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Keywords:

  • myeloma;
  • smouldering myeloma;
  • monoclonal gammopathy of undetermined significance;
  • complete response;
  • survival

Summary

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Author contributions
  8. References

Complete response (CR) is still considered an important surrogate marker for outcome in multiple myeloma (MM). Long-term survival after transplantation, however, has been observed in a substantial proportion of patients who never achieved CR. The tandem transplant trial, Total Therapy 2, enrolled 668 patients, who were randomised up-front to thalidomide (THAL) or no THAL; 56 patients were identified as having had, for at least 6 months prior to initiation of therapy, monoclonal gammopathy of undetermined significance (MGUS, n = 21), smouldering MM (SMM, n = 22) or solitary plasmacytoma of bone (SPC, n = 13). The clinical characteristics and outcomes of patients with such ‘evolved’ MM (E-MM) and of those with ‘unknown’ prior history (U-MM) were compared. Fewer patients with MGUS/SMM-E-MM had anaemia or renal failure; CR was lower (22% vs. 48%) but 4-year estimates of event-free survival (54% vs. 56% with U-MM) and overall survival (65% vs. 70% with U-MM) were similar to those with SPC-E-MM or U-MM. In the latter group, achieving CR was associated with prolonged survival. In comparison with U-MM, E-MM evolved from MGUS/SMM was associated with lower CR rate without adversely affecting survival. In contrast, CR was an independent favourable feature for survival in U-MM.

Peripheral blood stem cell-supported high-dose melphalan therapy has become the standard of care for patients with multiple myeloma (MM). Thus, median survival has been extended beyond 6 years, presumably as a result of profound tumour cytoreduction (Barlogie et al, 1999) reflected by complete response (CR) rates of 20% with single and 40% with tandem transplants (Attal et al, 1996; Attal et al, 2003; Child et al, 2003; Barlogie et al, 2005, 2006). Some patients, however, survive beyond 5 and even 10 years after transplant without ever having achieved CR. We recently reported the clinical results of Total Therapy 2 (TT2), a phase III randomised trial for newly diagnosed patients with MM that addressed the contribution of thalidomide (THAL) to CR, event-free survival (EFS) and overall survival (OS) (Barlogie et al, 2006). We now report on the outcome of a subset of patients who had fulfilled, at least 6 months prior to enrolment in TT2 for disease progression or symptom development, the criteria of monoclonal gammopathy of undetermined significance (MGUS), smouldering MM (SMM) or solitary plasmacytoma of bone (SPC).

Patients and methods

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Author contributions
  8. References

Patient eligibility

Between October 1998 and February 2004, 668 newly diagnosed patients with progressive or symptomatic MM (75 years or younger, no more than one cycle of prior therapy) were enrolled, after written informed consent had been obtained in keeping with institutional and National Cancer Institute guidelines. The protocol had been approved by the Institutional Review Board and the Food and Drug Administration and was monitored by a Data Safety and Monitoring Board, as required by the National Cancer Institute for phase III trials. Prior local radiotherapy for pain control or cord compression was permitted. Southwest Oncology Group (SWOG) performance status had to be <3, unless based solely on bone pain. Cardio-pulmonary functions had to be adequate; renal failure, even when haemodialysis-dependent, was not an exclusion criterion.

Treatment

Details of TT2 have been reported previously (Barlogie et al, 2006). Briefly, TT2 consisted of four treatment phases: (1) induction with VAD (vincristine, Adriamycin and dexamethasone), DCEP (dexamethasone, cyclophosphamide, etoposide and platinol), CAD (cyclophosphamide, adriamyacin and dexamethasone) with peripheral blood stem cell collection and further DCEP; (2) melphalan-based tandem transplant; (3) consolidation chemotherapy; and (4) interferon maintenance with dexamethasone pulsing during the first year (Fig 1). At registration, patients were randomly assigned to a control arm without THAL or to the experimental arm with THAL; THAL was applied throughout TT2 until relapse.

image

Figure 1.  Treatment schema.

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Laboratory evaluation

An MM work-up included serum and urine protein electrophoresis; quantification of serum immunoglobulin levels, 24-h urinary protein excretion, serum β2 microglobulin (B2M) and C-reactive protein (CRP) levels; bone marrow biopsies and aspirates for morphologic interpretation and metaphase cytogenetics. Such studies were performed at baseline and serially after initiation of therapy as per protocol requirements, in order to define response and relapse (see below).

