Targeting a Myeloma Translocation for the First Time: The t(11;14) Journey

A Phase 1/2, Multicenter, Dose-Escalation and Expansion Study of Combination Therapy With Venetoclax, Daratumumab and Dexamethasone (With and Without Bortezomib) in Subjects With Relapsed or Refractory Multiple Myeloma

NCT03314181 (ClinicalTrials.gov identifier)

AbbVie

90

32 centers in the United States, Canada, Australia, and Europe

This is a relatively complex study with two primary parts. Part 1 includes patients with relapsed/refractory multiple myeloma (MM) carrying a t(11;14) translocation, as determined by fluorescent in situ hybridization. Part 2 allows entry of any relapsed/refractory MM patients. Both parts begin with a dose-escalation phase (1a, 2a) followed by an expansion phase (1b, 2b). Part 1 patients will be treated with venetoclax, daratumumab, and dexamethasone, while part 2 patients will be treated with venetoclax, daratumumab, bortezomib, and dexamethasone. Although part 2b comprises a single-arm, open-label study of venetoclax (dose defined in 2a), daratumumab (16 mg/kg intravenously), bortezomib (1.3 mg/m² subcutaneously or intravenously, cycles 1-8), and dexamethasone (20 mg for cycles 1-8 and 40 mg weekly for cycles 9+), part 1b involves random assignment to one of two arms — either the venetoclax (dose defined in 1a), daratumumab (as above), and dexamethasone (as above) arm, or the placebo, daratumumab, and dexamethasone arm. Participants must not have been previously treated with venetoclax (or another BCL-2 inhibitor) or daratumumab (or another anti-CD38 antibody).

The primary endpoint for part 1 is objective response rate (ORR), defined as the proportion of participants with partial response (PR) or better based on IMWG criteria, or number of participants with dose-limiting toxicities. For part 2, the primary endpoint is complete response (CR) or better (CR or stringent CR, based on IWMG criteria), or number of participants with dose- limiting toxicities.

Secondary endpoints include progression-free survival (PFS), time to progression, duration of response, ORR, C_max of daratumumab, C_max of venetoclax, T_max of venetoclax, and minimal residual disease (MRD). MRD negativity is defined as less than 10^–5 tumor cells in bone marrow aspirates by next-generation sequencing at the time of suspected CR/stringent CR, and at six and 12 months post confirmation of CR/stringent CR for maintained response.

BCL-2 inhibition has been shown to be effective in myeloma in vitro and in clinical trials. More specifically, MM cell lines with t(11;14) translocation, as well as patients with t(11;14), have been shown to be particularly sensitive to BCL-2 inhibition. However, the role of BCL-2 inhibition in patients with t(11;14) is still under investigation. In this trial, BCL-2 inhibition by venetoclax is being tested for safety and efficacy in combination with bortezomib, dexamethasone, and daratumumab, an anti-CD38 monoclonal antibody that has recently been approved as first-line treatment for MM. The effects of BCL-2 inhibition on t(11;14) myeloma are assessed separately.

MM is genetically complex. Although there are genes that are recurrently mutated more often than expected based on their length, expression level, and replication timing, for several reasons those mutations cannot be used to effectively categorize myeloma patients. First, even the most commonly mutated genes, KRAS and NRAS, are only mutated in 20 percent of cases, and second, even collectively, cases with mutations in those genes only account for approximately 60 percent of the patient population. Structural variation, on the other hand, is much more reliable as a myeloma biomarker in that it accounts for all myeloma patients. Roughly half of cases have hyperdiploid genomes with multiple copies of the odd-numbered chromosomes, while the other half carry translocations involving IgH. These translocations comprise primary events that pair IgH enhancers with five partner genes, including CCND1 on chromosome 14, CCND3 on chromosome 6, MMSET/FGFGR3 on chromosome 4, cMAF on chromosome 16, and MAFB on chromosome 20, leading to upregulation of said genes and oncogenesis. Therapeutic targeting of t(9;22)-translocated cancer has been one of the biggest successes in the history of cancer treatment and precision medicine, which makes targeting translocated myeloma particularly appealing, especially t(11;14) cases, as this translocation occurs in other malignancies as well, most commonly in mantle-cell lymphoma (MCL).

