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During the Society of Hematologic Oncology (SOHO) annual meeting in Houston, US, Ajay Nooka, Winship Cancer Institute of Emory University, Georgia, US, provided a thorough overview of induction therapies for multiple myeloma (MM), with a focus on what to use in the era of monoclonal antibodies (mAbs), such as daratumumab (dara).1 Induction regimens were also discussed at the XVII International Myeloma Workshop (IMW), Boston, US, where Adam Olszewski, Brown University, Providence, US and Salomon Manier, Dana Farber Cancer Institute, Boston, US, presented oral abstracts AB8192 and AB2003, respectively, looking at the efficacy of lenalidomide- (R), bortezomib- (V) and dexamethasone- (d) based induction therapies.
The treatment paradigm for newly diagnosed MM (NDMM) involves disease and risk stratification, followed by assessment for autologous stem cell transplant (ASCT) eligibility. Transplant eligible (TE) patients receive induction, consolidation and maintenance therapy, whilst transplant ineligible (TI) patients receive induction followed by continuous therapy. Subsequent relapses are then managed according to the characteristics at the time.1
There are several well-established options for induction therapy, including Rd, VRd, V + thalidomide (T) + d (VTd), carfilzomib (K) + Rd (KRd) and V + melphalan (M) + prednisone (P, VMP). In the era of mAbs, these well-established doublet and triplet combinations are being investigated with the addition of dara with an aim of improving efficacy. Dr Nooka provided an overview of trials under investigation as shown in Table 1.1
Table 1. Induction therapies for NDMM4-12
AEs, adverse events; ASCT, autologous stem cell transplantation; d, dexamethasone; dara, daratumumab; HR, hazard ratio; I, ixazomib; m, melphalan; MRD, measurable residual disease; NDMM, newly diagnosed multiple myeloma; NR, not reached; p, prednisone; PD, disease progression ; PFS, progression free survival; PR, partial response; ORR, overall response rate; OS, overall survival; R, lenalidomide; sCR, stringent complete response; SOC, standard of care; T, thaldomide; TE, transplant eligible;TI, transplant ineligible; V, bortezomib |
||||
Trial name |
Trial overview |
Efficacy |
Conclusion |
|
---|---|---|---|---|
Joseph et al.,4 |
Retrospective analysis of patients with NDMM (N= 1000) treated with VRd induction at Winship Cancer Institute of Emory University |
Median PFS, months |
63 |
The largest reported cohort of patients with NDMM treated with VRd induction shows VRd provides impressive response rates and long-term outcomes in high- and standard-risk patients |
Median PFS (high vs standard risk), months |
37 vs 72
p< 0.001 |
|||
OS, months |
NR at 38-month follow-up |
|||
ORR, % |
97.3 |
|||
SWOG S07775 |
Phase III study of VRd vs Rd in patients with NDMM who were not planned for immediate ASCT |
Given as VRd (n= 242) vs Rd (n= 229) |
This trial additionally showed giving a triplet upfront gave improved PFS and survival rates, with an acceptable risk-benefit profile |
|
PFS, months |
43 vs 30 HR: 0.712 96% CI, 0.56–0.906 p= 0.0018 |
|||
OS, months
|
75 vs 64 HR: 0.709 95% CI, 0.524–0.959 p= 0.025 |
|||
ORR, % |
82 vs 72 |
|||
CASSIOPEIA6 |
Randomized phase III study of dara-VTd vs VTd in patients with NDMM, before and after ASCT |
Given as dara-VTd (n= 543) vs VTd (n= 542) |
The addition of dara to the VTd triplet resulted in a 53% reduction in the risk of progression or death and was superior across all subgroups.
