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Review | Latest updates on quadruplet therapy for newly diagnosed MM

Jul 7, 2020
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The therapeutic potential of monoclonal antibodies (mAbs) has been extensively investigated for multiple myeloma (MM). Due to their great clinical promise, mAbs are being exploited in the context of numerous novel technologies including bispecific T-cell engagers, antibody-drug conjugates, and chimeric antigen receptor T cells. In this article we will focus on the addition of mAbs to standard triplet regimens as frontline treatment for newly diagnosed MM (NDMM), and their latest clinical updates from the American Society of Clinical Oncology (ASCO) and the European Hematology Association (EHA) 2020 meetings.

Several antigens are being investigated to target MM cells, but the two main antigens that have been primarily targeted by mAbs in the frontline setting are CD38 and SLAMF7. CD38 targeting is accomplished by daratumumab (dara) and isatuximab (isa), while elotuzumab (elo) is an anti-SLAMF7 mAb.1 All three have shown promising results and have been approved in the relapsed/refractory MM (RRMM) setting combined with backbone regimens. Here we will focus on the latest updates on the clinical benefit of dara, isa, or elo in the NDMM setting.

Elotuzumab

Although elo has shown great clinical promise in the RRMM setting, its therapeutic potential in NDMM its controversial. At ASCO and EHA 2020, results from the phase I/II SWOG-12113,4 and the phase III GMMG HD65 trial showed that the addition of elo to bortezomib, lenalidomide, and dexamethasone (VRd) did not improve patient outcomes compared with VRd alone, either in high-risk or any risk patients. A breakdown of the key reported outcomes from each trial are shown below in Table 1. The available results to date indicate the potential superiority of anti-CD38 mAbs to elo as frontline addition to NDMM treatment. This can be further appreciated in Table 2, which shows the reported outcomes with elo-VRd, daratumumab-VRd, and isatuximab-VRd.

Table 1. Elo quadruplet induction outcomes reported at ASCO and EHA 2020

CI, confidence interval; CR, complete response; Elo, elotuzumab; LDH, lactate dehydrogenase; mF-up, median follow-up; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease; ULN, upper limit of normal; VGPR, very good partial response; VRd, bortezomib, lenalidomide, dexamethasone

*High-risk patients defined as poor risk score by gene expression profiling, or one or more pre-defined cytogenetic abnormalities (t(14;20), t(14;16), del(17p), amp(1q21)), or primary plasma cell leukemia, or LDH ≥ 2 × ULN

Patients with any adverse cytogenetics: 22.8% in the Elo + VRd vs 27.1% in the VRd arm

 

Outcome

Elo quadruplet induction outcomes

SWOG-12113,4

Phase I/II, mF-up 53 months

High-risk patients*

GMMG HD65

Phase III, after 4 cycles

Any-risk patients

VRd

(n = 52)

Elo + VRd

(n = 48)

p value

VRd

(n = 278)

Elo + VRd

(n = 278)

p value

Median PFS, months (95% CI)

34 (20–NR)

31 (19–54)

0.449

Awaited in 2021

Median OS, months (95% CI)

NR

68 (61–68)

0.239

ORR, %

88.0

83.0

85.6

82.4

0.35

≥ CR, %

6.0

2.1

CR, %

3.6

2.9

0.81

VGPR, %

20.0

21.3

 

≥ VGPR, %

54.0

58.3

0.35

PR, %

62.0

59.6

SD, %

6.0

12.8

 Daratumumab

Dara plus backbone triplets has repeatedly shown great promise for NDMM with its addition to bortezomib, melphalan, and prednisone (VMP), but also to bortezomib, thalidomide, and dexamethasone (VTd), having been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as frontline regimens for transplant non-eligible and eligible patients with NDMM. For more information on the pivotal phase III ALCYONE and CASSIOPEIA trials that respectively led to these approvals, read here.

At ASCO 2020, a subgroup analysis of the CASSIOPEIA trial based on the SLiM/CRAB criteria reported that response rates, measurable residual disease (MRD) negativity rates, and progression-free survival (PFS) remained similar between SLiM-only versus CRAB subgroups (SLiM-only patients seemed to be of lower risk and fitter than CRAB patients).2 Moreover, dara-VTd led to a significantly higher response and MRD-negativity rates among SLiM-only patients, and longer PFS rates amongst CRAB fulfilling patients.2

Another pivotal active study evaluating dara in the NDMM setting is the phase II GRIFFIN trial. This trial investigates dara in combination with VRd, and has reported that dara-VRd significantly improves response rates and MRD negativity in patients with transplant-ineligible NDMM (Table 2). For more details of the GRIFFIN trial design and outcomes read the article here.

Table 2. Comparative table of mAb additions to VRd

CI, confidence interval; CR, complete response; Dara, daratumumab; Elo, elotuzumab; Isa, isatuximab; mAb,  monoclonal antibody; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease; VGPR, very good partial response; VRd, bortezomib, lenalidomide, dexamethasone

Outcome

Elo + VRd

Dara + VRd

Isa + VRd

SWOG-12113,4

Phase I/II

(n = 48)

GMMG HD65

Phase III

(n = 278)

GRIFFIN6

Phase II

(n = 99)

Phase Ib7

(n = 26)

Median PFS, months (95% CI)

31 (19–54)

Awaited in 2021

NR

NR

Median OS, months (95% CI)

68 (61–68)

NR

ORR, %

83.0

82.4

99.0

100

≥ CR, %

2.1

51.5

42.3

CR, %

2.9

9.1

30.7

≥ VGPR, %

58.3

90.9

96.2

VGPR, %

21.3

39.4

53.8

PR, %

59.6

8.1

3.8

SD, %

12.8

1.0

 Isatuximab

At this year’s ASCO and EHA meetings, data from the interim analysis of the phase II GMMG-CONCEPT trial were reported. This study is investigating the efficacy of isa addition to carfilzomib, lenalidomide and dexamethasone (KRd) as frontline treatment exclusively in high-risk NDMM patients. Induction with isa + KRd led to deep responses with a 100% overall response rate and a tolerable safety profile (Table 3).8 Katja Weisel summarized the key results here.