Criteria for response and relapse

Of 668 patients enrolled in TT2, 651 began treatment and were assessed for response. CR was defined by using SWOG criteria, which are similar to those recently published (Blade et al, 1998; Barlogie et al, 2006). Relapse from CR was diagnosed upon the re-appearance of a monoclonal protein in serum or urine. Relapse from partial relapse (PR) entailed an increase in M-protein level in serum or urinary excretion by at least 50% or doubling from the lowest level/quantity, whichever occurred first. Primary refractoriness to therapy implied lack of PR but absence of progression (defined by at least 25% increase in serum M concentration or in 24-h urinary M-protein excretion). In case of non-secretory or hypo-secretory disease, bone marrow plasmacytosis had to exceed 30% or multiple magnetic resonance imaging (MRI)-defined focal lesions (MRI-FL), had to be present, one of which had to show >30% monoclonal plasma cells on DNA/cytoplasmic immunoglobulin flow cytometric examination.

Definition of preceding MGUS, SMM and SPC

Patient referral records were scrutinised by one of the authors; preceding diagnoses of MGUS (n = 21), SMM (n = 22) or SPC (n = 13) were rendered when the recently established diagnostic criteria pertained for at least 6 months prior to enrolment to the TT2 programme (International Myeloma Working Group., 2003). Collectively, MM with a documented phase of any of the three precursor conditions was termed ‘evolved’ MM (E-MM) in contrast to U-MM when such information was unknown.

Statistical analyses

Data are as of December, 2005. Baseline patient characteristics in the E-MM and U-MM groups were compared with Fisher's exact test. The Kaplan-Meier method was used to estimate EFS and OS (Kaplan & Meier, 1958). EFS was defined from date of registration to the occurrence of death from any cause, disease progression or relapse, or censored at the date of last contact. OS was defined from date of registration to the date of death from any cause or censored at the date of last contact. Cumulative incidence of response was determined by using off study or death as a competing risk (Gooley et al, 1999). A P-value of 0·05 was considered to indicate statistical significance in this analysis.

The Cox regression method (Cox, 1972) was used to examine multivariate prognostic factor models for EFS and OS with CR as time-dependent covariate. The same baseline prognostic factors were also considered in a multivariate Cox model for their association with CR. These models were all adjusted for the prior MGUS or SMM condition.

Results

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Author contributions
  8. References

Clinical features of E-MM and U-MM

Median times from precursor condition diagnosis to MM were similar: 33 months (range: 8–174 months) for MGUS, 35 months (range: 6–120 months) for SMM and 29 months (range: 11–106 months) for SPC. Probably owing to small sample size, no significant differences in baseline features were observed within E-MM subgroups (Table I). Compared with MGUS and SMM subgroups, patients with a preceding history of SPC presented less often with cytogenetic abnormalities (CA) (8% vs. 44%; P = 0·02). In relationship to E-MM as a group, patients with U-MM were more often anaemic (haemoglobin <100 g/l: 26% vs. 5%; P < 0·001) and presented more frequently with elevations of lactate dehydrogenase (LDH) >upper normal limit (28% vs. 9%; P < 0·001), creatinine ≥176·8 μmol/l (10% vs. 0%; P = 0·003), B2M ≥ 3·5 mg/l (38% vs. 23%; P = 0·011) and CRP ≥8·0 mg/l (41% vs. 24%; P = 0·004), with higher levels of bone marrow plasmacytosis (BMPC > 30%) (59% vs. 41%; P = 0·009) and with hypo-albuminaemia <35 g/l (19% vs. 7%; P = 0·013) (Table I). MRI-FL > 3 was observed in 45% of patients with U-MM, in 55% of those with prior SPC and in 27% of patients with E-MM evolved from MGUS or SMM (P = 0·06).

Table I.   Comparison of subgroups.
FactorE-MM (%)E-MM [Combined] (%)U-MM (%)Fisher's exact P E-MM v. U-MM
MGUS Smouldering Solitary plasmacytoma
  1. B2M, β2 microglobulin; CRP, C-reactive protein; LDH, lactate dehydrogenase; MRI-FL, magnetic resonance imaging-defined focal lesions.

