KRd plus auto-SCT induces high-quality durable responses in NDMM

Carfilzomib (K) in combination with lenalidomide (R) and dexamethasone (d; KRd) has shown very promising efficacy both in the relapsed multiple myeloma (MM) and newly diagnosed MM (NDMM) setting.¹

To date, the standard of care for the treatment of patients with NDMM is bortezomib in combination with R and d (VRd).¹ This was further supported by the initial results of the phase III ENDURANCE trial (NCT01863550), which was the first head-to-head comparison between VRd and KRd for the NDMM setting.² The results of this pivotal study were recently presented by Shaji Kumar at the 2020 American Society of Clinical Oncology (ASCO) meeting and are summarized at the Multiple Myeloma Hub, here. Briefly, KRd did not seem to improve progression-free survival (PFS) over the standard of care VRd in patients with NDMM. Overall survival (OS) and secondary endpoints, including measurable residual disease (MRD) negativity rates, are yet to be published.² Interestingly, the two triplets have distinct toxicity profiles with the incidence of peripheral neuropathy being higher with VRd, while cardiopulmonary and renal events being mostly associated with KRd.³

Recently, the results of a phase II trial (NCT01816971) that investigated the addition of autologous stem cell transplantation (auto-SCT) to KRd for NDMM, has shed more light into the activity of the triplet in this setting. The study was published in Blood by Jagoda Jasielec et al. and is summarized below. Fundamental differences between the study design of this trial and the ENDURANCE trial are discussed below in the ‘Conclusion’ section.

 Study design

 Multicenter, open-label, single-arm, phase II trial for NDMM transplant-eligible patients aged ≥ 18.

• Patients received:
  • Induction: four 28-day KRd cycles
  • Auto-SCT (conditioning with 200 mg/m² melphalan and granulocyte colony-stimulating factor plus plerixafor for stem cell mobilization 2–4 weeks after last dose of R)
  • Consolidation (within 70–90 days or < 120 days from auto-SCT): four 28-day KRd cycles
  • Maintenance: ten 28-day KRd cycles
• Dosing:
  • K: 20 mg/m² for Day 1 and 2 of Cycle 1, and then 36 mg/m² onwards. It was given on Day 1, 2, 8, 9, 15, and 16, per cycle
  • R: 25 mg on Day 1–21 per cycle
  • d: 40 mg on Day 1, 8, 15, and 22, per cycle
  • For the consolidation phase, K was given at the last tolerated induction dose; R was restarted at 15 mg, and escalated in the following cycles to last tolerated dose; and d was given at the same induction schedule but at a dose of 20 mg
  • All three regimens were administered at their last tolerated dose during the maintenance phase. K was administered on days 1, 2, 15, and 16
• Primary endpoint was the rate of stringent complete response (sCR) following eight KRd treatment cycles plus auto-SCT, with a predefined threshold of ≥ 50%. Secondary endpoints included overall response rate (ORR), PFS, OS, and MRD rates (by next-generation sequencing).
• Patient baseline characteristics are shown below in Table 1. Of note, 36% of patients were classified as high-risk based on the International Myeloma Working Group (IMWG) cytogenetic criteria. Of those, 15% had del(17p) and 11% had ≥ 3 abnormalities (ultra-high-risk subgroup).

 

Table 1. Patient baseline characteristics¹

Baseline characteristic	ITT population (N = 76)
ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; ISS, International Staging System; ITT, intention-to-treat. *Defined according to the International Myeloma Working Group (IMWG) criteria: t(4;14), del(17p), t(14;16), t(14;20), non-hyperdiploidy and 1q gain.
Age
Median age (range), years	59 (40–76)
≥ 65 years, n (%)	21 (27.6)
ECOG PS, n (%)
0–1	65 (85.5)
Unknown	11 (14.5)
ISS stage, n (%)
I	31 (40.8)
II	31 (40.8)
III	10 (13.2)
Unknown	4 (5.3)
Cytogenetic risk by FISH*, n (%)
High	27 (35.5)
Del(17p)	11 (14.5)
Ultra-high (≥ 3 abnormalities)	8 (10.5)
Standard	49 (64.5)

 Key results

•  Of the 76 patients included in the intention-to-treat (ITT) population, 64 completed all 18 treatment cycles; auto-SCT was completed by 72 patients.
• The efficacy outcomes at various treatment stages are shown below in Table 2. Of note, at the primary endpoint of eight KRd cycles plus auto-SCT, the sCR rate was 60% and the ≥ CR rate was 65%. The median time to sCR was 11.9 months (range, 0.9–26.4).
• Response rates were not significantly different when evaluating patients by their cytogenetic risk group, with the best response sCR rate in high-risk patients being 81%.

