Completion of premaintenance phases in total therapies 2 and 3 improves clinical outcomes in multiple myeloma

An important variable to be considered in clinical trial designs

Authors


  • Bart Barlogie and John Crowley conceptualized the work and wrote the article. Douglas Steward, Jennifer Gurley, and Bonnie Jenkins collected and verified data. Jeff Haessler and John Crowley analyzed data. Bart Barlogie, Mauricio Pineda-Roman, Elias Anaissie, Jeff Haessler, Frits van Rhee, and Elias Kiwan enrolled and treated patients on research protocols.

Abstract

BACKGROUND.

Total Therapy (TT) programs are complex and their execution over the course of several years is fraught with patient attrition due to failure and toxicity of therapy and patient/physician acceptance.

METHODS.

The impact of completion versus noncompletion of intended treatment steps was examined in protocols TT2 (n = 668) and TT3 (n = 303) on overall survival (OS) and event-free survival (EFS).

RESULTS.

By using appropriate landmarks of 36 months with TT2 and 18 months with TT3, representing the maxima to completion of premaintenance phases, postconsolidation OS was superior for 211 patients completing versus 311 patients not completing premaintenance steps on TT2 (P = .001), which also pertained to the 161 patients completing versus 47 not completing intended treatment steps on TT3 (P = .01). On multivariate analysis that included all patients, completion of therapy independently favored longer OS and EFS in the context of both standard prognostic factors and gene expression profiling-defined risk; in addition, TT3 prolonged EFS over results obtained with TT2.

CONCLUSIONS.

1) Completion of intended therapy was a significant independent variable conferring superior OS and EFS in TT programs; and 2) after adjusting for completion of therapy, EFS was still superior with TT3 versus TT2, supporting the beneficial role of bortezomib included in TT3. Collectively, these data point to the importance of designing clinical trials that balance the treatment requirements for disease control with host acceptance and tolerance. Cancer 2008. © 2008 American Cancer Society.

Our Total Therapy (TT) programs, modeled after those of St. Jude Hospital for children with acute leukemia, have been geared to bring to the frontline the entire treatment armamentarium available at any given time in an effort to maximally reduce tumor burden and thus avoid the development of resistance.1 Appreciating that multiple myeloma (MM) is a more hypoproliferative tumor than many other hematologic malignancies, the onset of complete remission (CR) occurs gradually over the course of 12 months to 18 months despite the use of high-dose therapy.2, 3 TT protocols used remission induction therapy, followed by melphalan (MEL)-based tandem transplants and maintenance treatment. In TT2 we introduced more intensive, hematopoietic growth factor-requiring induction regimens before and, for the first time, consolidation chemotherapy after transplants, before the maintenance phase.4 Thus, the TT protocols are very complex and their execution over the course of several years is fraught with patient attrition due to failure and toxicity of therapy and patient/physician acceptance. We therefore pondered the question whether patients' clinical outcome depended on the rate of compliance with intended protocols, which was determined by patient and physician preference, toxicities incurred, and insurance/financial considerations.

MATERIALS AND METHODS

Treatment Details

Regimen details of TT2 and TT3 have recently been published4–7 and their essential features are summarized in Figure 1. Briefly, TT3 used abbreviated induction and consolidation therapies with 2 rather than 4 cycles each in TT2, on the assumption that the addition of bortezomib (V) to DT-PACE (dexamethasone [DEX], thalidomide [THAL], cisplatin, doxorubicin, cyclophosphamide, etoposide) in VDT-PACE would be highly synergistic so that comparable antitumor activity would be delivered with 2 rather than 4 cycles. As a result, we anticipated and indeed accomplished higher compliance with both transplants so that the intended therapies could be delivered to a higher proportion of patients. Drug-free phases of TT2 were ‘bridged’ by THAL-DEX in an effort to suppress the potentially MM-stimulatory signals associated with postchemotherapy hematopoietic recovery. Finally, bortezomib was combined with THAL-DEX in VTD, which was applied in monthly cycles during the first year of maintenance, followed by THAL-DEX for 2 more years. In TT2, maintenance was comprised of interferon with added DEX pulsing during the first year; in case of randomization to THAL, the drug was continued indefinitely until disease progression or untoward toxicity.

Figure 1.

Treatment schema for Total Therapy (TT) TT2 and TT3 (for details of regimens, see References4–6).

We now examine the impact of completion versus noncompletion of all intended treatment steps in complex protocols TT2 (n = 668) and TT3 (n = 303) on clinical outcomes per protocol and across protocols.

