Shaji Kumar, MD

The BCL-2 inhibitor venetoclax (Venclexta) demonstrated activity in one-fifth of patients with heavily pretreated multiple myeloma, according to results of a phase I clinical trial presented at the 2016 ASH Annual Meeting.¹

Overall, 21% of patients achieved objectives responses to single-agent venetoclax. The response rate increased to 40% in the subgroup of patients with t(11;14) chromosomal translocation.

Regarding the safety profile, venetoclax was generally well tolerated and grade 3/4 toxicities were relatively infrequent, particularly nonhematologic toxicity, and no patient developed tumor lysis syndrome.

“Venetoclax monotherapy had an acceptable safety profile in this heavily pretreated multiple myeloma population,” said Shaji Kumar, MD, a myeloma consultant and professor of Medicine at the Mayo Clinic. “A higher response rate and deeper responses were seen in patients with the 11/14 translocation. These results confirm the single-agent antitumor activity of venetoclax in patients who have relapsed/refractory multiple myeloma with 11/14 translocation.”

“The results are encouraging enough that additional studies are planned, especially alternative combinations,” he added. “I think we have a drug that can change the outcome for a lot of patients with myeloma. It may be the first drug that is actually going to be a biomarker-driven drug in this disease.”

The rationale for evaluating venetoclax in multiple myeloma has support from the observation that the antiapoptotic proteins BCL-2 and MCL-1 promote survival of multiple myeloma cells.² Venetoclax induces cell death in myeloma cell lines and tissue samples. The drug has proven especially active in myeloma associated with t(11;14), which correlates with higher ratios of BCL-2:MCL1 and BCL-2:BCL2L1 (BCL-X_L) mRNA.³

Kumar reported findings from a phase I open-label, multicenter trial of venetoclax in patients treated with 1 or more prior myeloma regimens. All patients received venetoclax daily in 21-day cycles. Patients whose disease progressed on venetoclax monotherapy could receive dexamethasone and continue treatment.

Investigators enrolled 66 patients who had a median age of 63. About 60% had International Scoring System (ISS) stage II/III disease. The most common cytogenetic abnormalities were 13q deletion (48%), t(11;14) translocation (46%), and hyperdiploid (41%). The patients had received a median of 5 prior lines of therapy for myeloma. Two-thirds of the patients had disease that was refractory to both bortezomib (Velcade) and lenalidomide (Revlimid).

The objective response rate for the entire study population was 21%, including stringent complete responses (sCR) in 6%, complete responses (CR) in 4%, and very good partial responses (VGPR) in 8%. Among the 30 patients with the t(11;14) abnormality, 13% achieved sCR, 13% had VGPR, and 10% had CR. Venetoclax activity in t(11;14) myeloma was independent of refractory status to prior therapies, said Kumar.

Venetoclax had the greatest activity in a subgroup of patients with t(11;14) translocation associated with a high BCL-2:BCL2L1 ratio. Eight of 9 patients in the subgroup responded to treatment, including 3 sCR, 3 CR, and 1 VGPR. In contrast, 15 patients with a low BCL-2:BCL2L1 ratio had an overall response rate of 20%.

Two patients had dose-limiting toxicity (abdominal pain and nausea) at 600 mg of venetoclax. The most common grade 3/4 hematologic adverse events were thrombocytopenia (26%), neutropenia (21%), anemia (14%), leukopenia (14%), and lymphopenia (15%). The most common grade 3/4 nonhematologic adverse event was back pain (8%). Pneumonia was the most common serious adverse event (8%), followed by sepsis (5%), and pain, pyrexia, cough, and hypotension (3% each).

References

1. Kumar S, Vij R, Kaufman JL, et al. Venetoclax monotherapy for relapsed/refractory multiple myeloma: safety and efficacy results from a phase I study. Presented at: 58th ASH Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA. Abstract 488.
2. Touzeau C, Dousset C, Le Gouill S, et al. The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia. 2014;28:210-212.
3. Punnoose EA, Leverson JD, Peale F. Expression profile of BCL-2, BCL-XL, and MCL-1 predicts pharmacological response to the BCL-2 selective antagonist venetoclax in multiple myeloma models. Mol Cancer Ther. 2016;15:1132-1144.

