Time from First Symptom Onset to the Final Diagnosis of Multiple Myeloma - Possible Risks and Future Solutions: Large Retrospective and Confirmatory Prospective Analysis

Introduction:Multiple Myeloma (MM) has seen major advances in the understanding and management, among them revised disease definitions and recognition of early diagnosis-defining events. Early MM diagnosis and treatment initiation of symptomatic patients (pts) have been revised via IMWG criteria. In line, early recognition, especially of symptomatic MM, is important. However, MM represents an indolent malignancy with often unspecific initial symptoms. This may complicate diagnosis finding and result in substantial delays until the correct diagnosis is made. Objective literature and larger retro- or prospective analyses are lacking and possible risk factors, which might lead to a delayed diagnosis, remain undetermined. This project addressed this important aspect with the aim to optimize earlier diagnosis finding in MM and as a consequence avoid CRAB-defining events.

Methods:We performed an initial retrospective analysis in 101 MM pts, followed by a prospective analysis in 176 pts using a structured MM-specific questionnaire, which was developed within our research group, Comprehensive Cancer Center (CCC) and in close collaboration with our biometrics team. The questionnaire consisted of 9 items and was tested and modified for utmost comprehensibility in 5 successive rounds in 10 healthy volunteers. For both analyses all available medical reports on the duration and type of the initial symptoms leading to the diagnosis of MM were assessed and putative risks for possible delays were determined. The subsequent prospective analysis was complemented with the MM-pt-questionnaire. It also assessed pts' satisfaction with the diagnostic process and inquired suggestions how this could possibly be improved. The trial protocol and MM-questionnaire were approved by the ethics committees. All pts provided written informed consent and all procedures were conducted in accordance with the Declaration of Helsinki and GCP Guidelines.

Results:Both retro- and prospective analyses showed comparable pt characteristics with typical age and MM characteristics for tertiary/referral centers as previously described (Engelhardt et al. 2014, 2015, 2016). The median time from pts' first symptoms to the final MM diagnosis was 4 months (ms;0.5-120) in the retrospective and 6ms (0.5-60ms) in the prospective cohort, both analyses showing large variations of very prompt to extremely long diagnosis latencies. The frequency of pts with earlier vs. late diagnosis determination, defined in 4 groups as <3, 3-6, 7-11 and >12ms, was 38%, 28%, 14% and 20% within the retrospective and similar with 25%, 33%, 7% and 35% in the prospective analysis, respectively (Fig.1A). The prospectively assessed median time from the pts' first contact to a physician to the final MM diagnosis was 3.5ms (0-60ms). Actual CRAB-symptoms at diagnosis were perceived in 12%, 15%, 54% and 80% in the retrospective analysis, confirmed with 15%, 23%, 54% and 74% in the prospective analysis, respectively (Fig.1B). The definite diagnosis of MM was most often made by tertiary centers/hospitals in 81%, followed by outpts' hematologist/oncologist practices in 10% and rarer by general practitioners in 5% or nephrologists practices in 4%. Of interest, 61% of pts were completely or rather satisfied, whereas 39% were less satisfied with the diagnostic process (Fig.1C); 58% believed that their disease could have been diagnosed more expeditiously (Fig.1C). Those pts, who criticized a longer diagnosis latency vs. those that did not showed indeed a longer median time interval from symptom onset to the final MM diagnosis of 9 vs. 3ms, respectively. Risk factors for delays in diagnosis finding were light-chain-, oligo- or asecretory MM types, prior orthopedic and rheumatologic comorbidities disguising MM, unspecific disease symptoms, longer distance to referral centers and pts' residence in smaller rural areas.

Conclusions:Considerable latencies in diagnosis finding of ≥12ms occur especially in MM pts suffering from unspecific symptoms like bone pain or anemia-related symptoms. Longer time intervals from the onset of first symptoms to the final MM diagnosis substantially affected pts' satisfaction and illness processing. In times of pt-centered care, this analysis aims to generate relevant insight, how earlier diagnosis can possibly be achieved in the future; these ongoing analyses being presented at the meeting.

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