Overall, at the time of data extraction, there were 8600 patients in the CMRG database. 4713 patients started first-line treatment as induction with intent for ASCT. Patients who did not eventually receive ASCT were removed (442 patients). Only patients who commenced first-line induction therapy between January 2007 and December 2021 were included, leaving 3821 patients for the analysis.
Population characteristics
Baseline characteristics of the 3821 patients were stratified by single or tandem ASCT and are shown in Table 1. Overall, the median age was 61 years, and the majority were male. Race or ethnicity was not available. Sixteen percent of the patients presented with significant renal insufficiency (serum creatinine >177 umol/L). The median time from start of the induction therapy to ASCT was 5.6 months (25–75 percentile: 4.8 to 6.8 months). Most patients received a single ASCT (92%), while 8% received a tandem ASCT. The single and tandem ASCT groups were well balanced except for elevated LDH, higher median beta 2-microglobulin value, ISS/R-ISS stage III and high-risk cytogenetics which were, respectively, more frequent in the tandem ASCT group. Among the entire population, cytogenetic risk data was unknown or missing for 49.8% of the patients. For those of whom cytogenetic risk data was available, 36.7% were high-risk FISH cytogenetics and 63.3% were standard-risk. The majority of patients who underwent tandem ASCT (84%) had documented high-risk cytogenetics.
Induction therapy and ASCT
The majority of the 3821 patients (82%) received a bortezomib-based induction regimen, primarily CyBorD (cyclophosphamide, bortezomib and dexamethasone), in 72.1% (Table 2). Only 1.6% of the patients received an induction therapy with combination of a proteasome inhibitor (PI) and an immunomodulatory derivative (IMiD). For the most frequently used induction regimen, namely CyBorD, the ORR was 92% with 60.4% achieving ≥VGPR. Overall, for the entire cohort, the ORR was 90.7%, with a ≥VGPR rate of 55.5%.
Because of suboptimal response or progression on first induction, and based on physician decision, 10% of the patients received a second induction regimen before proceeding to ASCT (Table 3). Only four of them needed a third induction (4/376; 1%). The median time from the start of the second induction regimen to ASCT was 4.2 months (25–75 percentile: 3.1–5.7 months). Lenalidomide-based regimens were administered to 73.4% of the patients in this subgroup and resulted, as a second-line induction regimen, in an ORR of 78.6% and ≥VGPR rate of 38.4%. Regardless of the regimen used, patients treated with a second induction regimen had an ORR of 72.9% and a ≥VGPR rate of 35.4%.
For evaluable patients, the ORR and ≥VGPR rate were 96.4% and 81.1%, respectively, for the single ASCT subgroup (2984 patients) versus 98.3% and 79.4% respectively for the tandem ASCT subgroup (291 patients).
Consolidation therapy
Only 205 patients (5.3%) received consolidation. The consolidation regimen mostly often consisted of a PI combined with an IMiD (in 72%). Specific consolidation regimens included: lenalidomide + bortezomib +/- steroids in 55.6%, lenalidomide +/- steroids in 21%, lenalidomide + another PI (ixazomib) +/- steroids in 12.2%, carfilzomib + lenalidomide + steroids in 4.4%, bortezomib + steroids +/- cyclophosphamide in 3.9%, and other regimen in 2.9%. Overall, regardless of the consolidation regimen used, the ORR was 90.2%, with a ≥VGPR rate of 76.6% in the 205 patients. The median duration of consolidation therapy was 63 days (lower (25%) and upper (75%) quartiles: 56 days and 106 days). Most of the patients receiving consolidation also received maintenance therapy (90.7%).