 

Table 2. Efficacy outcomes with KRd plus auto-SCT for NDMM¹

Responses, %	After auto-SCT (n = 76)	After 8 KRd cycles (n = 72)	After 18 cycles (n = 76)	Best response after KRd + auto-SCT (ITT; n = 76)
Auto-SCT, autologous stem cell transplantation; CR, complete response; ITT, intention-to-treat population; KRd, carfilzomib, lenalidomide, dexamethasone; mITT, modified ITT; MRD, minimal (measurable) residual disease; neg, negative; sCR, stringent CR; VGPR, very good partial response.
MRD neg < 10-5 (in mITT)	—	52	61	70
sCR	20	60	74	76
≥ CR	25	65	75	79
≥ VGPR	84	90	84	91

•  The MRD negativity rate at < 10^-5 was 60% following eight KRd treatment cycles, 70% following 18 KRd cycles, and 81% as best response.
• Most patients remained on R maintenance at the end of the treatment (48/76). At 3 years R maintenance, 76% of patients who completed the last MRD evaluation were MRD negative at < 10^-5.
• Median PFS and OS were not reached at a median follow-up of 56 months (range, 2.9–75.1). The 5-year survival rates can be found in Table 3.

 

Table 3. 5-year survival rates¹

Population	5-year PFS, %	5-year OS, %
ITT, intention-to-treat; MRD, minimal (measurable) residual disease; neg, negative; PFS, progression-free survival; OS, overall survival.
ITT population	72% (95% CI, 60–81)	84% (95% CI, 71–92)
MRD neg at < 10-5	85% (95% CI, 69–93)	91% (95% CI, 75–97)
Standard-risk patients	81%	92%
High-risk patients	57%	72%

•  For high-risk patients, MRD negativity at < 10^-5 was achieved by 72% of patients (in the modified ITT population defined by Perrot et al.⁴) and it was significantly associated with better PFS (p = 0.04), but no significant change in OS was observed (p = 0.26).
• The results in survival outcomes in high-risk patients were not statistically different from the ones achieved by patients with standard-risk cytogenetics, supporting the reported data that MRD negativity is the only outcome that can overcome the worst prognosis of this subgroup.

 

The current Editorial Theme of the Multiple Myeloma Hub is focusing on how to identify and treat patients with high-risk MM. Read more information, here. 

Safety

•  Dose modifications for K occurred in 76% of patients, for R in 71% of patients, and for d in 66% of patients.
• Treatment discontinuation due to AEs occurred in four patients.
• All grade AEs and Grade 3–4 AEs are shown below in Table 4. Briefly, the most common AEs of any grade were infection, fatigue, and thrombocytopenia, while the most common Grade 3–4 AEs were neutropenia, lymphopenia, and infection.
• No Grade 3–4 peripheral neuropathy events occurred, but 42% of patients experienced Grade 1–2 peripheral neuropathy.
• Cardiac events were generally mild and infrequent with an incidence rate of 13%. Only two patients experienced more serious cardiac AEs (Table 4).
• No treatment-related deaths were reported.

 

Table 4. Safety profile of KRd plus auto-SCT in NDMM¹

KRd + auto-SCT AEs*	All grade AEs (> 10%; N = 76)	Grade 3–4 AEs (N = 76)
AEs, adverse events; Auto-SCT, autologous stem cell transplantation; KRd, carfilzomib, lenalidomide, dexamethasone; R, lenalidomide. *AEs during auto-SCT and single-agent R maintenance were not evaluated; †Two patients had asymptomatic ejection fraction of 45–50% prior to auto-SCT, and one had a transient ejection fraction decrease to 47%, which was linked to hypertension during KRd maintenance.
Hematological, n (%)
Thrombocytopenia	47 (62)	11 (14)
Anemia	32 (42)	9 (12)
Lymphopenia	32 (42)	24 (32)
Neutropenia	30 (39)	26 (34)
Non-hematological, n (%)
Infection	56 (74)	17 (22)
Fatigue	51 (67)	4 (5)
Diarrhea	39 (51)	7 (9)
Hyperglycemia	33 (43)	6 (8)
Dyspnea	30 (39)	2 (3)
Rash	33 (43)	4 (5)
Hypophosphatemia	22 (29)	11 (14)
Hypertension	15 (20)	4 (5)
Thromboembolic events	14 (18)	5 (7)
Cardiac events†	10 (13)	2 (3)

 Conclusion

 The results of this phase II trial indicate that KRd plus auto-SCT lead to a high rate and durable responses, which are further improved following extended KRd maintenance. The reported MRD negativity at < 10^-5 rates were also very high (70% in the modified ITT population), and when specifically evaluating high-risk cytogenetic patients.

According to the data, the initial rapid response to KRd required extended treatment with KRd in order to achieve the best responses. These results seem to contradict the phase II FORTE trial, which reported that the addition of auto-SCT to eight cycles of KRd did not alter outcomes for patients with NDMM. Nevertheless, a recent subanalysis of the FORTE trial showed that there is a lower risk for early relapse and a higher rate of sustained MRD with KRd plus auto-SCT, when compared to KRd alone.¹

When comparing the study design of the ENDURANCE trial to this phase II study,² the patient population used in ENDURANCE was mainly of standard cytogenetic risk, mostly transplant ineligible, and KRd was administered for fewer cycles (nine). Thus, the authors stipulate that their results indicate that KRd plus auto-SCT offers a very promising regimen for high-risk NDMM patients, and that there is a need for extended treatment with KRd to achieve more profound and durable responses.

Further prospective trials on specific NDMM subpopulations are needed to further validate these results and clarify the precise role of KRd in the management of NDMM.