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a
33%
b
33%
c
0%
d
33%
Venetoclax, an oral BCL-2 inhibitor, has been of particular interest in a specific subset of patients with t(11;14),1 a cytogenetic abnormality found in 15–20% of patients with multiple myeloma (MM). Venetoclax may enhance treatment response when combined with drugs that increase BCL-2 dependency, such as dexamethasone and bortezomib, and therapies that may eliminate resistant subclones to venetoclax, such as daratumumab.3
A phase I study sought to evaluate the safety and tolerability of venetoclax plus daratumumab and dexamethasone in patients with t(11;14) relapsed or refractory MM (RRMM), as well as the further addition of bortezomib in cytogenetically unselected patients. The results were published by Nizar Bahlis and colleagues in the Journal of Clinical Oncology2 and are summarized in this article.
Patients with RRMM aged ≥18 years were eligible if they had documented evidence of progression per the International Myeloma Working Group criteria during or after their last treatment regimen, an Eastern Cooperative Oncology Group performance status ≤2, acceptable laboratory parameters, and measurable disease confirmed by a central laboratory at screening.
The study was comprised of two parts (NCT03314181). In Part 1, venetoclax with daratumumab and dexamethasone (VenDd) was evaluated in patients with (t11;14) RRMM, and in Part 2, VenDd with bortezomib (VenDVd) was evaluated in cytogenetically unselected patients with RRMM. Patients in Part 1 must have received ≥1 prior line of therapy, including a proteasome inhibitor (PI) and immunomodulatory amide drug, and those in Part 2, must have received one to three prior lines of therapy and not be refractory to PIs.
VenDd treatment involved the following:
VenDVd treatment consisted of the following:
A total of 48 patients were enrolled; 24 patients with t(11;14) RRMM in Part 1, and 24 patients with RRMM in Part 2. The median follow-up for Part 1 and Part 2 was approximately 21 months and 21.5 months, respectively. Baseline characteristics are summarized in Table 1. The differences between the Part 1 and Part 2 participants did not allow for direct comparison between the two study arms.
Table 1. Characteristics of patients in Part 1 (VenDd) and Part 2 (VenDVd)*
Characteristic |
Part 1 |
Part 2 |
---|---|---|
Median age, years (range) |
63 (51–76) |
64 (41–80) |
ECOG performance status, n (%) |
|
|
0 |
13 (54) |
16 (67) |
1 |
11 (46) |
7 (29) |
2 |
0 (0) |
1 (4) |
ISS stage, n (%) |
|
|
I |
7 (29) |
9 (38) |
II and III |
14 (58) |
14 (58) |
Not evaluable or unknown |
3 (13) |
1 (4) |
Cytogenetic abnormalities, n (%) |
|
|
t(11;14) |
24 (100) |
6 (25) |
No. of prior lines of therapy, median (range) |
2.5 (1–8) |
1 (1–3) |
Prior PI, n (%) |
24 (100) |
22 (92) |
Refractory to prior PI |
11 (46) |
0 (0) |
Prior IMiD, n (%) |
24 (100) |
17 (71) |
Refractory to prior IMiD |
17 (71) |
8 (33) |
Prior PI plus IMiD, n (%) |
24 (100) |
15 (63) |
Refractory to prior plus IMiD |
10 (42) |
0 (0) |
ECOG, Eastern Cooperative Oncology Group; IMiD, immunomodulatory imide drug; ISS, International Staging System; PI, proteasome inhibitor; VenDd, venetoclax + daratumumab + dexamethasone; VenDVd, venetoclax + daratumumab + bortezomib + dexamethasone. |
Key safety outcomes are summarized in Table 2. The following notable points were observed:
Table 2. The most common any grade and Grade 3 and 4 TEAEs*
TEAE |
Part 1 |
Part 2 |
||
---|---|---|---|---|
Any grade |
Grade ≥3 |
Any grade |
Grade ≥3 |
|
Any TEAE, n (%) |
24 (100) |
21 (88) |
24 (100) |
17 (71) |
Nonhematologic TEAEs, n (%) |
|
|
|
|
Fatigue |
17 (71) |
2 (8) |
6 (25) |
1 (4) |
Diarrhea |
15 (63) |
2 (8) |
13 (54) |
2 (8) |
Nausea |
12 (50) |
1 (4) |
12 (50) |
0 (0) |
Insomnia |
10 (42) |
1 (4) |
13 (54) |
