Safety and efficacy of Elotuzumab in combination with carfilzomib, lenalidomide and dexamethasone in the treatment of newly diagnosed multiple myeloma

A four-drug regimen consisting of monoclonal antibodies, proteasome inhibitors, immunomodulators, and corticosteroids for newly diagnosed multiple myeloma (NDMM) improves progression-free survival (PFS)
compared with a three-drug regimen.
However, the optimal combination of the four-drug regimen and whether autologous hematopoietic stem cell transplantation (ASCT) can be omitted from first-line treatment remains unknown
.

In this non-randomized phase II study of 46 patients with NDMM, the investigators used a next-generation sequencing (NGS) MRD adaptive design to study the safety and efficacy
of Elotuzumab (Elo) plus carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) regimens (omitting ASCT) in patients with NDMM.
The editor is now organized as follows
.

This is a multicenter, single-arm, phase II study with inclusion criteria: (1) age≥ 18 years; (2) NDMM patients requiring systemic therapy according to International Myeloma Working Group (IMWG) criteria; (3) Regardless of whether ASCT conditions
are met.

Patients received 12 to 24 cycles of Elo-KRd, the number of treatment cycles based on the MRD results of the clonoSEQ NGS test, for 28 days
.
After cycles 8 and 12, patients are tested for two consecutive MRDs with NGS, and if the patient tests negative for MRD twice in a row (10-6 or 10⁻⁵), ^ELo-Rd maintenance therapy is given after cycle 12 until disease progression; If the patient transitions from MRD-positive (10−6) to MRD-negative (10⁻⁶), an additional 6 cycles of ELo-KRd therapy are added, followed by ELo-Rd maintenance therapy until disease progression; If the patient tests positive for MRD twice in a row (10-6), an additional 12 cycles of ELo-KRd therapy are added after cycle 12, followed by transfer to ^Elo-Rd maintenance therapy until disease progression
.

Elo: 10 mg/kg
intravenously on days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 of cycle 3 and thereafter, and day 1 of maintenance period, respectively.

Carfilzomib: intravenous infusion on days 1, 8, and 15 of each cycle, 20 mg/m2 on day 1 of cycle 1, then increased to 70 mg/^m2
.

Lenalidomide: 25mg
orally on the 1~21st day of each cycle.

Dexamethasone: 40 mg orally weekly (20 mg if age≥ 75 years)

The primary endpoint was sCR and/or MRD negativity after eight cycles of Elo-KRd treatment (NGS, 10⁻⁵).

Secondary endpoints included safety, response rate, MRD status, PFS, and overall survival (OS).

As an exploratory analysis, MRD evaluation
of peripheral blood samples is performed using liquid chromatography-mass spectrometry (MS).

• Patient characteristics

Between July 2017 and February 2021, a total of 46 patients entered treatment, with a median age of 62 years
.
Of these, 45 (98%) patients had an evaluable efficacy
at the primary endpoint after 8 cycles.
The median treatment cycle was 18 cycles (range: 2-38 cycles).

• Efficacy analysis

After 8 cycles of Elo-KRd treatment, 26 of the 45 patients (58%; 95% CI, 42% to 73%) met the primary endpoint, 17 (38%) achieved sCR, 21 (47%) achieved ≥complete response (CR), 38 (84%) achieved ≥very good partial response (VGPR), 39 (87%) achieved ≥ partial response (PR), 1 (2%) discontinued early after 4 cycles due to drug toxicity, and 1 (2%) died early
during cycle 2.
In addition, 4 patients developed disease progression before cycle 8 and all had 17p deletion and/or 1q amplification
.

Optimal response rates were analyzed in 46 patients with intention-to-treat (ITT), with 26 (57%) achieving sCR, 32 (70%) achieving ≥CR, 43 (93%) achieving ≥VGPR, 44 (96%) achieving ≥PR, and 33 (72%) achieving sCR and/or MRD negative (Figure 1).

Stratified by IMWG risk status (cytogenetic results unknown in 1 patient), 18 (78%) of the 23 standard-risk patients achieved ≥CR, and 14 (64%) of the 22 high-risk cytogenetic abnormalities achieved ≥CR (P=0.
34).

Fig.
1 Depth and duration of remission in each patient

• PFS and OS

The median follow-up was 28.
7 months (range: 1.
4-50.
1 months), with 9 disease progressions and 8 deaths, and median PFS and OS not achieved
.
The estimated three-year PFS rate and OS rate are 72% and 78%, respectively (Figure 2).

In patients with negative MRD in the eighth cycle, the estimated 3-year PFS rate and OS rate were 92% and 100%,
respectively.
The 3-year PFS rate and 3-year OS rate were 86% and 91% in standard-risk patients, respectively, and 61% and 3-year OS rates in high-risk patients (Figure 2).

Fig.
2 PFS and OS analysis of patients

• Safety and tolerability

3 (7%) patients discontinued treatment due to adverse events (AEs), of which 1 developed grade 5 AEs (myocardial infarction)
in cycle 2.

Hematologic adverse events (grade 3-4) included 5 neutropenia (11%), thrombocytopenia 4 (9%), lymphopenia 3 (7%), and anaemia 1 (2%)
.

The most common non-haematological adverse events were fatigue (72%, all grade 1 to 2), diarrhoea (63%, all grade 1 to 2), non-pulmonary infection (48%, 5 [11%]≥grade 3), dyspnea (44%, 1 [2%]≥grade 3), upper respiratory tract infection (41%, all grade 1 to 2), and peripheral neuropathy (41%, all grade 1 to 2).

Cardiac events occurred in 12 cases (26%), including 4 cases (9%) of grade ≥ 3: 2 cases of atrial fibrillation, 1 case of left ventricular systolic insufficiency, and 1 case
of grade 5 myocardial infarction.
Eleven cases of hypertension (24%, including 3 cases of grade ≥ 3 [7%]), and 5 cases of thromboembolism (11%, of which 2 cases of grade ≥ 3 [4%]).

Six patients (13%) were infected with SARS-CoV-2, one of whom was hospitalized for a long time due to a serious infection, but later resumed treatment
.

In summary, Elo-KRd treatment with NDMM (omitting ASCT) can improve the negative rate of sCR and/or MRD, and the response is durable
.
This approach provides support for further evaluation of MRD-guided degraded therapy to reduce treatment exposure and maintain deep remission
.

References:

Derman BA, Kansagra A, Zonder J, et al.
Elotuzumab and Weekly Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Without Transplant Intent: A Phase 2 Measurable Residual Disease-Adapted Study.
 JAMA Oncol.
 Published online July 21, 2022.
doi:10.
1001/jamaoncol.
2022.
2424.