There was also a higher rate of MRD-negativity in the dara-VTd arm with no significant increase in AEs or impact on stem cell collection
Limitation: T is not commonly used in the United States, meaning this specific combination is unlikely to become SOC
|
|
sCR, % |
29 vs 20 |
|||
18-month PFS, %
|
93 vs 85 |
|||
Median PFS from first randomization |
NR vs NR HR: 0.47 95% CI, 0.33–0.67 p< 0.0001 |
|||
OS |
Data immature |
|||
MRD-negativity rate at 10-5 by flow cytometry, % |
64 vs 44 p< 0.0001 |
|||
GRIFFIN7,8
|
Randomized phase II study of dara-VRd vs VRd in TE patients with NDMM
|
Run-in phase (n= 16) of VRd: ORR at end of consolidation was 100%, with an sCR + CR rate of 63%7 |
This trial had a similar design to CASSIOPEIA but is investigating R instead of T in the backbone triplet. The most recently released topline results indicated a higher sCR rate with dara-VRd
|
|
Given as dara-VRd vs VRd |
||||
Topline results:8 sCR, % |
42.4 vs 32 |
|||
MMY10019 |
Phase Ib study of dara-KRd in patients with NDMM, regardless of transplant eligibility (n= 21) |
Median follow-up, months |
10.8 |
In this early phase study, dara-KRd was shown to be well-tolerated with a promising efficacy and is being investigated further |
ORR (≥ PR), % |
100 |
|||
Six-month PFS, % |
100 |
|||
Kumar et al.,10 |
Phase II study of dara-Rd with the addition of dara-IRd in patients with NDMM, irrespective of transplant eligibility (n= 38)
|
ORR (≥ PR) after cycle two, % |
90 |
Dara-IRd shows high efficacy with responses that deepen over the initial cycles of therapy and will be investigated further |
ORR after cycle four, %
|
100 |
|||
Best response, % |
95 |
|||
ALYCONE11 |
Phase III trial of dara-VMP vs VMP in TI patients with NDMM
|
Given as dara-VMP (n= 350) vs VMP (n= 356) |
The dara-VMP regimen resulted in a lower risk of PD or death compared to VMP alone, though it was also associated with higher rates of grade III–IV infections |
|
18-month PFS, % |
72 vs 50
|
|||
Median PFS, months |
NR vs 18.1 HR: 0.5 95% CI, 0.38–0.65 p< 0.001 |
|||
ORR, % |
91 vs 74 p< 0.001 |
|||
MRD-negative, % |
22 vs 6 p< 0.001 |
|||
MAIA12 |
Phase III trial of TI patients with NDMM comparing dara-Rd to Rd |
Given as dara-Rd (n= 368) vs Rd (n= 369)
|
Patients in the dara-Rd arm had a lower risk of PD or death compared to those receiving Rd alone, but dara-Rd was associated with a higher rate of neutropenia and pneumonia |
|
30-month PFS, % |
71 vs 56 HR: 0.56 95% CI, 0.43–0.73 p< 0.001 |
|||
MRD-negativity, % |
24.2 vs 7.3 p< 0.001 |
In the phase III FORTE trial in TE patients with NDMM who were ≤ 65 years old, patients with Revised International Staging System (R-ISS) stage II/III disease had a higher rate of MRD-negativity indicating a benefit in this population.13
Dr Nooka then presented the current Winship Cancer Institute of Emory University algorithm for induction therapy for patients with NDMM:1
Dr Nooka concluded that mAb-containing induction regimens show promising efficacy, including deep rates of MRD-negativity. Additionally, Dr Nooka believes experience with VRd indicates patients will benefit from a quadruplet induction such as dara-VRd. When considering the cost implications of mAbs in the frontline setting, Dr Nooka stated he believes the cost is justifiable and that now is the time to “embrace the change”.1
Given the number of available induction regimens and new combinations under investigation, it is a challenge for treating physicians to determine the correct course of treatment for patients. Adam Olszewski and colleagues used population-based data to compare the efficacy of VRd with doublet therapies (Rd and Vd), and then Rd to Vd, in TI patients with NDMM. They analyzed OS and time to treatment failure (TTF) as shown in Table 2 and Table 3.
Table 2. Efficacy of VRd compared to Rd/Vd2
|
VRd (n= 740) |
Rd or Vd (n= 2,549) |
HR |
95% CI |
---|---|---|---|---|
TTF |
1.7 |
0.8 |
0.68 |
0.61–0.76 |
OS |
3.4 |
2.7 |
0.83 |
0.72–0.95 |
HR, hazard ratio; OS, overall survival; TTF, time-to-treatment; VRd, bortezomib, lenalidomide and dexamethasone |
VRd provided a longer TTF and OS compared to Rd/Vd, though it also led to higher hospitalization rates (relative risk [RR]: 1.17, 95% CI, 1.03–1.32), higher rates of anemia (RR: 1.16, 95% CI, 1.09–1.23), higher rates of neuropathy (RR: 1.49, 95% CI, 1.14–1.96) and increased consolidative transplant (26% vs 6%).
