Preexisting Oral Disease as a Risk Factor in Oral Complications during PBSCT in Multiple Myeloma Patients
Authors: Meiller Timothy F , Scheper Mark A , Weikel Dianna , Jabra-Rizk Mary Ann , Badros Ashraf Z. 
Published: April 2020

Oral complications have the potential to significantly increase patient morbidity when they occur during myelosuppressive chemotherapy. In a present cohort of multiple myeloma patients, 276 patients were evaluated for oral disease status prior to peripheral blood stem cell transplant (PBSCT) in order to validate the hypothesis that preexisting oral disease is predictive of complication outcomes. The incidence and frequency of periodontal diseases in this study population was 34% mild, 36% moderate and 30% severe/advanced, using the highest clinical classification present in at least 2 sextants of natural teeth. These assessments are part of the standard of care at the Greenebaum Cancer Center, and include panoramic radiography, selected periapical imaging and soft tissue assessment; with calculation of disease severity by dental sextant. Oral risks and complications that are regularly followed include the use of oral bisphosphonates and occurrence of osteonecrosis of the jaw (ONJ), incidence of mucositis and the incidence of viral and fungal infections during periods of myelosuppression. The results of this preliminary study indicate that patients with moderate to severe periodontal disease suffer complications at approximately a 2:1 ratio over those patients without preexisting periodontal/oral diseases. Specifically, oral mucositis occurred in 60% of those with preexisting periodontal diseases and 34% of the patients without disease. Relative to bisphosphonate induced ONJ, 66% of our 35 active ONJ patients had moderate to severe periodontal diseases prior to their development of ONJ. Analysis of fungal and viral infections was equivocal between the groups with and without disease. Since oral diseases are known to lead to elevations in local and plasma levels of proinflammatory cytokines, including TNF alpha, and IL17a among others, we have undertaken a preliminary assessment to relate oral disease to cytokine levels. To assess any potential relationship, analysis was performed on stored samples of plasma from selected patients in the cohort. Patients were identified by the characteristics of oral complications and then grouped into those with ONJ, those with preexisting moderate to advanced periodontal disease, and those with mild periodontal disease. Plasma from six patients was evaluated in an effort to demonstrate proof of principle that inflammatory cytokines vary based on these characteristics. Included in this analysis were 5 patients with multiple myeloma and one normal control. The normal control has a healthy periodontium and no evidence of chronic oral disease. Of the 5 patients undergoing PBSCT 1 patient had a healthy oral state with no evidence of oral disease and 4 patients had dental disease at initial examination. One patient had mild periodontal disease but demonstrated ONJ and 3 patients had moderate to severe disease, 1 with ONJ and 2 without ONJ.

Plasma Levels of TNF Alpha and IL17A

Patient MM Pre PBSCT Oral Disease ONJ Present TNF Alpha * IL17A * ‘expressed in picograms/ml 001 + ++ − 30.08 24.06 002 + ++ + 38.92 23.46 003 + ++ − 25.81 21.76 004 + + + 26.43 17.61 005 + − − 14.87 9.83 006 − − − 10.62 8.24

These data indicate a clear difference in cytokine levels of TNFalpha and IL17a. The patient with moderate to advanced periodontal disease coupled with the presence of ONJ had the highest levels of pro-inflammatory cytokines, whereas all other patients have lower levels as compared to the normal control. These data indicate that oral disease may correlate with elevations in cytokine levels and with the oral complication of ONJ after its onset. Even though there were 2 and 3 fold differences, this is a small sample of patients and the predictive value of these assessments in a larger more controlled study is the focus of our ongoing investigations.