Patient baseline and treatment characteristics
Among 368 patients transplanted between 2001 and 2009, 95 were excluded from analysis for reasons detailed in . The clinical characteristics of the remaining 273 patients are summarized in . Cytogenetic studies for del17p and t(4;14) were only available after 2005. Therefore complete cytogenetic testing was only available in 185 patients. The majority of patients received induction treatments based on thalidomide, lenalidomide, bortezomib, or combination of these drugs ().
The majority of R/POD is associated with serologic evidence of R/POD
Among 273 eligible patients, 173 had serologic R/POD post-transplant. Analysis of 100 remaining patients revealed 6 additional patients who met IMWG clinical criteria for R/POD without evidence of serologic R/POD, though 2 among them had no serologic data available on the date of R/POD and therefore had inadequate serologic follow up. In addition, one patient relapsed with leptomeningeal disease, one with plasma cell leukemia, and 2 had oligo-secretory disease. Interestingly, one of the latter 2 patients had IgA gammopathy and exhibited steadily rising IgA levels preceding symptomatic relapse without meeting IMWG serologic criteria for R/POD. Excluding patients with no serologic follow-up, only 4 patients (2 %) had symptomatic R/POD without evidence of serologic R/POD.
The majority of patients with R/POD have asymptomatic R/POD
In addition to the 6 patients who had symptomatic R/POD in the absence of serologic findings, 20 patients with serologic R/POD had concurrent evidence of clinical/radiologic R/POD (symptomatic group). These 26 patients exhibited often coinciding clinical findings consistent with aggressive disease including acute severe anemia (n=5), leptomeningeal relapse (n=2), soft tissue involvement (n=14), plasma cell leukemia (n=1), symptomatic skeletal lesions (n=21), renal failure (n=1), and hypercalcemia (n=1). In this group, a total of 4 out of 5 patients with IgA gammopathy had steady rise in their IgA level from baseline without meeting IMWG criteria for serologic R/POD prior to symptomatic R/POD. Although this study is not designed to determine the optimal serologic follow-up interval post-transplantation, 5 of the 26 symptomatic patients had intervals ranging from 143 to 469 days, probably contributing to their symptomatic presentation. The remaining 153 out of 179 patients with R/POD (85%) had isolated serologic R/POD without conspicuous evidence of concomitant clinical R/POD (asymptomatic group). There was evidence by univariate association that symptomatic patients tend to have younger age, high-risk cytogenetics, and shorter time from ASCT to R/POD (). Further attesting to the aggressive nature of the disease in symptomatic patients, the survival curves in show considerable separation in the time from relapse to death. Adjusting for the lag time between ASCT and relapse, the risk of death was significantly higher for the symptomatic group (HR: 3.43 (2.09, 5.63), p< 0.001).
Univariate associations between the type of R/POD and key baseline and treatment characteristics.
Kaplan-Meier estimates of overall survival from the time of R/POD for the symptomatic and asymptomatic groups
Role of imaging at the time of serologic R/POD in patients with asymptomatic R/POD
To determine whether patients in the asymptomatic group exhibited occult radiographic R/POD despite lack of suspicion of clinical R/POD, we examined all patients who had radiologic imaging within 4 weeks following the date of serologic R/POD. Sixty-four out of 153 asymptomatic patients had routine imaging available. Twenty-five (40%) among them had new bone lesions by SS (n = 12), PET/CT (n = 11), or MRI (n = 2) despite absence of any prior suspicion.
Role of yearly routine skeletal survey in the monitoring of patient with MM after ASCT
To determine whether yearly routine skeletal survey (SS) is useful to monitor patients after ASCT, we reviewed SS within one year prior to the date of serologic R/POD, available in 95 of the 179 patients with R/POD. Only 3 patients (3%) had evidence of radiologic R/POD anteceding serologic R/POD. All 3 patients were in the symptomatic group with no serologic follow-up on the day of radiologic R/POD and had poor prior serologic follow up, ranging from 208 to 252 days.