US FDA

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 6 to 2 in favor of the risk/benefit profile of subcutaneous daratumumab (daratumumab and hyaluronidase-fihj [Darzalex Faspro]) as monotherapy for the treatment of patients with high-risk smoldering multiple myeloma, based on data from the phase 3 AQUILA trial (NCT03301220).1

AQUILA evaluated subcutaneous daratumumab monotherapy in this patient population. Based on findings from AQUILA, in November 2024, the FDA received a supplemental biologics license application seeking the approval of subcutaneous daratumumab as monotherapy for the treatment of patients with high-risk smoldering multiple myeloma.2

Notably, there are currently no FDA-approved therapies for patients with high-risk smoldering multiple myeloma.3

AQUILA Trial Design and Key Data

The randomized, open-label AQUILA trial compared subcutaneous daratumumab with active monitoring in 390 patients with smoldering multiple myeloma per protocol-defined high-risk criteria and had measurable disease.

Patients were randomly assigned to receive subcutaneous daratumumab for a maximum of 39 cycles or 36 months, whichever occurred first (n = 194); or undergo active monitoring (n = 196). Internal review committee–assessed progression-free survival (PFS) served as the primary end point. Key secondary end points included objective response rate, time to progression on subsequent multiple myeloma therapy (PFS2), and overall survival (OS).

The median PFS was not reached (NR; 95% CI, 66.7-not evaluable) with subcutaneous daratumumab vs 41.5 months (95% CI, 26.4-53.3) with active monitoring (HR, 0.49; 95% CI, 0.36-0.67; P < .0001). The median PFS2 was NR in either arm (HR, 0.58; 95% CI, 0.35-0.96). The median OS was also NR in both arms (HR, 0.52; 95% CI, 0.27-0.98); the difference in 5-year OS rate between the 2 arms was 6%.

FDA’s Position

Smoldering Multiple Myeloma Disease Criteria

During the meeting, the FDA questioned the applicability of the AQUILA findings to patients with high-risk smoldering multiple myeloma. These concerns were raised due to differences between the post-2014 smoldering multiple myeloma high-risk models and the AQUILA protocol-defined high-risk criteria, which compiled criteria from various high-risk smoldering multiple myeloma high-risk models ranging from 2007 to 2020—as well as additional criteria—to define patients with high-risk disease.

The FDA explained that the AQUILA protocol–defined high-risk smoldering multiple myeloma criteria did not completely align with available high-risk smoldering multiple myeloma models and that the AQUILA protocol allowed for patients in various risk groups to be enrolled. Based on individual criteria for the PETHEMA 2007, Mayo 2008, Mayo 2018, and IMWG 2020 high-risk smoldering multiple myeloma models, 4% to 25% of patients in AQUILA would have been classified as low risk, whereas 72% to 85% of patients would have been classified as high risk. Moreover, fewer than half of patients enrolled on AQUILA would have been classified as high risk per the Mayo 2018 risk model; the remainder would have been classified as low or intermediate risk per Mayo 2018 criteria.

“In clinical practice, there’s some flexibility about how high risk is defined, as all definitions have been found to lead to similar outcomes,” Sagar Lonial, MD, FACP, of the Winship Cancer Institute of Emory University in Atlanta, Georgia, stated during the ODAC meeting.1 “The PFS curve…for the control arm is consistent with a high-risk smoldering myeloma group, no matter what definition you use. This point is important, as all these definitions rely on a key set of biomarkers, and patients with elevated levels of these disease markers are more likely to progress to myeloma. [Therefore], while they may differ on the surface, ultimately, they agree and give you the same end point.”

