Pulmonary Hypertension Induced by Thalidomide ( and Derivatives ) in Patients with Multiple Myeloma : A Systematic Review

Thalidomide is widely used in the treatment of multiple myeloma (MM). In recent years, several cases of pulmonary hypertension have been reported following treatment with thalidomide. The aim of this review was to evaluate the published literature on multiple myeloma patients with pulmonary hypertension following thalidomide treatment. A literature search was performed between 2000 and 2016. A total of 7 eligible studies were identified and deemed eligible, including 11 cases—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). In conclusion, pulmonary hypertension induced by thalidomide or derivatives in multiple myeloma (MM) patients is related to a multifactorial etiology including the pathophysiology of the disease, thromboembolic events, preexisted cardiovascular conditions, comorbidities, and combination with other chemoor bio-therapeutic agents. MM patients should be evaluated for signs and symptoms underlying cardiopulmonary disease before initiating, and during treatment with thalidomide. How to cite this paper: Nashwan, A.J., Al-Dewik, N.I., Al Sabah, H.M., Yassin, M.A., Mohamed, S.F., Omar, N.H. and Mansour, D.B. (2016) Pulmonary Hypertension Induced by Thalidomide (and Derivatives) in Patients with Multiple Myeloma: A Systematic Review. Journal of Cancer Therapy, 7, 971-978. http://dx.doi.org/10.4236/jct.2016.713094 Received: October 19, 2016 Accepted: November 30, 2016 Published: December 2, 2016 Copyright © 2016 by authors and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/


Introduction
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 [1] [2].
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 [3] [4] [5].
Thalidomide has been linked with an increased risk of thromboembolic events (TEEs), including pulmonary hypertension (PH) and venous thromboembolism (VTE) [18] [19] [20].The underlying cause of this VTE remains unclear, although several mechanisms have been postulated.It is well known that VTE can lead to PH [21].
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 [22].
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) [23].
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) [24].

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.

Search Strategy and Eligibility Criteria
A literature search was conducted using various databases-including PubMed, Science-Direct, and Google Scholar-for articles published between 2000 and August 1, 2016.The following keywords: (thalidomide), (thalidomide derivatives), (lenalidomide), (pomalidomide), (pulmonary hypertension), (pulmonary arterial hypertension), and (multiple myeloma) were entered, and the search was limited to articles in English describing the association between thalidomide and thalidomide derivatives and the development of pulmonary hypertension in patients with different types of multiple myeloma.The resulting abstracts were screened, and only full-text articles published in peer-reviewed journals were retrieved for review.Reference lists were also searched to find further eligible articles.Particular attention was taken to ensure that each study was represented only once.

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 [25] (Table 1).

Discussion
The studies differed in several important aspects, including specific diagnosis, age *Plasma cell leukemia (PCL), a rare but particularly aggressive form of multiple myeloma (MM), is defined by an absolute count of 2.0 × 10 9 /l (or 20% of peripheral white blood cell count) circulating plasma cells.[26]; 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 [26] 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 [27] 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 [28] 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 [23]  In 2011, Villa [29] 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 [30] 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 [31] 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.

Table 1 .
List of published literature on PH following treatment with Thalidomide (and derivatives).