Laboratory Investigations

Protocol-directed laboratory monitoring for response and toxicities was applied with both trials as reported previously.4, 6 Standard laboratory studies included hemogram and multichemical scans. Cytogenetic abnormalities (CAs) were detected by metaphase analysis of Giemsa-banded chromosomes in 20 cells.8 By using the Affymetrix platform,9 gene expression profiling (GEP) was performed on CD138-purified plasma cells to establish a risk score applying a 70 gene model, as recently published.10

Clinical Endpoints of Study

Response and relapse definitions used criteria similar to those reported by Blade et al.7, 11 CR required the absence of M-protein in serum and urine on immunofixation analysis as well as normal bone marrow aspirate and biopsy by microscopy and flow cytometry (absence of aneuploidy and monoclonal cytoplasmic light chain); in addition, metaphase CAs had to be absent. Response criteria had to be documented on at least 2 subsequent occasions at least 2 months apart. Relapse from CR suggested the reappearance of M-protein in serum or urine on immunofixation, reappearance of monoclonal bone marrow plasmacytosis or of CA, the development of extramedullary disease or of new bone lesions recognized on at least annually performed magnetic resonance imaging (MRI) or skeletal survey. Nonsecretory relapses in the absence of M-protein recurrence also constituted relapse, such as new focal lesions on MRI or positron emission tomography (PET) / computed tomography (CT) scan, reemergence of bone marrow monoclonal plasmacytosis, or extramedullary disease often associated with elevated levels of lactate dehydrogenase (LDH).

Statistical Methods

The Kaplan-Meier Method was used in estimating event-free survival (EFS) and overall survival (OS),12 with group comparisons made using the log-rank test. EFS was defined as the time from the date of registration to death from any cause, disease progression, or relapse. Patients experiencing no event were censored at the time of last contact. OS was defined from the date of registration until death from any cause; survivors were censored at the time of last contact. The cumulative incidence of CR was estimated using the method outlined in Gooley et al.13; results of different trials were compared using the log-rank test. Multivariate models of prognostic factors were carried out using Cox regression.14

Informed Consent

Both the TT3 and TT2 protocols were approved by the Institutional Review Board and the Food and Drug Administration. Patients signed an informed consent indicating that they understood the investigative nature of the trials along with treatment alternatives, in keeping with Institutional Review Board, National Institutes of Health, and Food and Drug Administration policies.

Audits of Response and Toxicity Data

Response and toxicity details had been monitored by an independent certified audit team that reviewed data on 285 of 303 patients enrolled in TT3 and on 651 of 668 patients enrolled in TT2. A Safety and Monitoring Board reviewed data twice and gave permission for article submission.

RESULTS

Patient Characteristics

Data presented in Table 1 show that prognostically relevant parameters were similar in patients treated on TT3 and TT2 regimens. Notably, the proportions of patients with CA as the major standard adverse prognostic feature in our TT trials were in the 30% range, and GEP-defined high-risk percentages were virtually identical in TT2 and TT3 protocols. Differences were observed with regard to greater representation of patients in TT3 who were older than 65 years of age, had advanced International Staging System for multiple myeloma (ISS) stage II, anemia, elevation of beta-2 microglobulin (B2M) levels and hypoalbuminemia; also, higher C-reactive protein (CRP) levels were more frequent in TT2. The median follow-up of live patients on TT3 is 2 years and on TT2 5 years.

Table 1. Patient Characteristics
FactorTT3 (%)TT2 (%)P
  1. TT3 indicates total therapy protocol 3; TT2, total therapy protocol 2; CRP, C-reactive protein; B2M, beta-2-microglobulin; Hb, hemoglobin; LDH, lactate dehydrogenase; ISS, International Staging System for multiple myeloma; GEP, gene expression profiling.

Male sex193/303 (64)396/668 (59).192
Age ≥ 65 yr84/303 (28)136/668 (20).011
CRP > 8 mg/L100/302 (33)261/658 (40).052
B2M ≥ 3.5 mg/L135/302 (45)243/668 (36).014
B2M > 5.5 mg/L64/302 (21)122/668 (18).283
Bone marrow plasma cells > 30%162/269 (60)314/547 (57).443
Albumin < 3.5 g/dL74/303 (24)119/664 (18).019
Hb < 10 g/dL94/303 (31)161/667 (24).024
Creatinine ≥ 2 mg/dL23/303 (8)62/654 (9).339
LDH ≥ 190 U/L81/303 (27)204/666 (31).217
ISS stage 1140/302 (46)374/664 (56).004
ISS stage 298/302 (32)169/664 (25).024
ISS stage 364/302 (21)121/664 (18).277
Cytogenetic abnormalities (CA)100/302 (33)197/661 (30).302
GEP high risk40/275 (15)46/351 (13).603