Lonial noted that the 2-year risk of progression in high-risk patients was similar regardless of whether the PETHEMA 2007, Mayo 2008, Rajkumar Consensus paper 2015, or Mayo 2018 criteria were used.

Clinical Relevance of the AQUILA End Points

The FDA also raised concerns about the clinical relevance of the AQUILA end points.3 The regulatory agency noted that although PFS measurement typically requires a relatively smaller sample size and can be assessed earlier than OS, the readout of this end point may be skewed by assessment bias, PFS can be defined differently across clinical trials, and it does not necessarily correlate with OS.

The updated 2014 IMWG criteria for smoldering multiple myeloma resulted in the reclassification of some patients who met the criteria for smoldering multiple myeloma prior to 2014, instead being classified as having multiple myeloma. Before 2014, multiple myeloma was defined as greater than 10% bone marrow plasma cells and any CRAB criteria (hypercalcemia, renal failure, anemia, and lytic bone lesions). The 2014 IMWG update to the multiple myeloma criteria includes the previous criteria, although patients can meet multiple myeloma criteria per the CRAB criteria or SLiM biomarkers (≥60% clonal bone marrow plasma cell levels; involved/uninvolved free light chain ratio >100; and >1 focal lesion on MRI). Additionally, patients who meet multiple myeloma criteria may be symptomatic. Conversely, patients who meet smoldering multiple myeloma criteria must be asymptomatic with absent CRAB criteria.

In AQUILA, the primary end point of PFS—defined as progression to CRAB or SLiM criteria or death—was met with subcutaneous daratumumab. Notably, the PFS benefit with subcutaneous daratumumab was pronounced in the subgroup of AQUILA patients who met the Mayo 2018 high-risk criteria (HR, 0.36; 95% CI, 0.23-0.58). However, the FDA noted that although the trial met its PFS end point, this was primarily due to delayed diagnosis of multiple myeloma, as most patients in AQUILA who experienced PFS events were diagnosed with multiple myeloma based on SLiM criteria. Notably, few PFS events were attributed to symptomatic CRAB criteria events or death. Additionally, 21% of patients across both arms did not initiate subsequent multiple myeloma therapy after experiencing progressive disease. The regulatory agency emphasized that these factors collectively add to the lack of clarity regarding the clinical meaningfulness of the PFS improvement with subcutaneous daratumumab in high-risk smoldering multiple myeloma.

Regarding secondary end points, the regulatory agency added that PFS2 outcomes were not substantially different between the AQUILA arms. Additionally, many patients did not receive subsequent therapies that were considered standard of care (SOC) for patients with newly diagnosed multiple myeloma. Therefore, the FDA argued that the effect of high-risk smoldering multiple myeloma treatment on outcomes following first-line multiple myeloma treatment remains unclear. Moreover, the regulatory agency noted that the AQUILA trial sample size was not large enough to show a significant OS benefit with subcutaneous daratumumab. However, at the time of the PFS analysis, the number of OS events was lower than anticipated, and most deaths had occurred in the “other” category following treatment with subsequent therapy.

“These risk groups are phenomenal, but they're terrible for regulatory approval,” Daniel Spratt, MD, of Case Comprehensive Cancer Center in Cleveland, Ohio, stated during the discussion. “These are prognostic risk groups; these are not predictive...The problem is we don't know [which] subgroup is really benefiting from this therapy...I'm very torn here in that many of the [meaningful] things we're trying to show were not demonstrated [in the trial], but there are definitely some strong signals. [Patient] anxiety from biochemical changes is a physician's failure to reassure patients. We are...incentivized as physicians to essentially not fully reassure patients, and biochemical changes, as shown in the study, did not always translate to harm...We heard pretty powerful statements from some patients today [about] how fearful they are when they have MGUS or smoldering myeloma...[but] that alone—anxiety from biochemical changes—should not be the definition of clinical meaningfulness to me.”