In Table 3, the recently reported outcomes of dara + KRd in patients with NDMM of any risk are also shown for relative comparison.9 It is evident that both mAbs show great clinical activity as induction treatment for NDMM when combined with backbone triplets (VRd, KRd, etc.), even in subgroups with poorer outcomes. Moreover, preliminary data from a phase Ib study presented at ASCO 2020 showed that the addition of isa to bortezomib, dexamethasone with either cyclophosphamide (VCd) or lenalidomide (VRd), also improve patient outcomes leading to deep responses and are well tolerated (Table 2).7 Review the reported results of this trial with Enrique M. Ocio, here.

The ongoing phase III trial IMROZ, investigating the efficacy of Isa-VRd vs VRd alone in NDMM will further validate the clinical efficacy of isa addition to backbone triplets for induction.

Table 3. Anti-CD38 addition to KRd for NDMM patients

AHCT, autologous hematopoietic cell transplant; ASCT, autologous stem cell transplantation; CR, complete response; Dara, daratumumab; Isa, isatuximab; KRd, carfilzomib, lenalidomide, dexamethasone; MRD, measurable residual disease; ORR, overall response rate; VGPR, very good partial response

*82 patients completed induction; 63 patients completed post-ASCT assessment

Same value for standard and high-risk patient sub-analysis

Post-induction outcomes unless otherwise stated

Dara + KRd

Results include 29% high-risk patients9

(n = 82)*

Isa + KRd

GMMG-CONCEPT

100% high-risk patients8

(n = 50)

ORR, %

100

≥ CR, %

92, after AHCT and MRD-guided consolidation

46

≥ VGPR, %

91, after induction

90

MRD negative patients during/post induction, %

42

61

Conclusions

The latest updates on the addition of mAbs to backbone triplets as frontline for NDMM indicate that dara or isa (anti-CD38) provide a greater clinical benefit than elo (anti-SLAMF7), which did not significantly improve outcomes when investigated in two separate clinical trials vs VRd alone. Moreover, the data show that anti-CD38 (dara, isa) mAb-based quadruplets are a very promising induction treatment, especially for high-risk cytogenetics, and will potentially become a new standard of care for patients with NDMM.

  1. Martin TG, Corzo K, Chiron M, et al. Therapeutic opportunities with pharmacological inhibition of CD38 with isatuximab. Cells. 2019.;8(12): 1522. DOI: 3390/cells8121522
  2. Touzeau C, Moreau P, Perrot A, et al. Daratumumab + bortezomib, thalidomide, and dexamethasone (D-VTd) in transplant-eligible newly diagnosed multiple myeloma (TE NDMM): Baseline SLiM-CRAB based subgroup analysis of CASSIOPEIA. Oral Abstract #8538. 2020 ASCO Annual Meeting; May 29–31, 2020; Virtual.
  3. Usmani SZ, Ailawadhi S, Sexton R, et al. Primary analysis of the randomized phase II trial of bortezomib, lenalidomide, dexamethasone with/without elotuzumab for newly diagnosed, high-risk multiple myeloma (SWOG-1211). Oral Abstract #8507. 2020 ASCO Annual Meeting; May 29–31, 2020; Virtual.
  4. Usmani SZ, Ailawadhi S, Hoering A, et al. Primary analysis of the randomized phase II trial of bortezomib, lenalidomide, dexamethasone with/without elotuzumab for newly diagnosed, high risk multiple myeloma (SWOG-1211). Oral Abstract #S201. 2020 EHA Annual Congress; Jun 12, 2020; Virtual.
  5. Goldschmidt H, Mai EK, Salwender H, et al. Bortezomib, lenalidomide and dexamethasone with or without elotuzumab as induction therapy for newly-diagnosed, transplant-eligible multiple myeloma. Oral Abstract #S203. 2020 EHA Annual Congress; Jun 12, 2020; Virtual.
  6. Voorhees PM, Kaufman JL, Laubach JP, et al. Daratumumab, lenalidomide, bortezomib, & dexamethasone for transplant-eligible newly diagnosed multiple myeloma: GRIFFIN. 2020;blood.2020005288. DOI: 10.1182/blood.2020005288
  7. Ocio EM, Otero PR, Bringhen S, et al. Updates from a phase Ib study of isatuximab (Isa), bortezomib (V) and dexamethasone (D) plus cyclophosphamide (C) or lenalidomide (R) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM). Oral Abstract #8529. 2020 ASCO Annual Meeting; May 29–31, 2020; Virtual.
  8. Weisel K, Asemissen AM, Basemer B, et al. Depth of response to isatuximab, carfilzomib, lenalidomide and dexamethasone (isa-KRd) in front-line treatment of high-risk multiple myeloma: Interim analysis of the GMMG-CONCEPT trial. Oral Abstract #S204. 2020 EHA Annual Congress; Jun 12, 2020; Virtual.
  9. Costa L, Chhabra S, Goldy K, et al. Daratumumab, carfilzomib, lenalidomide and dexamethasone (dara-KRd) induction, autologous transplantation and MRD response-adapted consolidation in newly diagnosed multiple myeloma. Oral Abstract #EP928. 2020 EHA Annual Congress; Jun 12, 2020; Virtual.