Age ≥ 65 years2/21 (10)4/22 (18)0/13 (0)6/56 (11)130/612 (21)0·023
IgA Isotype3/21 (14)3/22 (14)1/13 (8)7/56 (13)152/611 (25)0·014
Creatinine ≥ 176·8 μmol/l0/20 (0)0/22 (0)0/13 (0)0/55 (0)62/599 (10)0·003
Hemoglobin < 100 g/l1/21 (5)1/22 (5)1/13 (8)3/56 (5)158/611 (26)<0·001
Albumin < 35 g/l1/21 (5)2/22 (9)1/12 (8)4/55 (7)115/609 (19)0·013
B2M > 3·5 mg/l7/21 (33)5/22 (23)1/13 (8)13/56 (23)230/612 (38)0·011
CRP > 8·0 mg/l4/21 (19)5/21 (24)4/13 (31)13/55 (24)250/603 (41)0·004
LDH > upper normal limit3/21 (14)1/22 (5)1/13 (8)5/56 (9)173/610 (28)<0·001
Bone marrow plasma cells > 307/16 (44)8/20 (40)3/8 (38)18/44 (41)296/503 (59)0·009
Cytogenetic abnormalities (CA)9/21 (43)10/22 (45)1/13 (8)20/56 (36)177/605 (29)0·071
MRI-FL > 37/20 (35)4/21 (19)6/11 (55)17/52 (33)258/578 (45)0·03

Frequencies of CR and near-CR

Times to and frequencies of CR were significantly longer and lower in E-MM with prior MGUS/SMM than in the case of E-MM with prior SPC or in U-MM (Fig 2A), justifying their combined depiction in Fig 2B. However, rates of less profound M-protein reduction (≥75% or ≥50%) were similar among the two groups (Fig 2C and D). EFS and OS from initiation of TT2 were similar in E-MM subgroups and in U-MM (Fig 3A and B), independent of randomisation to THAL (data not shown).

image

Figure 2.  (A) Times to complete response (CR) according to multiple myeloma (MM)-type (U-MM; MGUS/SMM-E-MM; SPC-E-MM). Those with prior MGUS/SMM experienced delayed onset of CR, which also occurred at lower frequency in comparison with patients with U-MM or MM evolved from solitary plasmacytoma (SPC). (B) Slower onset and frequency of CR with MM evolved from MGUS/SMM in comparison with U-MM plus SPC-E-MM groups combined. (C) Times to M-protein reduction by at least 75% were similar among MGUS/SMM-type E-MM and other subgroups. (D) Times to M-protein reduction by at least 50% were almost identical in MGUS/SMM-type E-MM and other subgroups.

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image

Figure 3.  (A) Event-free survival was similar in patients with multiple myeloma (MM) evolved from monoclonal gammopathy of undetermined significance (MGUS)/SMM and other subgroups. (B) Overall survival was similar in patients with MM evolved from MGUS/SMM and other subgroups.

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Prognostic factors including E-MM vs. U-MM

When all patients with E-MM and U-MM were considered, multivariate analysis showed higher CR rates in the absence of E-MM evolved from MGUS/SMM, in case of randomisation to THAL and when LDH was elevated (Table II). Longer EFS and OS both were observed in the absence of CA and LDH elevation and when albumin level was normal. Achieving CR was an independent favourable predictor of EFS and OS. Prior MGUS/SMM, although predicting a lower CR rate, did not affect EFS or OS adversely. Longer EFS but not OS was linked to randomisation to THAL, low B2M and absence of IgA isotype. Restricting the analysis to U-MM showed similar results (Table III). Within the E-MM population, prior MGUS/SMM was the only negative predictor of CR, while B2M ≥ 3·5 mg/l was associated with inferior EFS and OS (Table IV).

Table II.   Multivariate analysis of factors predicting for complete response, event-free survival and overall survival – all patients.
All patientsFactor%HR (95% CI)P-value
  1. HR, hazard ratio; 95% CI, 95% confidence interval; P-value from Wald chi-squared test in Cox regression multivariate model uses stepwise selection with entry level 01 and variable remains if meets the 005 level.

