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Long-term outcomes of patients with MM after bortezomib, lenalidomide, and dexamethasone induction therapy

May 19, 2020

Bortezomib, lenalidomide, and dexamethasone (VRD) combination is widely used as an induction regimen for patients with newly diagnosed multiple myeloma (NDMM). Phase III trials have shown its effectiveness in both transplant-eligible and ineligible patients. However, follow-up in these trials has been relatively short, and the type of maintenance therapy used varied, making it hard to determine long-term outcomes accurately.

In this study, published in the Journal of Clinical Oncology, Nisha S Joseph et al. present the results of a long-term follow-up from the largest cohort of patients with NDMM, treated uniformly with VRD as induction therapy. The authors report key information on long-term outcomes in different subgroups of patients, including older patients (≥ 65 years) eligible for transplantation and those with high-risk cytogenetics. 1

Study design

  • Primary endpoint: Progression-free survival (PFS)
  • Secondary endpoints: Overall survival (OS), response according to the International Myeloma Working Group definition
  • Cytogenetic abnormalities, such as t(4;14), t(14;16), and del(17p), were detected by fluorescence in situhybridization (FISH) analysis
  • Genetic risk-stratification and response assessment was defined using the International Myeloma Working Group classification

The study retrospectively analyzed 1,000 patients with NDMM who had been uniformly treated with VRD as induction therapy between January 2007 and August 2016. After induction, the majority of patients (n = 751) underwent autologous stem cell transplantation (ASCT) followed by risk-adapted maintenance (n = 620):

  • Standard-risk patients received single-agent maintenance therapy: Lenalidomide (76%), bortezomib (5%), or other (3%)
  • High-risk patients received a combination of a proteasome inhibitor and an immunomodulatory drug (16%)

On the other hand, a small subgroup of patients with a standard-risk disease, who achieved very good responses to VRD (n = 168), deferred ASCT until the first relapse. While in response after induction, most of these patients (n = 119) received maintenance therapy with lenalidomide (95%).  

Results

At data cutoff, the median follow-up time was 67 months. Table 1summarizes patient characteristics at baseline. The authors highlight that 35.2% of the patient population was African American, consistent with their demographics, but unusual in published MM studies.

After a median of four cycles of VRD (2–15), almost every patient had an evaluable response (overall response rate, 97.1%), and in line with previously reported prospective clinical trials, the responses deepened after ASCT ( Table 2).

Table 1. Patient characteristics 1

ASCT, autologous stem cell transplant; ISS, International Staging System

Characteristic

Number of patients (%)

N = 1,000

Median age, years (range)

61 (16–83)

≥ 65 years

340 (34.0)

Cytogenetic risk status

Standard risk

633 (63.3)

High risk

251 (25.1)

Missing

116 (11.6)

ISS staging

I

344 (34.4)

II

231 (23.1)

III

176 (17.6)

Missing

116 (11.6)

ASCT

Up-front

751 (75.1)

Deferred

168 (16.8)

Table 2. Responses to treatment 1

ASCT, autologous stem cell transplant; CR, complete response; ORR, overall response rate; PD, progressive disease; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response

Response  (%)

Post-induction  (n = 977)

Day 100 after up-front ASCT  (n = 742)

sCR

3.9

33.7

sCR + CR

35.9

71.0

³ VGPR

67.6

89.9

ORR

97.1

98.5

SD

1.5

0.3

PD

1.1

1.2

The estimated median PFS for the whole cohort was 65 months (95% CI, 58.7–71.3 months) and the median OS for the whole cohort was 126.6 months (95% CI, 113.3–139.8 months). Univariable analysis of patient outcomes by subgroup is reported in Table 3.

Table 3. Progression-free survival and overall survival by subgroup 1

ASCT, autologous stem cell transplant; CI, confidence interval; HR, hazard ratio; ISS, International Staging System; OS, overall survival; PFS, progression-free survival
*Patients who went for deferred transplantation were removed from this analysis

 

Median PFS (months)

HR
(95% CI)

p value

Median OS (months)

HR
(95% CI)

p value

Age

 

 

 

 

 

 

 < 65 vs≥ 65

 

65.71 vs58.19

1.08
(0.88–1.32)

0.468

129.05 vs100.40

1.50
(1.19–1.91)

< 0.001

Cytogenetic risk

 

 

 

 

 

 

Standard vshigh

76.52 vs40.25

2.28
(1.86–2.79)

< 0.0001

NR vs78.16

2.60
(2.04–3.33)

< 0.0001

ISS

 

 

 

 

 

 

I/II vsIII

73.86 vs50.69

1.67 (1.31–2.12)

< 0.0001

129.84 vs95.34

1.87

(1.41–2.49)

< 0.0001

ASCT*

 

 

 

 

 

 

Yes vsno

65.45 vs29.01

3.03 (2.09–4.39)

< 0.0001

123.37 vs42.55

4.05
(2.91–5.65)

< 0.0001

Maintenance

 

 

 

 

 

 

Yes vsno

65.45 vs47.02

1.38 (1.10–1.72)

0.005

129.84 vs81.15

2.48 (1.94–3.15)

< 0.0001

Conclusion

Nisha S Joseph et al. report the long-term outcomes of the largest cohort to date of patients with NDMM treated with VRD induction therapy. These results demonstrate the ability of VRD as induction therapy to offer deep responses and positively impact on survival.

Response rates observed in this analysis are comparable to those in the GEM2012/MENOS65and the IFM2009 randomized, controlled phase III trials, 2,3and the authors expect that both will report similar survival outcomes to this real-world retrospective study. Significant limitations that will affect future comparisons are fewer timepoints for assessment and no data on safety and minimal residual disease.

Interestingly, this cohort included a higher number of patients older than 65 years old, commonly excluded from transplantation-eligible clinical trials. Their response to induction and ASCT was as good as younger patients, and age itself was not an independent predictor of decreased PFS, confirming that age alone should not be used as a criterion for transplantation eligibility.

Consistent with previous publications, high-risk patients experienced a shorter PFS and OS compared with standard-risk patients, although achieving similar responses. Nevertheless, the risk-adapted algorithm benefited these patients: PFS and OS amongst high-risk patients were improved with maintenance therapy using a proteasome inhibitor and immunomodulatory drug compared with no maintenance (42.1 vs16.2 months [p = 0.007]; 91.3 vs23.6 months [p < 0.0001], respectively).

The authors highlight that the significantly shorter OS in patients not receiving maintenance, regardless of cytogenetic risk, might also reflect the importance of not saving therapies for later stages of disease, since doing so reduces their impact on survival.

A further analysis on VRD and future induction regimens for transplant-eligible patients with NDMM can be found here.

  1. Joseph NS, Kaufman JL, Dhodapkar MV, et al. Long-term follow-up results of lenalidomide, bortezomib, and dexamethasone induction therapy and risk-adapted maintenance approach in newly diagnosed multiple myeloma. J Clin Oncol. 2020. DOI: 10.1200/JCO.19.02515

  2. Rosiñol L, Oriol A, Rios R, et al. Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplant in multiple myeloma. Blood. 2019;134(16):1337-1345. DOI: 10.1182/blood.2019000241

  3. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. DOI: 10.1056/NEJMoa1611750