of risk factors to calculate EM risk in patients with NDMM. Identifying patients at risk for EM may provide new opportunities to implement patient‐specific treatment strategies to improve outcomes.

Treatment Outcomes and Health Care Resource Utilization in Patients With Newly Diagnosed Multiple Myeloma Receiving Lenalidomide-only Maintenance, Any Maintenance, or No Maintenance: Results from the Connect MM Registry

PURPOSE Maintenance therapy after autologous stem cell transplantation (ASCT) improves clinical outcomes in multiple myeloma (MM), but the effect of continued treatment with lenalidomide-only maintenance, or any maintenance, on health care resource utilization (HCRU) is largely unknown. METHODS Here we present an analysis of HCRU and clinical outcomes in a cohort of patients from the Connect MM registry, the largest, ongoing, observational, prospective US registry of patients with symptomatic newly diagnosed MM. In this study, patients with newly diagnosed MM who completed induction and single ASCT without subsequent consolidation received lenalidomide-only maintenance (n = 180), any maintenance (n = 256), or no maintenance (n = 165). HCRU (hospitalization, surgery/procedures, and concurrent medications [growth factors, bisphosphonates, or neuropathic pain medication]) was assessed starting from 100 days post-ASCT for up to 2 years. FINDINGS Although the rates of hospitalization per 100 person-years were similar across groups at the end of years 1 and 2, the median duration of hospitalization was numerically longer with no maintenance. The rates of use of growth factors, bisphosphonates, and neuropathic pain medication were generally similar in all 3 groups. The receipt of any maintenance was associated with significantly reduced use of neuropathic pain medications during year 1. Of note, lenalidomide-only maintenance was associated with significantly longer progression-free survival (54.5 vs 30.4 months; hazard ratio [HR] = 0.58; 95% CI, 0.43-0.79; P = 0.0005) and overall survival (OS) (median OS not reached in either group; HR = 0.45; 95% CI, 0.28-0.73; P = 0.001) compared with no maintenance. Likewise, the group treated with any maintenance had significantly longer median progression-free survival (44.7 vs 30.4 months; HR = 0.62; 95% CI, 0.47-0.82; P = 0.0008) and OS (median OS not reached in either group; HR = 0.50; 95% CI, 0.33-0.76; P = 0.001) than did the group that did not receive maintenance. IMPLICATIONS These findings suggest that in this largely community-based study population, post-ASCT maintenance therapy, including lenalidomide-only maintenance, improves clinical outcomes without negatively affecting HCRU. ClinicalTrials.gov identifier: NCT01081028.

Heterogeneity of Second-Line Treatment for Patients With Multiple Myeloma in the Connect MM Registry (2010-2016)

Background: The treatment landscape for multiple myeloma (MM) has undergone recent changes with the regulatory approval of several new therapies indicated for second‐ and later‐line disease. Using data from Connect MM, the largest multisite, primarily community‐based, prospective, observational registry of MM patients in the United States, selection of second‐line treatments was evaluated during a 5‐year period from 2010 to 2016. Patients and Methods: Eligible patients were aged ≥ 18 years, had newly diagnosed MM ≤ 2 months before study entry, and were followed for up to 8 years. Patients who received ≥ 2 lines of therapy were analyzed. “Tepee” plots of stacked area graphs differentiated treatments by color to allow visualization of second‐line treatment trends in MM patients. Results: As of February 2017, 855 of 2897 treated patients had progressed to second‐line treatment. Treatment selection was heterogeneous; shifting patterns of treatment choices coincided with the approval status of newer agents. The most common treatment regimens in the early part of the decade were lenalidomide and/or bortezomib, with or without dexamethasone, with increasing use of newer agents (carfilzomib, pomalidomide, daratumumab, and elotuzumab) and triplet combinations over time. The influence of the baseline patient characteristics of age, history of diabetes, peripheral neuropathy, and renal function on treatment choice was also examined. Conclusion: These findings indicate that community physicians are current in their MM management practices, with uptake of new drugs and acquaintance with results of randomized clinical trials using combinations almost concurrent with their regulatory approval and publication. Micro‐Abstract Connect MM is a large prospective observational US‐based disease registry that was used to evaluate second‐line treatment patterns in patients with relapsed or refractory multiple myeloma during a 5‐year period, from 2010 to 2016. Treatment uptake was found to coincide with clinical milestones (ie, regulatory approvals, clinical study results), with growing preference for newer agents and triplet combinations over time.

Impact of post-ASCT maintenance therapy on outcomes in patients with newly diagnosed multiple myeloma in Connect MM

Autologous stem cell transplantation (ASCT) followed by lenalidomide maintenance therapy is the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). Clinical trials show progression-free survival (PFS) benefits, with some studies (Cancer and Leukemia Group [CALGB] trial and meta-analysis) also showing overall survival (OS) benefits, but applicability to real-world clinical settings is unclear. Using data from Connect MM, the largest US-based observational registry of NDMM patients, we analyzed effects of maintenance therapy on long-term outcomes in 1450 treated patients enrolled from 2009 to 2011. Patients who received induction therapy and ASCT (n = 432) were analyzed from 100 days post-ASCT (data cut 7 January 2016): 267 received maintenance (80% lenalidomide-based [of whom 88% received lenalidomide monotherapy]); 165 did not. Lenalidomide maintenance improved median PFS and 3-year PFS rate vs no maintenance (50.3 vs 30.8 months [hazard ratio (HR), 0.62; 95% confidence interval (CI), 0.46-0.82; P < .001] and 56% vs 42%, respectively). Improvements in median OS and 3-year OS rate were associated with lenalidomide maintenance vs no maintenance (not reached in either group [HR, 0.54; 95% CI, 0.36-0.83; P = .005] and 85% vs 70%, respectively). Five hematologic serious adverse events were reported with lenalidomide maintenance (pancytopenia [n = 2], febrile neutropenia, anemia, and thrombocytopenia [n = 1 each]) and 1 with no maintenance (thrombocytopenia). Second primary malignancies occurred at rates of 1.38 and 2.19 events per patient-year in lenalidomide maintenance and no maintenance groups, respectively. Survival benefits associated with lenalidomide maintenance previously demonstrated in clinical trials were observed in this community-based Connect MM Registry.