Table 3. Efficacy of Rd compared to Vd2
HR, hazard ratio; OS, overall survival; TTF, time-to-treatment; VRd, bortezomib, lenalidomide and dexamethasone |
||||
|
Rd (n= 1,440) |
Vd (n= 1,526) |
HR |
95% CI |
---|---|---|---|---|
TTF |
1 |
0.6 |
0.74 |
0.68–0.81 |
OS |
2.7 |
2.3 |
0.91 |
0.83–0.99 |
Rd surprisingly provided a longer TTF and OS compared to Vd. Rd was associated with higher rates of thromboembolism (RR: 1.44, 95% CI, 1.13–1.83), but lower rates of neuropathy (RR: 0.39, 95% CI, 0.29–0.53) and there was no difference in rates of hospitalization or anemia (RR was 0.96 and 0.95, respectively).
Adam Olszewski and colleagues found that VRd offers a TTF and OS benefit for older patients with MM who can tolerate slightly higher, short-term toxicity. This confirms the results of the SWOG S0777 trial in a population-based setting. With regards to doublet therapies, unexpectedly, Rd showed an advantage over Vd indicating it may be the more efficacious option, despite Vd being the most commonly used in this population.2
During the IMW meeting, Salomon Manier presented the results of a meta-analysis which aimed to obtain a pooled estimate for PFS and OS from phase III trials utilizing Rd for patients with NDMM who are not intended for ASCT. The trials analyzed were the FIRST14, MAIA12 and SWOG S07775 trials (Rd arms).
Table 4. Efficacy results from the FIRST, MAIA and SWOG S0777 trials12,14,15
|
FIRST3,14 (n= 535) |
MAIA3,12 (n= 369) |
SWOG S07773,15 (n= 207) |
---|---|---|---|
ORR, % |
80.7 |
81.4 |
78.8 |
CR, % |
22.2 |
12.5 |
12.1 |
Duration of follow-up, months |
67 |
28 |
84 |
Median PFS, months |
26 |
31.9 |
29 |
Median OS, months |
59.1 |
NR |
69 |
CR, complete response; ORR, overal response rate; OS, overall survival; PFS, progression free survival |
Table 5. Select grade 3–4 AEs affecting ≥ 5% of patients on study5,12,14
NA, not applicable; SPM, secondar primary malignancy | |||
|
FIRST14 (n= 532), % |
MAIA12 (n= 365), % |
SWOG S07775 (n= 226), % |
---|---|---|---|
Hematologic |
|||
Neutropenia |
30 |
35 |
NA |
Blood or bone marrow toxicity |
NA |
NA |
46 |
Anemia |
19 |
20 |
NA |
Thrombocytopenia |
9 |
NA |
NA |
Non-hematologic |
|||
Infection |
32 |
23 |
14 |
Pneumonia |
9 |
8 |
NA |
Diarrhea |
5 |
4 |
NA |
Fatigue |
NA |
4 |
NA |
Invasive SPM |
7 |
NA |
7 |
Discontinuation due to infection |
4.3 |
1.4 |
NA |
Dr Manier concluded that Rd provided a consistent benefit across the three phase III trials evaluated, with median PFS exceeding two years and OS exceeding five years. No new safety signals were identified in MAIA or SWOG S0777.
The meta-analysis performed by Dr Manier and colleagues support the European Myeloma Network, European Society of Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN®) recommendations that Rd is used as frontline SOC. It also supports the investigation of Rd in novel combinations such as dara-Rd and dara-VRd.
These presentations highlight the vast availability of induction regimens for the treatment of NDMM, in both the TE and TI setting, as well as how many new combinations are under investigation. The addition of mAbs to traditional doublet and triplet backbones will likely become the SOC regimens, though this will vary in each specific patient scenario, with further data required to reach a consensus. In the meantime, traditional induction regimens, such as Rd and VRd, continue to prove efficacious in meta-analyses and population-based studies.
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