Clinical Outcomes According to the Completion of Protocol Steps

Thirty-six months were required to complete all premaintenance steps in TT2 and only 18 months in TT3 (Fig. 2). Postmaintenance OS in TT2 (36 months landmark) was superior for the 211 patients completing versus the 311 patients not completing premaintenance steps (P = .001), which pertained regardless of the absence (P = .04) or presence of CAs (P = .03) (Fig. 3a–c). Postmaintenance OS in TT3 (18 months landmark) was also superior among the 161 patients who completed versus the 47 who did not complete premaintenance steps (P = .01), pertaining especially to those with CA (P = .006) (Fig. 3d-f). Comparing TT3 versus TT2 outcomes and using a joint landmark of 27 months (mean of maxima to maintenance for TT2 and TT3), 1-year postlandmark EFS estimates were 98% with TT3 versus 90% with TT2 (P = .04) (Fig. 4a); OS was not different (Fig. 4b).

Figure 2.

Completion times of premaintenance protocol steps in Total Therapy 2 (TT2) and TT3. Provided are the cumulative proportions of patients completing induction cycle 2 on (A) TT3 and (B) TT2; first transplant on (C) TT3 and (D) TT2, second transplant on (E) TT3 and (F) TT2; consolidation cycle 1 on (G) TT3 and (H) TT2; and initiated maintenance on (I) TT3 and (J) TT2.

Figure 3.

Overall survival according to completion of premaintenance protocol steps. a: All Total Therapy 2 (TT2) patients, 36 months landmark: (a) completed and (b) did not complete protocol steps. b: TT2 according to cytogenetic abnormalities, present (CA) versus absent (no CA), from 36 months landmark: (a) protocol steps completed without CA; (b) protocol steps completed with CA; (c) protocol steps not completed without CA; (d) protocol steps not completed with CA. Note the superior postlandmark survival among patients completing protocol steps without CA (a vs c) and with CA (b vs d). c: All TT3 patients, 18 months landmark: (a) completed and (b) did not complete protocol steps. d: TT3 according to cytogenetic abnormalities present (CA) versus absent (no CA), from 18 months landmark: (a) protocol steps completed without CA; (b) protocol steps completed with CA; (c) protocol steps not completed without CA; (d) protocol steps not completed with CA. Note the superior postlandmark survival among patients completing protocol steps with CA (b vs d).

Figure 4.

Comparison of postlandmark clinical outcomes (27 months as the mean of maxima to completion of premaintenance phases in Total Therapy [TT] TT2 and TT3) in TT3 versus TT2. a: Event-free survival. b: Overall survival.

In a multivariate analysis of postmaintenance outcomes, completion of therapy independently favored longer OS, whether examined in the context of standard prognostic factors (SPFs) (hazard ratio [HR] = 0.50, P < .001) or with added information on GEP-defined risk (HR = 0.46, P = .003); similar results pertained to EFS (Table 2). Additional independently significant variables were baseline CA, GEP-defined risk, LDH and creatinine for both OS and EFS, along with CR as a favorable time-dependent variable. EFS was also significantly prolonged by TT3 versus TT2, supporting a critical contribution of bortezomib to TT3's success.

Table 2. Multivariate Analysis of Features Associated With Overall Survival (OS) and Event-free Survival (EFS)
SPFOverall survivalEvent-free survival
n/N (%)HR (95% CI)Pn/N (%)HR (95% CI)P
  • P from Wald chi-square test in Cox regression multivariate model used stepwise selection with entry level 0.1 and the variable remained if it met the .05 level. A multivariate P>.05 indicates a variable was forced into the model with significant variables chosen by using stepwise selection. Other univariately significant variables were age, creatinine, Hb, and CRP.

  • HR indicates hazard ratio, 95% CI, 95% confidence interval; SPF, standard prognostic factors; TT2, total therapy protocol 2; B2M, beta-2-microglobulin; LDH, lactate dehydrogenase; GEP, gene expression profiling; NA, not available.

  • *

    Time-dependent variables.