Maintenance therapy
In the entire cohort, 2061 patients (54%) received maintenance therapy. The following individual regimens were: lenalidomide +/- steroids in 78.3%, bortezomib +/- steroids in 2.9%, lenalidomide + bortezomib +/- steroids in 1.7%, another PI (ixazomib) +/- steroids in 1.6%, lenalidomide + another PI (ixazomib) +/- steroids in 5.5% and thalidomide +/- steroids in 8.5%. In the 1614 evaluable patients receiving maintenance with lenalidomide +/- steroids, the best ORR was 95.5%, with a ≥VGPR rate of 89.7%
Most of the maintenance patients receiving a combination of lenalidomide and bortezomib +/- steroids (33/36 evaluable patients, 91.7%) or bortezomib +/- steroids (37/47 evaluable patients, 78.7%) were high-risk by cytogenetic classification. Conversely, for the lenalidomide +/- steroids subgroup, only 28.5% were considered as high-risk (278/976 evaluable patients) while 71.5% were standard-risk (698/976 evaluable patients) (cytogenetic risk data was unknown for the remaining patients). Of note, 278 patients in the high-risk cytogenetics subgroup (62.8%) received a lenalidomide-based maintenance regimen (lenalidomide +/- steroids).
Of the 2061 patients that received any maintenance regimen, 1173 patients (56.9%) had already discontinued treatment at time of study datalock; the median duration on maintenance therapy for these individuals was 15.7 months (0.1–154 months). For evaluable patients receiving any maintenance therapy (926 patients), median treatment duration was 17.6 months (0.1–122.5 months). For the 859 patients (41.7%) that discontinued maintenance with lenalidomide + /- steroids, the median duration of maintenance was 17.8 months (0.1–122.6 months). The reasons for discontinuation of most common maintenance therapy are summarized in Table 4. Disease progression was the most common reason for discontinuation of maintenance (61.0%), and the median maintenance duration for these 716 patients was 18.8 months (0.5–154 months); the median duration of maintenance was 9.4 months (0.1–122.6 months) for the 363 patients (31.5%) who discontinued for toxicities, secondary malignancies, and death.
Outcomes
Outcomes according to different ASCT components and cytogenetic risk category are summarized in Table 5.
The median PFS and OS for all patients with a single ASCT as frontline therapy were 35.4 months (95% CI 33.7-37.3) and 126 months (95% CI 120–138), respectively. In high-risk FISH patients, the median PFS for single vs tandem ASCT was 25.1 vs 35.4 months (p = 0.01) and median OS, 91.5 vs 84.4 months (p = 0.008), respectively. For those without high-risk FISH, median PFS and OS for single vs tandem ASCT were, respectively, 46.5 vs 33.8 months (p < 0.001) and 158.6 vs NYR (not yet reached). For patients with standard-risk MM receiving a single ASCT and any type of maintenance therapy, the median PFS and median OS were 54.7 months (95% CI 47.9–60.3) and 164.2 months (95% CI 158.4-NYR). For patients with high-risk MM receiving a tandem ASCT and any type of maintenance therapy, the median PFS and OS were 35.3 months (95% CI 26.2–47.8) and 84.1 months (95% CI 69.7–133). Looking only at the high-risk patients receiving any type of maintenance therapy, the median PFS for single vs tandem ASCT was 36.7 vs 35.3 months (p = 0.80) and median OS, 99.8 vs 84.1 months (p = 0.70), respectively.
Those given a second induction regimen had significantly inferior outcomes (median PFS 27.9 vs 36.2 months [p = 0.001]; median OS 118 vs 126 months [p = 0.011]), although when maintenance was used, results were comparable regardless of the number of induction regimens administered (median PFS 55.3 vs 51.1 months [p = 0.11]; median OS 158.6 months vs NYR [p = 0.13]). For patients receiving any type of maintenance therapy, the median PFS and OS for one vs two induction regimens were, in standard-risk patients, 55.1 vs 47.1 months (p = 0.08) and 164 months vs NYR (p = 0.90), respectively, and in high-risk patients, 35.6 vs 36.5 months (p = 0.80) and 97.0 vs 84.1 months (p = 0.50), respectively.
