Multiple myeloma (MM) is thrombogenic as a consequence of multiple hemostatic effects, including elevated interleukin-6 levels, procoagulant antibody formation, paraprotein interference with fibrin structure, activated protein C resistance, and endothelial damage   .
MM is a treatable, mature B-cell malignancy, which accounts for approximately 10% of the hematologic malignant neoplasms, and progress in improving survival has been rapid in recent years    .
Thalidomide is active in both newly diagnosed      and advanced MM, and as first-line therapy in combination with dexamethasone or other cytotoxic chemotherapy    . Its mode of action includes direct apoptotic, antiangiogenic effects, and modulation of the bone-marrow microenvironment   . However, the exact mechanism of action of thalidomide has not yet been clearly explained   .
Thalidomide has been linked with an increased risk of thromboembolic events (TEEs), including pulmonary hypertension (PH) and venous thromboembolism (VTE)    . The underlying cause of this VTE remains unclear, although several mechanisms have been postulated. It is well known that VTE can lead to PH  .
Pulmonary hypertension is defined by a mean pulmonary artery pressure ≥25 mm Hg at rest, measured during right-side heart catheterization. The term pulmonary arterial hypertension (PAH) describes a subpopulation of patients with PH characterized hemodynamically by the presence of pre-capillary PH including an end-expiratory pulmonary artery wedge pressure (PAWP) ≤15 mm Hg and a pulmonary vascular resistance >3 Wood units  .
Pulmonary hypertension was previously classified into two categories (primary and secondary) according to the presence of identified etiology. In 1998, a clinical classification was established to personalize different classes of PH sharing similar pathological findings, hemodynamic characteristics, and management. Five groups were identified: pulmonary arterial hypertension (Group 1); PH due to left-side heart disease (Group 2); PH due to chronic lung disease and/or hypoxia (Group 3); chronic thromboembolic PH (Group 4); and PH due to unclear multifactorial mechanisms (Group 5)  .
Clinical signs include fatigue, dyspnea, dizziness, leg swelling, and chest tightness. It often progresses to right-side heart failure, which might be due to cardiac amyloidosis (CA)  .
2. Study Objective and Significance
There has been a limited amount of research focusing on the link between thalidomide and the development of pulmonary hypertension. The findings of this review will provide more knowledge about one of the adverse events following thalidomide treatment. The aim of this review was to evaluate the published literature on multiple myeloma patients with pulmonary hypertension following thalidomide treatment.
3. Materials and Methods
Search Strategy and Eligibility Criteria
4.1. Publications Search
A total of 7 eligible studies were identified and deemed eligible: case reports (6) and a pilot study (1) published between 2003 and 2015. One study was excluded because the patient was diagnosed with Angiodysplasia, and the article was published in Spanish  (Table 1).
4.2. Patient Characteristics
Only 11 cases of MM with pulmonary hypertension following thalidomide (and derivatives) treatment have thus far been reported: age ranges from 51 to 79 years (mean = 67.5). With regard to gender: five males (46%), 4 (36%) females, and 2 (18%) with (not available) gender. Approximately 37% (4 cases) with IgA (k), 27% (3 cases) with IgG (λ) MM, 27% (3 cases) with IgG (k) MM, and one case (9%) with primary plasma cell leukemia (PPCL). The vast majority of cases 82% (9 cases) are associated with thalidomide, while only 18% (2 cases) are related to thalidomide derivatives (lenalidomide and pomalidomide). On the other hand, the described doses varied from 50 mg/d to 400 mg/d for thalidomide. Most of the patients were presented with dyspnea, peripheral edema, and asthenia, or incidentally discovered following continual follow-up with echocardiography.
The studies differed in several important aspects, including specific diagnosis, age
Table 1. List of published literature on PH following treatment with Thalidomide (and derivatives).