Spratt contextualized his positive vote by saying, “I would implore the FDA that...the high-risk definition is somehow defined [in the future]. I would [also] implore the sponsor that these data...become available for further understanding [and] for optimal risk stratification, so that when you add on multiple drugs...we can have a stronger, more enriched [patient] group.”

Safety and PROs

The FDA pointed out the higher rates of toxicities in the daratumumab arm vs active monitoring. More patients in the daratumumab arm vs the active monitoring arm experienced any-grade treatment-emergent adverse effects (TEAEs; n = 97 vs 84), grade 3/4 TEAEs (n = 40 vs 30), serious AEs (n = 29 vs 19), TEAEs leading to trial discontinuation (n = 6 vs 0), and TEAEs leading to dose modification (n = 47 vs 0). However, the incidence of grade 5 TEAEs was lower in the daratumumab arm (n = 1) vs the active monitoring arm (n = 2).

Notably, the FDA explained that the rate of infections was higher in the daratumumab arm (any-grade, 80%; grade ≥ 3, 17%) vs the active monitoring arm (45%; 5%). However, S. Vincent Rajkumar, MD, of Mayo Clinic in Rochester, Minnesota, noted that these infections were typically not severe and short lived.1

Jeffrey Rubin, a patient with high-risk smoldering multiple myeloma, echoed the favorable opinions about the use of subcutaneous daratumumab in smoldering multiple myeloma that were shared by many patients and patient advocates that were voiced during the meeting. “I consider myself lucky to be receiving treatment at an early stage of the disease process. More research should be done to optimize the timing of treatment for people with this condition,” Rubin emphasized. “Nonetheless, I firmly believe it is worthwhile to provide people with a SOC treatment option, such as daratumumab monotherapy, that they could choose based on personal and medical factors.”

Notably, the FDA argued that they could not make meaningful conclusions from the patient-reported outcome (PRO) data collected on the trial due to infrequent PRO assessments; the potential inappropriateness of the PRO measures used in the trial for assessing symptoms and function due to the nature of smoldering multiple myeloma as an asymptomatic precursor condition with progression driven primarily by biochemical events; and the fact that AQUILA was not designed to detect PRO differences between the 2 arms.3 The FDA also noted that similar PRO scores between 2 arms of a trial are not evidence of equivalence between the arms or tolerability of the investigational regimen.

“Is daratumumab appropriate for all patients with smoldering myeloma? No, not by any stretch,” Solly Chedid, MD, of Singing River Cancer Center in Gulfport, Mississippi, stated during the open public hearing. Notably, Chedid was not a member of the voting committee. “Its [use is] contingent on the medical community to define...which patients have a high risk of converting to multiple myeloma, [and] treat those patients appropriately with a relatively low toxic agent... I think the benefit of daratumumab for high-risk smoldering multiple myeloma is well worth the effort for most of these patients and properly defined patients.”

“Risk is such a personal perception [and] decision that I do see a sizeable portion of a population whose perception of benefit would outweigh the risk, even apart from what we see in the data today,” Mark Conaway, MD, of the University of Virginia School of Medicine in Charlottesville, concluded during his explanation of his vote in favor of the regimen's risk/benefit profile.

References

1. May 20, 2025, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. https://www.youtube.com/live/iSGFdhMgh1E
2. Johnson & Johnson submits applications in the U.S. and EU seeking approval of Darzalex Faspro/Darzalex (daratumumab) as subcutaneous monotherapy for high-risk smouldering multiple myeloma. News release. Johnson & Johnson. November 8, 2024. Accessed November 8, 2024. https://www.jnj.com/media-center/press-releases/johnson-johnson-submits-applications-in-the-u-s-and-eu-seeking-approval-of-darzalex-faspro-darzalex-as-subcutaneous-monotherapy-for-high-risk-smoldering-multiple-myeloma
3. Daratumumab and hyaluronidase-fihj FDA opening remarks. FDA. May 20, 2025. Accessed May 20, 2025. https://www.fda.gov/media/186559/download