General MM

SOHO & IMW 2019 | Induction therapies for multiple myeloma

During the Society of Hematologic Oncology (SOHO) annual meeting in Houston, US, Ajay NookaWinship 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 OlszewskiBrown University, Providence, US and Salomon ManierDana 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.  

Options for induction therapy

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

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 progression-free survival (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

Overall survival (OS), months

Not reached (NR) at 38-month follow-up

Overall response rate (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

Hazard ratio (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 adverse events (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 standard of care (SOC)

 

 

Stringent complete response (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

Measurable residual disease (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 (≥ partial response [PR]), %

100

Six-month PFS, %

100

Kumar et al.,10

Phase II study of dara-Rd with the addition of ixazomib (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 disease progression (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

  • TE, standard-risk: dara-VRd
  • TE, high-risk: KRd
  • TI, standard-risk: dara-Rd, dara-VRd or dara-VMP
  • TI, high-risk: VRd-lite

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

Population-based analysis of VRd, Rd and Vd as frontline therapies for older patients with MM2

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

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

 

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

Meta-analysis of trials utilizing Rd3

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).

Efficacy

  • Median PFS, OS and ORRs were similar across the three trials (Table 4)
  • Median PFS with Rd was estimated to be 28.9 months (95% CI, 26.8–31.3 months)

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

Safety

  • Grade 3–4 AEs with Rd were in line with the known safety profiles for the regimen (Table 5)
  • More patients discontinued treatment with R due to AEs in the FIRST trial compared to MAIA and SWOG S0777, though there were no differences in the starting dose of R between the FIRST and MAIA trials (Table 6)
  • Patients stayed on treatment for longer in the MAIA trial (Table 6) which may reflect increased physician experience at the time of study

Table 5. Select grade 3–4 AEs affecting ≥ 5% of patients on study5,12,14

 

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 secondary primary malignancy (SPM)

7

Not applicable

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.

Conclusion

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.

References
  1. Nooka A.K. Induction Therapy for Newly Diagnosed MM: What to Use in the Era of Monoclonal Antibodies? Society of Hematologic Oncology (SOHO) annual meeting, Houston, US. 2019 Sep 12. Oral presentation.
  2. Olszewski A. Comparative effectiveness of lenalidomide, bortezomib, and their combination as first-line treatment of older patients with myeloma. XVII International Myeloma Workshop (IMW), Boston, US. 2019 Sep 13. Oral presentation and abstract #AB819
  3. Manier S. Lenalidomide and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients: Meta-analysis of Efficacy in Pivotal Randomized Controlled Trials. XVII International Myeloma Workshop (IMW), Boston, US. 2019 Sep 13. Oral presentation and abstract #AB820
  4. Joseph N. et al. Efficacy of Induction Therapy with Lenalidomide, Bortezomib, and Dexamethasone (RVD) in 1000 Newly Diagnosed Multiple Myeloma (MM) Patients. Blood. 2018 Nov 21. DOI: 10.1182/blood-2018-99-119895
  5. Durie B.G.M. et al., Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2016 Dec 22. DOI: 10.1016/S0140-6736(16)31594-X
  6. Moreau P. et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019 Jun 03. DOI: 10.1016/S0140-6736(19)31240-1
  7. Voorhees P.M. et al. Efficacy and Updated Safety Analysis of a Safety Run-in Cohort from Griffin, a Phase 2 Randomized Study of Daratumumab (Dara), Bortezomib (V), Lenalidomide (R), and Dexamethasone (D; Dara‐Vrd) Vs. Vrd in Patients (Pts) with Newly Diagnosed (ND) Multiple Myeloma (MM) Eligible for High‐Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT). Blood. 2018 Nov 21. DOI: 10.1182/blood-2018-151
  8. Genmab Announces Positive Topline Results in the Phase II GRIFFIN Study of Transplant Eligible, Newly Diagnosed Patients with Multiple Myeloma Treated with Daratumumab in Combination with Lenalidomide, Bortezomib, and Dexamethasone. https://ir.genmab.com/news-releases/news-release-details/genmab-announces-positive-topline-results-phase-ii-griffin-study [Accessed 2019 Oct 03]
  9. Jakubowiak A.J. et al. Daratumumab (DARA) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in patients (pts) with newly diagnosed multiple myeloma (MMY1001): An open-label, phase 1b study. J Clin Onc. 2017 May 30. DOI: 10.1200/JCO.2017.35.15_suppl.8000
  10. Kumar S.K. et al. Phase 2 Trial of Ixazomib, Lenalidomide, Dexamethasone and Daratumumab in Patients with Newly Diagnosed Multiple Myeloma. Blood. 2018 Nov 21. DOI: 10.1182/blood-2018-99-111065
  11. Mateos V-M. et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Eng J Med. 2018 Feb 08. DOI: 10.1056/NEJMoa1714678
  12. Facon T. et al. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N Eng J Med. 2019 May 30. DOI: 10.1056/NEJMoa1817249
  13. Gay F. et al. Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: Results from the FORTE trial. American Society of Clinical Oncology meeting 2019, Chicago, US. 2019 Jun 02. Abstract #8002.
  14. Facon T. et al. Patients with Revised International Staging System (ISS) stage II/III disease had a higher rate of MRD-negativity showing a benefit in this population. Blood. 2018 Jan 18. DOI: 10.1182/blood-2017-07-795047
  15. Durie B.G.M. et al. Longer Term Follow up of the  Randomized Phase III Trial SWOG S0777: Bortezomib, Lenalidomide and Dexamethasone Vs. Lenalidomide and Dexamethasone in Patients (Pts) with Previously Untreated Multiple Myeloma without an Intent for Immediate Autologous Stem Cell Transplant (ASCT). Blood. 2018 Nov 21. DOI: 10.1182/blood-2018-99-117003 and oral presentation at ASH
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