Melphalan‐based autologous transplant in octogenarian multiple myeloma patients
Authors: Neeraj Y. Saini, Romil Patel, Ankur Varma, Qaiser Bashir, Ruby Delgado, Gabriela Rondon, Uday R. Popat, Chitra M. Hosing, Yago Nieto, Partow Kebriaei, Amin M. Alousi, Sairah Ahmed, Donna M. Weber, Sheeba K. Thomas, Hans C. Lee, Elisabet E. Manasanch, Krina K. Patel, Robert Z. Orlowski, Richard E. Champlin, Muzaffar H. Qazilbash
Journal: American Journal of Hematology (2018)

Multiple myeloma (MM) is primarily a disease of the elderly, with the highest peak of age-specific rate of 43.4 per 100 000 people at age ≥80 years.1 Over the last two decades, the novel anti-myeloma drugs in combination with autologous hematopoietic stem cell transplantation (auto-HCT) have increased overall survival (OS) in younger (age < 65) MM patients. However, the benefits in the elderly are less noticeable.2, 3 Increasing life expectancy of the general population and survival rates in younger MM patients has led to a substantial rise in the prevalence of geriatric MM population.4, 5 This highly relevant population group is often underrepresented in clinical trials and undertreated due to toxicity concerns.6 Moreover, auto-HCT is under-utilized in older population,3 despite the ample data supporting the efficacy and safety.7 Fit octogenarians MM patients are rarely referred for auto-HCT due to toxicity concerns, and on our literature search in PubMed, we did not find a study evaluating outcomes of auto-HCT in MM patients of age ≥80 years. We conducted a retrospective study to evaluate the safety and feasibility of auto-HCT in patients ≥80 years of age who received this treatment at our institution. Among 1740 patients with MM who received an auto-HCT at our institution from January, 2007 to June, 2018, 9 (0.5%) patients were ≥ 80 years of age at time of first auto-HCT. Supporting Information Tables 1 and (Supporting Information) S2 summarizes the patient characteristics of these nine patients. Patients were evaluated for responses (hematologic, radiologic and clinical), toxicity, progression-free survival (PFS) and OS. International Myeloma Working Group (IMWG) frailty score and Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) was calculated for every patient.8 Toxicities were defined per the Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv4.0). Td, Vd, Doxil Clinical trial The median age of the cohort was 81 years (80-83). All patients had an Eastern Cooperative Oncology Group performance status of either 0 or 1. The median IMWG Frailty score was 3 (range, 2-3). The median HCT-CI score for the cohort was 3 (range, 0-5). Peripheral blood stem cells were collected with granulocyte colony-stimulating factor (G-CSF) in 8 patients. One patient needed a second attempt at the collection with cyclophosphamide and G-CSF chemo-mobilization. All patients received melphalan at a reduced dose of 140 mg/m2 as the conditioning regimen. For the 7 patients with available data, the median CD34 stem cells dose collected was 5.34 × 106 (3.4-7.26). A total of 8 (89%) patients were in the first remission, and 1 (11%) patient had relapsed disease at auto-HCT. Three patients received lenalidomide-based induction, and 5 patients received a bortezomib-based induction regimen. One patient with the relapsed disease at auto-HCT had received thalidomide-dexamethasone; bortezomib-dexamethasone, liposomal doxorubicin; and cyclophosphamide, lenalidomide, dexamethasone regimens. The median follow-up from auto-HCT was 19 months (range 1.5-50 months). No (0%) patient died within 100 days of auto-HCT. The chemotherapy-related gastrointestinal toxicities were mostly grade 1 or 2. The other toxicities during hospitalization were atrial fibrillation (4/9, 44%), fluid retention (6/9, 67%), neutropenic fever (4/9, 44%), pulmonary edema (2/9, 22%), stroke (1/9, 11%), and pleural effusion (1/9, 11%). Eight patients were discharged to home but one patient required inpatient rehabilitation at another facility. The median length of hospitalization for auto-HCT was 17 (15-28) days. Only 1 (11%) patient required re-hospitalization within 100 days post-transplant. Four 4 (45%) achieved a complete response, 2 (22%) very-good partial, and 3 (33%) achieved a partial response with an overall response rate of 100%. Eight (89%) patients were alive until the last follow-up. One patient died at 22 months post-transplant due to relapsed disease in the central nervous system and had a sudden cardiac arrest. Median PFS was 31.5 months, while the median OS has not been reached (Supporting Information Figure S1). Two-year PFS and OS were 62.5% and 75% respectively. Eight patients (89%) went on to receive maintenance therapy with lenalidomide. We also analyzed the referral patterns and trends in utilization for auto-HCT in octogenarians from our institutional database. Between January 2013, and December 2017, out of a total of 1465 MM patients referred for evaluation for auto-HCT at our institution, only 10(0.68%) were of age ≥ 80 years. Also, between January 2002 and December 2017, a total of 873 MM patients with age ≥ 80 years were treated at our institution, and only 7(0.8%) underwent auto-HCT. This highlights the exceptionally low utilization rates of auto-HCT in the octogenarian population. The geriatric population group is highly heterogeneous regarding frailty, consisting of fit, intermediate-fitness, and frail patients.8 Both under-treatment of fit patients and over-treatment of frail patients can lead to significantly poor outcomes. IMWG frailty score assessment is not an appropriate way to assess the consideration for auto-HCT as it assigns every octogenarian patient into frail category (age > 80 is assigned a score of 2, ≥2 is considered frail).8 Other geriatric assessment tools should also be taken into consideration for risk-assessment in this, particularly vulnerable population.9 In the current era of novel therapies, limited retrospective studies in octogenarian MM patients have shown poorer outcomes.5, 10 One study showed a median survival of 26 months in octogenarian MM patients with the use of upfront novel agents without auto-HCT.5 Our analysis shows that in highly selected octogenarian MM patients, auto-HCT was feasible with 0% treatment-related mortality, manageable toxicities, 100% response rate, and a 2-year OS of 75%. Almost 90% of these patients went on to receive maintenance therapy. In conclusion, auto-HCT is under-utilized in octogenarians MM patients, and selected patients who are deemed fit have favorable outcomes with upfront auto-HCT with acceptable toxicity. The authors decalre that they have no conflict of interest with the contents of this article. Supporting Information Figure S1. Kaplan Meir curve for Progression-Free and OS Supporting Information Table S2. Patient Characteristics of the patient above age 80 years. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.