  2. MGUS, monoclonal gammopathy of undetermined significance; SMM, smouldering multiple myeloma; B2M, β2 microglobulin; CRP, C-reactive protein; LDH, lactate dehydrogenase; MRI-FL, magnetic resonance imaging-defined focal lesions; CR, complete response.

Complete response (n = 637)Prior MGUS/SMM70·45 (0·25,0·81)0·007
Thalidomide arm491·54 (1·24,1·91)<0·001
LDH > upper normal limit271·28 (1·00,1·62)0·045
Event-free survival (n = 654)Prior MGUS/SMM71·12 (0·71,1·76)0·637
Thalidomide arm490·75 (0·59,0·95)0·016
LDH > upper normal limit271·51 (1·17,1·96)0·002
Cytogenetic abnormalities301·55 (1·22,1·98)<0·001
Albumin < 35 g/l181·52 (1·14,2·02)0·004
B2M ≥ 35 mg/l361·47 (1·14,1·88)0·003
IgA isotype241·45 (1·12,1·89)0·006
CR (time dependent)520·64 (0·49,0·83)0·001
Overall survival (n = 654)Prior MGUS/SMM71·04 (0·59,1·81)0·900
LDH > upper normal limit271·66 (1·22,2·25)0·001
Cytogenetic abnormalities301·88 (1·41,2·52)<0·001
Albumin < 35 g/l181·85 (1·33,2·56)<0·001
CR (time dependent)520·52 (0·37,0·72)<0·001
Table III.   Multivariate analysis of factors predicting for complete response, event-free survival and overall survival – patients with U-MM.
U-MM groupFactor%HR (95% CI)P-value
  1. HR, Hazard Ratio; 95% CI, 95% confidence interval; P-value from Wald chi-squared test in Cox regression multivariate model uses stepwise selection with entry level 01 and variable remains if meets the 005 level.

  2. LDH, lactate dehydrogenase; B2M, β2 microglobulin; CR, complete response.

Complete response (n = 593)Thalidomide arm491·56 (1·25,1·95)<0·001
LDH > upper normal limit291·30 (1·02,1·65)0·035
IgA isotype251·32 (1·03,1·68)0·029
Event-free survival (n = 599)Thalidomide arm490·73 (0·57,0·93)0·012
LDH > upper normal limit291·50 (1·15,1·95)0·003
Cytogenetic abnormalities301·59 (1·23,2·04)<0·001
Albumin < 35 g/l191·53 (1·14,2·05)0·004
B2M ≥ 35 mg/l371·40 (1·08,1·81)0·011
IgA isotype251·52 (1·15,2·00)0·003
CR (time-dependent)540·61 (0·46,0·81)<0·001
Overall survival (n = 599)LDH > upper normal limit291·65 (1·21,2·25)0·002
Cytogenetic abnormalities301·92 (1·42,2·60)<0·001
Albumin < 35 g/l191·82 (1·31,2·55)<0·001
CR (time-dependent)540·50 (0·35,0·70)<0·001
Table IV.   Univariate analysis of factors predicting for complete response, event-free survival and overall survival – patients with E-MM.
E-MM groupFactor%HR (95% CI)P-value
  1. HR, Hazard Ratio; 95% CI, 95% confidence interval; P-value from Wald chi-squared test in Cox regression. MGUS, monoclonal gammopathy of undetermined significance; SMM, smouldering multiple myeloma.

Complete response (n = 54)Prior MGUS/SMM780·22 (0·09,0·55)0·001
Event-free survival (n = 55)B2M ≥ 35 mg/l242·95 (1·28,6·84)0·011
Overall survival (n = 56)B2M ≥ 35 mg/l232·80 (1·02,7·65)0·045

Discussion

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Author contributions
  8. References

Based on the experience in acute leukaemia, achieving CR has been considered key to long-term disease control in MM with high-dose therapies (Attal et al, 1996; Attal et al, 2003; Child et al, 2003; Barlogie et al, 2005, 2006) and, according to some investigators, independent of dose intensity (Alexanian et al, 2001) The new generation of immunomodulatory agents (IMIDs) (Richardson et al, 2002) and the first-in-class proteasome inhibitor bortezomib (Richardson et al, 2003) effect CR rates, especially when used in combination with each other and with standard agents, that approach those with transplant regimens (Jagannath et al, 2005; Orlowski et al, 2005; Palumbo et al, 2005a,b; Rajkumar et al, 2005; Wang et al, 2005). However, data translating these responses into survival prolongation are lacking. According to a large data set from the SWOG, absence of disease progression rather than frequency or quality of response was associated with prolonged survival (Durie et al, 2004). These findings, however, need to be interpreted in the context of a low CR frequency in the 5% range.