Association between paraprotein types at times of diagnosis and R/POD
To determine whether one could predict the pattern of serologic R/POD in individual patients, and thereby identify the most appropriate serologic testing for monitoring, we examined the association between the type of paraprotein at times of R/POD and diagnosis in patients who had complete serologic data available. Serologic paraprotein types singularized included intact immunoglobulin only (Ig-only) detected by serum immunofixation (IF) and/or protein electrophoresis (PEP), FLC only (FLC-only) detected by FLC assay, and both (Ig/FLC). Among 66 evaluable patients with CR, 13 had FLC-only at diagnosis, 7 Ig-only, and 47 Ig/FLC. All patients with FLC-only relapsed with FLC-only; 6 of 7 with Ig-only relapsed with Ig-only and 1 with Ig/FLC; 5 of 47 with Ig/FLC relapsed with FLC-only, 23 with Ig-only, and 19 with Ig/FLC. Among 54 evaluable patients achieving <CR, 13 had FLC-only at diagnosis, 6 Ig-only, and 35 Ig/FLC. All patients with FLC-only progressed with FLC-only; 5 of 6 with Ig-only progressed with Ig-only and 1 with Ig/FLC; 13 of 38 with Ig/FLC progressed with FLC-only, 9 with Ig-only, and 13 with Ig/FLC ().
Association between the types of monoclonal protein present at diagnosis and R/POD
Clinical significance of R/POD by FLC-only disease
To determine whether detection of R/POD by FLC testing is clinically relevant, we examined the records of the 51 patients who met R/POD criteria by FLC-only. Four had symptomatic R/POD and 6 additional patients among 22 with imaging available within 4 weeks following serologic R/POD, had new radiographic findings. Importantly, when focusing on the 21 patients who relapsed with FLC-only according to the proposed criterion in methods, 1 was symptomatic and 4 additional patients of 12 with available imaging within 4 weeks following serologic R/POD had new radiographic findings. Thus, at least 23% of patients meeting the proposed FLC criterion had radiographic/clinical relapse.
Role of urine studies in the monitoring of patients with MM after ASCT
Among patients with urine studies available at the time of serologic R/POD, 12 of 59 (20%) with CR and 4 of 47 (8%) with <CR had evidence of R/POD by Urine IF and/or PEP. Among patients who had urine studies available within 3 months prior to serologic R/POD, 5 of 52 (9%) with CR and none of 43 with <CR demonstrated evidence of R/POD anteceding serologic R/POD by UIF. Overall, only 1 of the 95 patients had symptomatic relapse raising uncertainty regarding the clinical relevance of urine testing. Interestingly, this patient also had an IgA gammopathy.
In this retrospective study, we examined the patterns of R/POD in patients treated with induction therapy followed by ASCT. We have made several observations that could be relevant to current monitoring guidelines of patients after ASCT.
Based on this analysis, the overwhelming majority of R/POD is associated with concurrent serologic R/POD, with only a small percentage of patients (2%) presenting with symptomatic clinical disease in the absence of serologic R/POD. Furthermore, we find that the vast majority of patients with R/POD present with serologic abnormalities as the initial manifestation of R/POD. Only 15 % present with symptomatic overt clinical disease. Although the small number of patients in the latter group precludes a multivariate analysis, the univariate analysis indicates that poor cytogenetics, aggressive disease with early R/POD, and younger age are associated with symptomatic R/POD. Further examination of this group also shows leukemic transformation, soft tissue involvement, and leptomeningeal disease prominently featured at the time of R/POD. An important corollary of these observations would be that monitoring patients after ASCT with serologic testing appears to be adequate in heralding the occurrence of R/POD, except for a minority of patients who have biologically aggressive disease, predicted by poor cytogenetics and manifested by aggressive patterns of transformed R/POD, early R/POD, and poor survival as similarly described by others18
Interestingly, we observed retrospectively that patients with IgA gammopathy often tend to have progressive elevation in IgA levels, without meeting IMWG criteria for R/POD by SPEP prior to symptomatic R/POD 15
. We therefore caution that serologic monitoring of these patients using IMWG criteria alone may not be sufficient. IgA level measurements in these patients may be more revealing. The development and incorporation of the new Hevylite assay may well remedy this inadequacy of the currently available tests, as suggested by others.19, 20
