Outcome of patients with multiple myeloma and hypotension during high‐dose chemotherapy
Authors: Noa Biran, Priya Sehgal, Gagan Sahni, John Doucette, Ajai Chari
Journal: American Journal of Hematology (2015)

To the Editor: The median age of diagnosis of multiple myeloma (MM) is 69 1. Patients of this age group are at risk for hypertension, and are likely to be on ≥1 anti-hypertensive medication (anti-HTN) 2. For transplant-eligible patients, standard treatment is induction chemotherapy followed by consolidative high-dose melphalan with autologous stem cell rescue (ASCT) 3. Weight loss, febrile neutropenia (40% incidence), and hypovolemia from chemotherapy-related toxicity—including mucositis, nausea/vomiting, decreased oral intake, and diarrhea—can precipitate hypotension during ASCT 4. Concomitant light-chain (AL) amyloidosis (10–15% of MM) may cause autonomic insufficiency and diarrhea, increasing the risk for hypotension 5. The implications of hypotension during high-dose chemotherapy have never been evaluated. Our aims were to determine the incidence and prognostic factors for the development of hypotension in MM patients treated with high-dose chemotherapy. We retrospectively analyzed 101 consecutive MM patients with or without concurrent AL amyloidosis admitted for high-dose chemotherapy between May 2011 and June 2013. This study was approved by our Institutional Review Board. Patients who did not meet any of the above criteria were classified as non-hypotensive. Characteristics were compared using the Pearson chi-square, Fisher's exact, or t-test. Progression-free survival was calculated from high-dose chemotherapy by Kaplan–Meier analysis. A multivariate cox-regression analysis was performed for progression-free survival among early ASCT patients (i.e., prior to first relapse). The incidence of hypotension during ASCT was 43%, with 43/101 meeting ≥1 inclusion criteria for hypotension. Of the hypotensive patients, 18/43 had ≥1 anti-HTN discontinued during the admission (Criterion A), 21/43 were hypotensive on the date of discharge, although normotensive prior to admission (Criterion B), and 23/43 had a decrease in SBP of ≥20 mmHg between the outpatient visit prior to admission and discharge (Criterion C). Seventeen (40%) met two criteria for hypotension. The groups were similar in almost all peri-ASCT characteristics (Table 1). There was, however, an increased number of patients on angiotensin-converting-enzyme inhibitor (P = 0.02) and angiotensin-receptor blocker (P = 0.04) in the hypotensive versus the non-hypotensive group. The median weight loss was 3.59 kg and 2.09 kg in the hypotensive and non-hypotensive groups, respectively (P = 0.06). The most common reason for anti-HTN discontinuation was an episode of hypotension (9/18, 50%). Other reasons included normalization of BP by discharge (4/18, 22%), renal insufficiency (2/18, 11%), and bradycardia (1/18, 6%). Interestingly, 15/101 patients were reported to have hypotension in the discharge summary; of those, 3/15 experienced hypotension for only 1–2 days and did not meet hypotensive group inclusion criteria. In the post-ASCT setting, there was a greater incidence of anti-HTN discontinuation due to an episode of hypotension in the hypotensive versus the non-hypotensive group (4 versus 0 patients, P = 0.03). All had fever, diarrhea, and weight loss during ASCT, with two patients losing 13.6 kg and 15.5 kg. Two patients were on an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. With a median follow-up of 14 months after high-dose chemotherapy, the median progression-free survival for all patients (N = 101) was 17 months. As expected, progression-free survival was longer in patients who received an early (N = 49) versus a late (N = 52) ASCT (i.e., with second-line therapy or later)—not reached versus 15 months, P = 0.02. Of all variables included in multivariate analysis, (hypotension, Durie–Salmon stage, use of an angiotensin-converting-enzyme inhibitor or an angiotensin receptor blocker, use of maintenance therapy, high-risk cytogenetics), only the use of maintenance therapy (hazard ratio 0.182 [95% confidence interval 0.044–0.762], P = 0.05) emerged as prognostic for progression-free survival. Notably, 36% of patients did not have cytogenetic results available. Our study has limitations due to its retrospective nature. However, the 43% incidence of hypotension was unexpectedly high. Hypotension was only mentioned in the discharge summaries of 30% of those affected, indicating its under-recognition. Fifty-two percent of patients had a late ASCT, making them more likely to have comorbidities predisposing them to hypotension. Weight loss (although P = 0.06) and use of angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers emerged as prognostic for the development of persistent hypotension. The consequences of angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers on BP can be explained by several mechanisms. First, angiotensin-converting-enzyme inhibitor effects are amplified compared to other anti-HTNs when patients are volume depleted due to a compensatory activation of the renin angiotensin axis and an angiotensin II surge 6. Indeed, in the hypotensive group, 72% of the patients had diarrhea and 53% had fever during ASCT, setting the stage for volume depletion. Second, the clearance of angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers are particularly affected in the setting of reduced glomerular filtration rate (27% in the hypotensive group), compared to other anti-HTNs, leading to drug accumulation and persistent hypotension. Third, amyloid-induced autonomic dysfunction, (7% in the hypotensive group) may cause an increased reliance on the renin angiotensin axis for maintenance of adequate BP, amplifying the effects of angiotensin-converting-enzyme-inhibition. Hypotension associated with angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers highlights the need for close BP monitoring, and dose adjustments in the peri-ASCT setting. A retrospective, non-validated study of 163 patients, without a multivariate analysis, found inferior progression-free survival and overall survival with the use of angiotensin-converting-enzyme inhibitors 7. Although the current study includes a heterogeneous group of MM patients, there was no significant difference in progression-free survival for those who had early ASCT (more than half of whom were on maintenance therapy), with the use of angiotensin-converting-enyzme inhibitors or angiotensin receptor blockers or in the presence of hypotension. Eighteen patients met criteria for hypotension based on discontinuation of anti-HTNs. Perhaps if these medications had not been discontinued, more adverse events would have occurred. The 43% incidence of hypotension associated with high-dose chemotherapy has significant implications for BP monitoring and anti-HTN adjustment, in a patient population that is often fatigued/deconditioned, hypovolemic, febrile, and thrombocytopenic and therefore at a high fall risk without early intervention. AC was the principal investigator and takes primary responsibility for the paper; NB participated in manuscript preparation, statistical analysis, and data collection. PS participated in manuscript preparation and data collection. GS participated in manuscript preparation and study design. JD conducted the statistical analysis. Noa Biran,1 Priya Sehgal,2 Gagan Sahni,3 John Doucette,4 and Ajai Chari5* 1Multiple Myeloma Division, John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, New Jersey; 2Department of Medicine, Icahn School of Medicine at Mount Sinai School, New York; 3Division of Cardiovascular Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York; 4Division of Biostatistics and Data Management, Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York; 5Division of Hematology and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York Additional Supporting Information may be found in the online version of this article. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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