6 (25) |
Hypertension |
8 (33) |
4 (17) |
2 (8) |
0 (0) |
Peripheral sensory neuropathy |
0 (0) |
0 (0) |
6 (25) |
1 (4) |
Infection-related TEAEs, n (%) |
|
|
|
|
Any infection |
23 (96) |
6 (25) |
15 (63) |
5 (21) |
Upper respiratory tract infection |
9 (38) |
0 (0) |
5 (21) |
1 (4) |
Hematologic TEAEs, n (%) |
|
|
|
|
Neutropenia |
7 (29) |
5 (21) |
4 (17) |
1 (4) |
TEAE, treatment-emergent adverse event; VenDd, venetoclax + daratumumab + dexamethasone; VenDVd, venetoclax + daratumumab + bortezomib + dexamethasone. |
Figure 1. Response rates and MRD negativity rates*
A Response rates and MRD negativity rates in patients treated with B VenDd in Part 1 and those treated with C VenDVd in Part 2. The 95% CIs for response rates in Part 1 were 78.9–99.9 for ORR, 36.6–77.9 for ≥CR, and 78.9–99.9 for ≥VGPR. The 95% CIs for response rates in Part 2 were 73.0–99.0 for ORR, 25.6–67.2 for ≥CR, and 57.8–92.9 for ≥VGPR.
CI, confidence interval; CR, complete response; MRD, minimal residual disease; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VenDd, venetoclax, daratumumab, and dexamethasone; VenDVd, venetoclax, daratumumab, bortezomib, and dexamethasone; VGPR, very good partial response.
*Adapted from Bahlis, et al.2
The authors concluded that both VenDd and VenDVd led to a high rate and sustained responses in patients with RRMM with and without t(11;14). Favorable responses with these new combinations versus venetoclax monotherapy,1 daratumumab monotherapy,3,4 and venetoclax and dexamethsone5 seen in previous studies suggest an additive effect when daratumumab is administered with venetoclax and warrants further investigation. Encouragingly, the safety profile was favorable, with no new safety signals identified. The phase II portion of the study will follow on after the high response rates in Part 1 with VenDd, enrolling patients with t(11;14) RRMM into a randomized, open-label cohort to further assess VenDd compared with daratumumab, bortezomib, and dexamethasone (DVd). On the other hand, in Part 2, the addition of bortezomib did not appear to be beneficial in patients identified as having t(11;14), and they experienced a higher rate of neuropathy. Therefore, Bahlis and colleagues conclude that the findings support further study of a personalized treatment approach, identifying predictive biomarkers to aid treatment decisions in BCL-2-dependent MM.
Gupta and colleagues sought to better understand factors contributing to venetoclax sensitivity beyond t(11;14), and their findings were published in Blood.6 They studied 31 myeloma cell lines and 25 patient samples for venetoclax sensitivity and discovered venetoclax-sensitive myeloma retains a partially activated B‑cell gene expression program usually downregulated during plasma cell differentiation. They identified a B cell-like chromatin accessibility pattern suggestive of increased binding of a transcription factor involved in B‑cell development in venetoclax-sensitive cell lines. This process may drive BCL-2 dependence and therefore contribute to venetoclax sensitivity.
The aberrant B-cell pattern of gene expression described was observed almost exclusively in venetoclax-sensitive t(11;14) and not in venetoclax-resistant t(11;14), suggesting that t(11;14) alone could not explain this. No single gene was consistently expressed in venetoclax-sensitive samples; however, a panel of cell surface markers identified by flow cytometry correctly grouped MM cell lines and primary samples into sensitive and resistant to venetoclax. This panel included CD20, CD28, CD45, CD79a, and CD86. There is a possibility that a panel like this could be used to predict sensitivity to venetoclax and allow personalized treatment approaches for patients with MM beyond t(11;14).
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