Although it appears that serologic testing alone may well be adequate for monitoring patients after ASCT, it is also interesting to highlight that our observations may not fully support the IMWG recommendations regarding the specific type of laboratory testing needed during monitoring. Indeed, the IMWG consensus recommends the use of serum FLC assay for serial monitoring and assessment of response in patients with oligo-secretory disease only and does not advocate its use for serial follow-up or relapse assessment in patients with measurable M spike “due to lack of sufficient data to suggest that addition of FLC assay to serum IFE and SPEP may improve patient outcomes”9
. Furthermore, the IMWG consensus also states that “it is important for a particular patient to use the same method for follow-up of disease”14
. In contrast, our observations indicate that all patients should be followed using all available serologic testing including SPEP, IF, and FLC assay, except for patients with FLC-only disease who always have serologic R/POD detected by FLC assay only. Indeed, among patients who had Ig-only or Ig/FLC disease at diagnosis, a substantial percentage present with abnormal FLC as first serologic indicator of R/POD, which we show to be clinically relevant. This testing would particularly be useful for patients who lose expression of immunoglobulin heavy chain, a phenomenon coined by others “FLC-escape”21, 22
In this study, we further propose a new FLC criterion for patients who relapse
from CR since the IMWG criteria have no provision pertaining to such patients 9, 14
. It consists of an abnormal FLC ratio and involved FLC level after at least 2 prior normal measurements, with subsequent confirmation of the abnormal measurements and demonstration of >50% further increase in the involved FLC. Supporting the clinical relevance of such a criterion, we find that a least 23% of the patients meeting this criterion have concurrent evidence of radiographic R/POD.
In this study, yearly imaging with SS was not useful for earlier detection of R/POD in any patients who had a SS within a year prior to serologic R/POD. Thus, yearly SS cannot be recommended for routine follow-up in the absence of other evidence for R/POD. This observation supports the IMWG recommendation that was not previously clearly substantiated 14
. This statement however, may not apply to MRI, which was found useful by investigators who showed a poor correlation between clinical CR and MRI CR in patients with more than 7 focal lesions and superior survival with resolution of MRI focal lesions 23
. Based on these findings, the authors recommended routine use of MRI every 6 months until resolution of focal lesions and annually thereafter, a recommendation awaiting validation 23
On the other hand, among patients with asymptomatic
R/POD, a significant percentage had evidence of occult new skeletal findings by MRI, PET or SS obtained within 4 weeks after serologic R/POD, despite the complete lack of suspicion of progressive clinical disease. These findings suggest that imaging should be recommended in patients with serologic R/POD to uncover potential occult lesions. This recommendation is in contrast with that of the IMWG consensus stating that in patients with relapsed disease, “a SS may be indicated to detect possible lesions at risk for fracture. Other imaging studies (CT, MRI, and PET-CT) may be indicated according to clinical circumstances” 14
. Uncovering these occult lesions is important since it would signify clinical relapse/progression and would compel physicians, in agreement with the IMWG consensus, to initiate salvage therapy15
The role of urine testing has been controversial in the literature, with some arguing that it may be obsolete in the era of FLC assay 24-27
. In this study, urine testing was far less sensitive to detect R/POD since only a small percentage of patients with serologic R/POD had evidence of concomitant UIF/UPEP abnormalities. However, UIF did herald serologic R/POD in a small percentage of patients with CR, an observation of uncertain clinical relevance. We would therefore conclude that UIF/UPEP could be helpful in the subset of patients achieving CR post-ASCT, although clinical relevance needs to be further examined.
In summary, we have described the patterns of R/POD in patients with MM after ASCT and propose evidence based recommendations for monitoring and management (). Our findings differ from previous reports in the literature. This discrepancy may reflect the use of the FLC assay and better-defined criteria for R/POD established by the IMWG. Although we acknowledge the limitations of the study due to the retrospective nature of the analysis and the heterogeneity of the patient population, we believe that our findings may strengthen the current guidelines for monitoring patients with MM after ASCT and provide a blueprint for further validation studies addressing our findings in large prospective populations.
Summary of observations and recommendations