Now recognised as sites of eventual osteolysis and potential reservoirs of resistant myeloma, MRI-FL (>3) tended to be less common in the MGUS/SMM-E-MM group. This finding is consistent with the recognition that the diagnosis of ‘true’ SPC requires MRI examination (Dimopoulos et al, 2000) as standard skeletal bone surveys detect bone destruction only in the late stages. MM not infrequently presents with macro-focal rather than microfocal or diffuse bone marrow involvement, the extreme of which is referred to as ‘multiple plasmacytomata’ (International Myeloma Working Group, 2003).

Monoclonal gammopathy of undetermined significance progresses to symptomatic MM at a low annual rate of about 1·5% (Kyle et al, 2002), although it is unclear whether all MM evolve from MGUS (Bataille & Harousseau, 1997). SMM can be considered as a more advanced form of MGUS without qualitative distinctions; its probability of progression to overt MM has been linked to higher M-protein levels and the presence of focal lesions detected by MRI (Weber et al, 1997). Low CR rates in E-MM probably result from a lower plasma cell proliferative activity typical of both MGUS and SMM (Rajkumar & Greipp, 1999) that may extend to the advanced stages with symptom manifestation. Greater proliferative activity renders tumours in general more susceptible to the lethal effects of most cytotoxic agents, but also constitutes an unfavourable scenario of early relapse and death when tumour cytoreduction is not sufficiently profound. Reflective of this notion in our study were (1) a higher CR rate but shorter EFS and OS seen in cases with elevation of LDH, a marker of aggressive disease in MM (Barlogie et al, 1989; Dimopoulos et al, 1991) and in lymphoma; (Shipp, 1994) and (2) the independent favourable effect of CR (reflecting more profound cytoreduction) on clinical outcome, which was, however, not observed in patients with MGUS/SMM-E-MM.

We advance the hypothesis that failure to achieve CR with current high-dose regimens may identify patients with a high probability of having evolved through MGUS/SMM if their disease remains stable for many years. De novo MM, on the other hand, is characterised by greater proliferative activity from the outset; when tumour cell kill is profound and CR achieved, longer survival ensues. Complementarity-determining region 3-polymerase chain reaction technology enables more quantitative assessment of ‘minimal residual disease’ (Tricot et al, 2004). Its application may reveal whether the high risk conferred by the presence of cytogenetic and certain molecular abnormalities results from insufficient tumour cell kill (with a higher remaining sub-clinical tumour burden) or more rapid tumour re-growth. Gene expression profiling, readily distinguishing normal plasma cells from those of both MGUS and MM patients (Zhan et al, 2002), also seems to distinguish MGUS and MM. Preliminary data suggest that some patients in the U-MM group have an E-MM signature (Dhodapkar et al, 2005). Such investigations ultimately will enable the removal of ‘US’ (undetermined significance) from ‘MGUS’ by recognising a subset with virtually nil propensity for disease progression (truly ‘benign’ monoclonal gammopathy) and help recognise de novo MM presenting, incidentally, in early stages but with a high probability of early symptom development, justifying prompt intervention (Zhan et al, 2006).

Acknowledgement

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Author contributions
  8. References

This work was supported in part by a program project grant from the National Cancer Institute (CA55819).

Author contributions

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Author contributions
  8. References

Performed research: M. Pineda-Roman, V. Arzoumanian, E. Anaissie, F. van Rhee, M. Zangari, R. Walker, K. Hollmig, J. Shaughnessy, J. Epstein, B. Barlogie. Analyzed data: V. Bolejack, J. Crowley. Designed research: J. Shaughnessy, B. Barlogie. Wrote paper: B. Barlogie.

References

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Author contributions
  8. References
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