KRd as maintenance therapy: results from the ATLAS trial

In patients with newly diagnosed multiple myeloma (NDMM), lenalidomide is the preferred choice for maintenance therapy after autologous stem cell transplantation (ASCT). Currently, there are limited data from phase III trials surrounding any alternatives to lenalidomide as a form of post-ASCT therapy.

Below, we summarize an interim analysis from the phase III, open-label, randomized ATLAS trial investigating carfilzomib, lenalidomide and dexamethasone (KRd) versus lenalidomide alone (R) for the treatment of NDMM after ASCT, recently published in The Lancet Oncology by Dytfeld et al.

Study design

In total, 180 patients across 12 academic and clinical centers in the USA and Poland were randomized at a 1:1 ratio in block sizes of four and six to receive KRd or R. The study protocol is outlined in Figure 1.

IV, intravenous; KRd, carfilzomib, lenalidomide, and dexamethasone; MRD, measurable residual disease; R, lenalidomide monotherapy.
*Adapted from Dytfeld, et al.^1
†Patients in the combination treatment group with no detectable MRD after Cycle 6 and standard risk cytogenetics were switched to R (best tolerated dose up to 15 mg) as of Cycle 9. This was done to limit toxic effects and financial burden on patients.

The eligibility criteria for enrolled patients are shown in Figure 2.

ASCT, autologous stem cell transplantation; ECOG, Eastern Cooperative Oncology Group;
*Adapted from Dytfeld, et al.¹

Results

• The primary endpoint was progression free survival (PFS) from randomization to disease progression or death.
• Secondary endpoints included the rate of measurable residual disease (MRD) negativity at Months 6, 12, 18, 24, and 36, duration of MRD, depth of response, overall survival, and safety.
• The baseline patient characteristics were well balanced between the two treatment groups (Table 1).

Table 1. Baseline patient characteristics*

ASCT, autologous stem cell transplantation; ECOG, Eastern Cooperative Oncology Group; ISS, international staging system; KRd, carfilzomib, lenalidomide, and dexamethasone; R, lenalidomide monotherapy. *Adapted from Dytfeld, et al.1 †Presence of del(13)(q14), t(4;14)(p16;q32), t(14;16)(q32;q23), del(17)(p13.1), or hypodiploidy. ‡Other induction regimens included carfilzomib, lenalidomide, and dexamethasone; bortezomib and dexamethasone; bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide; bortezomib, doxorubicin, and dexamethasone; and bortezomib, lenalidomide, and dexamethasone.
Characteristic, % (unless otherwise stated)	KRd (n = 93)	R (n = 87)
Median age, years	57	59
Sex
Female	53	40
Male	47	60
ECOG Performance Status, %
0	49	38
1	51	62
ISS stage
I	42	32
II	42	48
III	16	20
Cytogenetic profile
Standard risk	77	79
High risk†	23	21
Median time from ASCT, days	92	98
Type of induction
Bortezomib, thalidomide, and               dexamethasone	69	61
Bortezomib, cyclophosphamide, and               dexamethasone	15	20
Other‡	16	20
Previous treatment
Lenalidomide-containing regimen	11	13
Carfilzomib-containing regimen	4	6
Number of induction regimens
1	92	94
2	8	6

Efficacy

After a median follow-up of 33.8 months,

• 41% of patients from the KRd group had discontinued treatment compared with 57% of patients in the R group;
• dose reductions occurred in 34% of patients in the KRd group and 40% of patients in the R group;
• after Cycle 8, 44% of patients in the KRd group had switched to the R group;
• PFS was higher in the KRd group compared with the R group (Table 2);
• patients with standard risk cytogenetics in the KRd group had a longer PFS vs patients with standard risk in the R group (median not reached vs 65.5 months); and
• overall survival was not significantly different between the two treatment groups (Table 2).

No significant difference in the depth of response was observed between the two groups.

• Improvement in depth of response at 6 months post-ASCT was observed in 54% of patients in the KRd group and 44% of patients in the R group (p = 0.18).
• A higher percentage of patients recorded a complete response or better in the KRd group compared with the R group (Figure 3).
• The rate of MRD negativity after 6 cycles was higher in patients in the KRd group compared with the R group (Figure 3).
• MRD was assessed by centralized next-generation sequencing; if this was unavailable, centralized and standardised multiparametric flow cytometry was used.

Table 2. Survival outcomes in the KRd and R patient groups*

KRd, carfilzomib, lenalidomide, and dexamethasone; NR, not reached; OS, overall survival; PFS, progression-free survival; R, lenalidomide monotherapy. *Adapted from Dytfeld, et al.1
Outcome, months	KRd	R	p value
Median PFS	59.1	41.4	0.012
Median OS	NR	61.8	0.68

CR, complete response; MRD, measurable residual disease; KRd, carfilzomib, lenalidomide and dexamethasone; R, lenalidomide monotherapy.
*Adapted from Dytfeld, et al.¹

Safety

Grade 1/2 adverse events (AEs) were more common in the KRd group compared with the R group (93% and 83%, respectively).

• The most common Grade 1/2 hematologic AEs were thrombocytopenia, lymphopenia, and anemia (Figure 4).
• The most common Grade 1/2 non-hematologic AEs were upper respiratory tract infection, fever, and aminotransferase increase (Figure 4).

Grade 3/4 AEs occurred in 76% and 73% of patients in the KRd and R group, respectively; these included neutropenia, thrombocytopenia, and lower respiratory tract infection (Figure 5). AEs that led to treatment discontinuation were recorded in 4% of patients in the KRd group and 12% in the R group. Serious AEs were experienced by 28% of patients in the KRd group and 22% in the R group, the most common being lower respiratory tract infection (12% and 3%, respectively).

There was one treatment-related death, this was due to respiratory failure from pneumonia experienced by a patient in the KRd group. Two patients treated in the KRd group and one patient in the R group recorded secondary primary malignancies.

AE, adverse event; KRd, carfilzomib, lenalidomide, and dexamethasone; R, lenalidomide monotherapy; URTI, upper respiratory tract infection.
*Adapted from Dytfeld, et al.¹

 

AE, adverse event; KRd, carfilzomib, lenalidomide, and dexamethasone; LRTI, lower respiratory tract infection; R, lenalidomide monotherapy.
*Adapted from Dytfeld, et al.¹

Conclusion

Overall, these findings outline the potential of KRd as a treatment for patients with NDMM. After 6 cycles of therapy, a higher percentage of patients achieved negative MRD-status and longer PFS in the combination group compared with lenalidomide-only treatment. The authors noted several limitations of this study, including the interim nature of the analysis and the low number of patients; although sufficient for the evalution of PFS, low patient numbers prevented statistical analysis among subgroups. Longer follow-up and MRD monitoring will further elucidate the efficacy of triplet-based maintenance and the safety of MRD-guided treatment reduction.