Consolidation patients had a longer median PFS (55.3 vs 34.4 months [p = 0.001]), but no significant gain in median OS (p = 0.065). For the standard-risk patients, the median PFS was 45.9 months (95% CI 41–50.8) when no consolidation was given versus 52.2 months (95% CI 43.9–78.3) when consolidation was administered (p = 0.01). Median OS in this subgroup was 164.4 months (95% CI 147.1-NYR) vs NRY (95% CI 114-NRY), respectively, (p = 0.5). For the high risk population, the median PFS was 26.6 months (95% CI 23.6-32) when no consolidation was given versus 42.4 months (95% CI 26.7-NRY) when consolidation was given (p = 0.002). Median OS in this subgroup was 87.9 months (95% CI 76.4-103) vs NRY (95% CI 68.5-NRY) respectively (p = 0.6).
For the maintenance vs non-maintenance cohorts, respectively, when all types of maintenance were included, the median PFS and median OS were 48.8 vs 24.5 months (p < 0.001) and 159 vs 105 months (p < 0.001) (Fig. 1). For patients receiving lenalidomide, bortezomib or both (+/- steroids), the median PFS was 53.7 months vs 43.5 months vs 48.2 months, respectively, while the median OS was 159 months vs 115 months vs NYR, respectively. Amongst patients receiving such maintenance, outcomes for patients with known high-risk FISH were compared with those without documented high-risk cytogenetics. The median PFS was 36.6 months (95% CI 32.2-47.5) vs 54.7 months (95% CI 47.9-60.3), and the median OS was 97.4 months (95% CI 87.9-NRY) vs 164.4 months (95% CI 158.6-NRY), respectively. The subgroup of patients with known high-risk FISH and no maintenance therapy did poorly with a median PFS of only 13.4 months (95% CI 11.9–18.8) and a median OS of 63.5 months (95% CI 52.3–82.9). In all risk subgroups, the use of maintenance therapy was associated with better outcomes (p < 0.0001). For patients receiving lenalidomide-based maintenance, those who discontinued due to progressive disease had a median PFS of 25 months (95% CI 23.2–27.4) and a median OS of 94 months (95% CI 83–106).
Although some patients received maintenance therapy, including lenalidomide or PIs via mechanisms such as private drug insurance or limited access programs, PFS and OS were also calculated before and after 2013, the year that lenalidomide maintenance until progression was funded throughout Canada and therefore widely accessible (Supplementary Fig. 1). A statistically significant improvement for PFS and OS was identified after 2013 compared to the previous era: median PFS 48.8 versus 24.5 months and OS 159 versus 105 months, respectively (p < 0.0001 for both). Thus, universal access to lenalidomide maintenance positively influenced national outcomes of myeloma among transplanted patients.
Univariable and multivariable analysis for PFS and OS
Table 6 summarizes the results of the univariate and multivariable analysis. In the multivariable analysis for PFS, the disease features significantly associated (p < 0.001) with a less favourable PFS included a high beta 2-microglobulin level (HR 1.23 [95% CI 1.10–1.37]) and high-risk cytogenetics (HR 1.56 [95% CI 1.36–1.78]); the administration of ≥2 induction regimens was also associated with an inferior PFS (HR 1.35 [95% CI 1.17–1.56]) while the use of maintenance was correlated with a significantly longer PFS (HR 0.56 [95% CI 0.47–0.57] p < 0.001). Multivariable analysis of OS identified increasing age (HR 1.02 [95% CI 1.00–1.28]), LDH > 250 U/L (HR 1.51 [95% CI 1.27–1.78]) and high-risk cytogenetics (HR 1.91 [95% CI 1.60–2.28]) as adverse factors, while patients who received any type of maintenance therapy vs no maintenance experienced a significantly better OS (HR 0.58 [95% CI 0.51–0.67]).
Looking at only maintenance with lenalidomide +/- steroids versus no maintenance as predictors, the multivariate analysis was still significant for the risk of progression (HR 0.48 (95% CI, 0.43–0.53)) as well as the risk of death (HR 0.53 (95% CI, 0.46–0.62)), favoring maintenance therapy in lowering those risks. The same tendency was observed when looking at other maintenance regimens versus no maintenance with a HR of 0.67 (95% CI, 0.58–0.77) for the risk of progression and of 0.73 (95% CI, 0.60–0.89) for the risk of death, also favouring maintenance therapy (Supplementary Table 1).