Lactic acidosis and hypoglycemia as markers of disease progression of multiple myeloma: A case report

Abstract Case report: A 64‐year‐old man was hospitalized in the intensive care unit with pneumonia, lactic acidosis, and hypoglycemia. Investigations revealed a kappa light chain multiple myeloma. The patient underwent chemotherapy by bortezomib, lenalidomide, and dexamethasone. Serum lactate level and glycemia normalized. Evaluation at day 28 showed a disease progression. Lenalidomide was switched for daratumumab, bortezomib, and dexamethasone. In front of the inefficiency of the chemotherapy, the patient underwent third‐line chemotherapy by melphalan. There was a correlation between the evolution of the myeloma, serum lactate level, and hypoglycemia, with a normalization after chemotherapy, and a rise at myeloma's relapse. Daratumumab was continued as a maintenance treatment. The patient died 4 months and 10 days after his first hospital admission. Discussion: Our case is consistent with a type B tumor‐associated aerobic glycolytic lactic acidosis, called the Warburg effect. It is well described in association with other hematologic malignancies, but rarely in association with myeloma. All reported cases of myeloma with type B lactic acidosis died within 1 year. Conclusion: When associated with multiple myeloma, tumor‐associated aerobic glycolytic lactic acidosis is correlated with the disease progression and has a very high mortality rate. Significance Statement : Aerobic glycolytic lactic acidosis also known as the Warburg effect can be encountered in multiple myeloma, resulting of a metabolic shift to increased glycolysis operating in malignant cells. Together with hypoglycemia, it is well correlated with the disease progression and has a very poor outcome.

with a median presentation age of 70 years [1][2][3]. The improvement of multiple myeloma treatment has globally improved its mortality, with an overall 5-year survival rate of 52% [4].
A wide variety of metabolic disorders are observed in patients presenting hematological malignancies, such as hyperuricemia, hypercalcemia, hypo-or hyperglycemia, lactic acidosis, and inappropriate secretion of antidiuretic hormone syndrome [5]. Pathogenetic mechanisms of these metabolic abnormalities are extremely various, including neoplastic cell turnover, tumor secretion factors, auto-immune reactions, and can also be treatment-induced [5].
We describe a case of multiple myeloma associated with high and recurrent hyperlactatemia and profound hypoglycemia.

CASE REPORT
A 64-year-old man, smoker, without any specific medical history or treatment, was admitted to the emergency department of our hospital in June 2019 with progressive dyspnea, bone pain, and a recent loss of 10 kg.
On examination, blood pressure was normal (126/69 mm Hg), heart rate was raised to 107 beats/min, oxygen saturation was 97% while breathing room air, respiratory rate was raised to 23
In normal aerobic conditions, glycolysis converts glucose to pyruvate, which is oxidized to acetyl-CoA, releasing CO2 and entering the Krebs cycle. This reaction produces NADH, which is then used in oxidative phosphorylation and produces 36 molecules of ATP. Under anaerobic conditions, pyruvate is converted to lactate [9]. The Warburg effect is an aerobic glycolytic state where, despite the presence of oxygen, pyruvate is metabolized to lactate producing only two molecules of ATP, appearing to be paradoxically inefficient [10]. However, malignant transformation is linked with changes in the metabolic cellular pathway necessary for cancer cell proliferation, and aerobic glycolysis provides additional substrates, such as amino acids, nucleotides, and lipids, that are not provided if converting all the glucose to CO2 via oxidative phosphorylation. Lactate can also be used as an alternative energy source and facilitates rapid cell growth [10]. The Warburg effect in hematological or solid malignancy is well described in the literature [8,11]. Most of the cases are associated with lymphomas and acute leukemias, but multiple myelomas are also reported [12][13][14][15][16]. Moreover, it has been hypothesized that cancer cells induce aerobic glycolysis on stromal cells, that in turn produce lactate and pyruvate, re-incorporated by the cancer cells for the Krebs cycle and oxidative phosphorylation. This is known as the "reverse Warburg effect" [9,17], and has specifically been described in myeloma cells [18].
Increased glycolysis also explains an often coexisting hypoglycemia with the Warburg effect [19][20][21][22]. Hypoglycemia can also result from intense glucose consumption by an important tumor cell mass [8,19,23]   symptoms. This fact has already been described [23] and is explained by the use of lactate as a major alternative metabolic source for the brain. In our patient, hypoglycemia could be multifactorial, but its evolution is well correlated with the serum lactate level (Figure 1), suggesting a relationship with the myeloma cell mass.
However, in a critically ill patient presenting a hematological malignancy with lactic acidosis and hypoglycemia, other diagnoses must be ruled out, before concluding to the Warburg effect. Our patient presented upon admission to the ICU a hypoxemic pneumonia with septic shock, which could explain lactic acidosis. However, despite hemodynamic and respiratory stabilization, serum lactate levels remained over 10 mmol/L. There was no evidence for mesenteric ischemia, no liver failure, no drugs inducing acidosis, and the patient was supplied with thiamine. Acute renal failure could not entirely explain lactic acidosis, as lactate level remained over 5 mmol/L despite continuous renal replacement therapy. We observed a correlation between the evolution of the myeloma, serum lactate level, and hypoglycemia, with a decreasing of the lactate level and normalization of glycemia after the administration of corticosteroids and chemotherapy, and a rise of serum lactate level and hypoglycemia at myeloma's relapse ( Figure 1). This makes our case consistent with a tumor-associated aerobic glycolytic lactic acidosis.
Interestingly, to the best of our knowledge, this case is the first description of a newly diagnosed myeloma immediately associated with type B lactic acidosis, as all other cases reported myelomas evolving for several years, with lactic acidosis appearing only in relapses (Table 1). This could be linked with the important myeloma cell mass presented by our patient, as witnessed by the massive bone marrow infiltration. The mortality rate of the Warburg effect is very high.
Indeed, all reported cases of myeloma with type B lactic acidosis, including ours, died within 1 year (Table 1). However, understanding the importance of the metabolic shift to increased glycolysis operating in cancer cells has been a major step in the development of glycolysis inhibitors in solid cancers and is studied as a novel approach in the treatment of hematological malignancies [28].
Aerobic glycolytic lactic acidosis and hypoglycemia are serious metabolic abnormalities encountered in hematological malignancies, resulting from changes in the metabolic pathway of the malignant cells. When associated with multiple myeloma, this condition is correlated with the disease progression and has a very high mortality rate.

AUTHOR CONTRIBUTIONS
All authors were involved in the management of the patient. Caroline Ziegler, Lev Volkov, and Agnès Melone collected the data. Caroline Ziegler, Lev Volkov, Aurore Perrot, and Sébastien Gibot wrote the manuscript.