Myeloma patients with t(11;14) comprise approximately 15 to 20 percent of all cases, making t(11;14) the most common of its translocations. Notably, its frequency is even higher in cases with plasma cell leukemia (~40%). Although t(11;14) used to be considered a standard risk factor, it is increasingly thought of as an intermediate risk factor in the era of novel agents, conferring inferior outcome compared with standard-risk myeloma. By juxtaposing IgH with CCND1, the latter is overexpressed, leading to kinase activation and tumor cell proliferation.

Myeloma cases with t(11;14) are predicted to be BCL-2–dependent. BCL-2 is a member of the BCL-2 family of antiapoptotic proteins, which also includes MCL-1 and BCL-X_L. MM is heterogeneous with respect to BCL-2, MCL-1, and BCL-XL dependency, with some cases being more dependent on MCL-1 over BCL-2 and vice versa.¹  Multiple studies in human myeloma cell lines demonstrated that the presence of t(11;14) was predictive of BCL-2 dependency, making BCL-2 a potential target in this subtype of myeloma. These studies also showed that t(11;14) lines were significantly more sensitive to BCL-2 inhibition — an effect that was associated with the ratio between BCL-2 and MCL-1/BCL-X_L expression. Higher MCL-1 expression weakened the effect of BCL-2 inhibition but could be circumvented with concurrent use of bortezomib, which suppresses MCL-1. Furthermore, dexamethasone was shown to act synergistically with BCL-2 inhibition through alterations in the interplay between BCL-2 and the proapoptotic binder Bim. In vitro, BCL-2 inhibition, either as monotherapy or in combination with bortezomib and dexamethasone, had superior performance in myeloma with t(11;14).

A couple of clinical trials followed. BCL-2 inhibition by venetoclax as monotherapy in patients with relapsed/refractory MM was shown to be safe and effective. Dr. Shaji Kumar and colleagues observed that almost all of the responses recorded happened in patients with t(11;14), while BCL-2/MCL-1 and BCL-2/BCL-X_L expression ratios were predictive of that effect, just like in cell lines.²  In parallel, Dr. Philippe Moreau and colleagues tested the combination of venetoclax with bortezomib and dexamethasone in patients with relapsed/refractory MM and found a significantly higher ORR in cases with higher BCL-2 expression, but failed to observe a difference based on the presence of t(11;14).³  This of course could be because of the small number of cases harboring t(11;14) in that particular study, or it could be that the presence of t(11;14) is not the only/strongest predictor of BCL-2 dependency. This study’s results, however, challenged the importance of BCL-2 inhibition in t(11;14) myeloma cases in the context of bortezomib/dexamethasone treatment.

This is a phase 1/2 trial, and as such it cannot answer clinically important questions regarding the superiority of treating t(11;14) myeloma patients with venetoclax. However, it is positioned to generate interesting preliminary data that will fuel the trials that will. Following the negative results of the study by Dr. Moreau and colleagues as far as t(11;14) status is concerned, in the context of bortezomib treatment, this trial will generate data of a preliminary comparison between venetoclax-daratumumab-dexamethasone and venetoclax-daratumumab-bortezomib-dexamethasone. At the same time, thanks to this trial’s nested randomized approach, there will be data comparing the combination of venetoclax-daratumumab-dexamethasone to placebo-daratumumab-dexamethasone, which will give us a sense of whether there is a benefit in adding venetoclax to the existent combination in the context of t(11;14) or not. This trial will not be powered to allow a definitive answer to that question. But, as this is the first trial that recruits t(11;14) patients separately, the number of t(11;14) cases is expected to be much higher than that in previous trials. This in and of itself places this trial in a better position to address BCL-2 inhibition in t(11;14) myeloma.

Why is that important? Because t(11;14) patients are quite common and are generally predicted to have worse outcome compared to standard-risk myeloma, and even standard-risk myeloma is an incurable disease with improving, yet still quite poor prognosis. A targeted approach to therapy for patients with MM based on their underlying genetic abnormalities is a promising step forward.