*Plasma cell leukemia (PCL), a rare but particularly aggressive form of multiple myeloma (MM), is defined by an absolute count of 2.0 × 109/l (or 20% of peripheral white blood cell count) circulating plasma cells.  ; NA = Not Available, Thal = Thalidomide, L = Lenalidomide, P = Pomalidomide, RVSP = Right Ventricular Systolic Pressure, mPAP = Mean Pulmonary Artery Pressure.
groups, combination protocols, duration of treatment, and the presence of comorbidities―especially thromboembolic events―which made comparisons somehow challenging.
In 2003, Younis  reported the first case of possible association between thalidomide and reversible PH in MM. A direct impact of thalidomide on the pulmonary vascular endothelial cells was suggested since a rapid reduction of pulmonary artery pressure after thalidomide interruption was observed.
Likewise, Hattori  and colleagues in 2005 also experienced the occurrence of PH in a MM patient during treatment with thalidomide by reporting the clinical course and autopsy findings. However, they clearly stated that the exact mechanism remains to be revealed; PH assessment and follow-up should be considered when thalidomide is used for MM patients. On the other hand, an autopsy revealed an extensive formation of plexogenic pulmonary arteries accompanied by the thickening of intimae and media arteries.
Six years later, Antonioli  and colleagues reported that one case diagnosed with IIA MM IgG kappa progressed from monoclonal gammopathy of unknown significance (MGUS). The patient was refractory to different chemotherapy regimens. Later, she refused further chemotherapy and autologous transplant, which is the reason why the patient started on thalidomide, 100 mg daily, with a progressive increase to 200 mg daily and dexamethasone for seven months without significant side effects. After one year and while on thalidomide, the patient presented to the center with dizziness, asthenia, and dyspnea. Moreover, the findings of this report supported the previous two reports in the need to clarify whether pulmonary hypertension is considered as an adverse effect of thalidomide and how the drug eventually affects the endothelial cells of blood vessels.
In 2008, Lafaras  and colleagues conducted the first clinical (pilot) study to detect the clinical and subclinical non-thromboembolic PH in MM patients after thalidomide treatment. The clinical and echocardiographic evaluation revealed four patients (out of 82 patients, 4.87%) with PH. Non-imaging and imaging diagnostic methods excluded thromboembolic PH. Statistical analysis demonstrated a significant correlation between structural heart disease and PH (r = 14.078; P = 0.008). No significant correlation between age, gender, International Staging System (ISS), and PH was found. Moreover, clinical assessment is essential when initially evaluating patients with suspected PH, but echocardiography is a key screening tool in the diagnostic algorithm to eliminate any secondary causes of PH, predict the prognosis, observe the efficacy of specific therapeutic interventions, and detect the preclinical stage of the disease.
In 2011, Villa  and colleagues reported a case of a 79-year-old woman with MM who was started on thalidomide treatment. About a month later, she presented with signs and symptoms of PH. Echocardiography revealed severe PH without cardiogenic origin, and pulmonary embolism was excluded; a previous echocardiography was normal. Thalidomide was promptly interrupted about a month later; and a physical examination and echocardiography revealed the absence of PH signs and exhibited normal parameters in both pulmonary artery pressure and right ventricular function.
In 2014, Tamura  and colleagues, described a case of a 76-year-old man with primary plasma cell leukemia (PPCL) complicated by renal failure and pulmonary hypertension. Bortezomib/dexamethasone (BD) induction therapy with lenalidomide was administered in association with continuous hemodiafiltration (CHDF). However, the authors described PH as a complication for the VRD protocol (bortezomib, lenalidomide, and dexamethasone), and not only the thalidomide derivative.
The most recent case report was published in 2015 by Krishnan  and colleagues, where three patients with MM developed severe PH. One case was excluded due to the history of cardiac amyloidosis, and no thalidomide or derivatives were initiated. In conclusion, all authors agreed that additional studies are needed to define the incidence, prevalence, prognosis, follow-up, and pathogenesis of PH in patients with different types of MM―especially for patients on thalidomide or thalidomide-derivative treatment. Further clinical trials will be needed to confirm the association between thalidomide (and derivatives) with PH in MM patients, as well as looking to the genetic predisposition for different MM mutations.
Conflict of Interest
The authors state that they have no conflict of interest.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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