Enrolled in TT2634/934 (68)1.00 (0.69–1.44).997634/934 (68)1.74 (1.26–2.42)<.001
Albumin < 3.5 g/dL194/934 (21)1.44 (1.10–1.90).009194/934 (21)1.37 (1.08–1.75).010
B2M > 5.5 mg/L179/934 (19)1.52 (1.15–2.00).003179/934 (19)1.54 (1.21–1.97)<.001
LDH ≥ 190 U/L276/934 (30)1.75 (1.36–2.24)<.001276/934 (30)1.55 (1.25–1.93)<.001
Cytogenetic abnormalities287/934 (31)1.87 (1.46–2.38)<.001287/934 (31)1.59 (1.29–1.96)<.001
Completed steps*0.50 (0.35–0.72)<.0010.77 (0.58–1.02).073
Complete response*0.47 (0.36–0.62)<.0010.55 (0.44–0.69)<.001
SPF+GEPn/N (%)HR (95% CI)Pn/N (%)HR (95% CI)P
Enrolled in TT2334/607 (55)0.93 (0.61–1.44).759334/607 (55)1.65 (1.14–2.40).008
Creatinine ≥ 2.0 mg/dL58/607 (10)1.66 (1.08–2.56).02158/607 (10)1.56 (1.01–2.40).043
B2M > 5.5 mg/LNANANA127/607 (21)1.42 (1.00–2.02)0.047
LDH ≥ 190 U/L187/607 (31)2.05 (1.45–2.89)<.001187/607 (31)1.64 (1.23–2.17)<.001
Cytogenetic abnormalities202/607 (33)1.93 (1.37–2.72)<.001202/607 (33)1.48 (1.11–1.96).007
GEP high risk84/607 (14)2.88 (1.92–4.34)<.00184/607 (14)2.91 (2.04–4.15)<.001
Completed steps*0.46 (0.28–0.77)0.0030.64 (0.44–0.94).022
Complete response*0.44 (0.30–0.64)<.0010.46 (0.34–0.63)<.001

DISCUSSION

Clinical trial designs need to take into consideration the objectives of therapy and the host for whom the treatment is prescribed. In the case of MM, palliation had been the mainstay of therapeutic intent for decades until, with the advent of autotransplant- supported high-dose melphalan, the emphasis shifted toward prolonging EFS and OS through markedly enhancing the frequency of CR. Once CR rates reached the 50% mark with tandem transplants, the term ‘cure’ could be entertained in earnest, as such levels had been critical to observing continuous CRs and cures in acute leukemia, as a result of profound tumor cytoreduction and lack of regrowth in a subset of such patients.

As we embarked on the TT concepts in 1989 with TT1, the median times to CR onset for those achieving CR status were 8 months in TT1, 10 months in TT2, and 7 months in TT3. In the latter study we purposely shortened induction and consolidation phases before and after tandem transplant, respectively, to attempt to increase compliance with the intended therapies without sacrificing efficacy through the addition of bortezomib, a goal that indeed was accomplished.6, 7

Here we show that completion of premaintenance treatment steps significantly extended OS in both TT2 and TT3, using appropriate 36 months and 18 months landmarks (see Fig. 3a,c). In both protocols we demonstrated that the major benefit of completion of intended therapies was derived by patients with high-risk features as defined by CA in both TT2 and TT3 studies (see Fig. 3b,d). Applying a joint landmark of 27 months for both trials (mean of maxima required in TT3 and TT2 to complete premaintenance steps), we observed that TT3 was superior to TT2 among the subjects completing premaintenance steps in terms of EFS but not OS, which may be an issue in short follow-up (see Fig. 4).

Interestingly, when Cox regression analyses were used to determine whether completion of intended treatment steps was an independent feature for clinical outcome of the entire population, we indeed noted this to be the case for both OS and EFS regardless of risk and how it was defined (by CA or GEP). Attaining CR status independently favored superior OS and EFS in the context of SPF alone and with GEP. Importantly, CA and elevated serum levels of both LDH and creatinine still conferred independently adverse implications for OS and EFS in both models with and without GEP.

We conclude from these observations: 1) completion of intended therapy was an independently significant variable conferring superior OS and EFS in TT programs; 2) attaining CR was beneficial independent of completion of therapy; and 3) the superior performance of TT3 versus TT2 for EFS, independent of completion of intended treatment steps, supports the beneficial role of bortezomib included in TT3. Collectively, these data point to the importance of executing in their entirety clinical trials designed to significantly prolong survival in MM. It will be important to determine whether, in the case of new agent combinations such as MPT (melphalan, prednisone, thalidomide) or MPT with added bortezomib, greater compliance with intended therapies is at least partially responsible for their unexpected high success rate.15, 16

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