Silas Inman

For patients with relapsed or refractory myeloma, Belamaf (belantamab mafodotin) plus bortezomib and dexamethasone — a regimen referred to as BVd — lengthened the time that patients lived before experiencing disease progression compared to those treated with Darzalex (daratumumab), bortezomib and dexamethasone (DVd), according to research presented at the 2024 

American Society of Clinical Oncology Annual Meeting

A new three-drug regimen, called BVd, was found to be more effective than the standard regimen, DVd, for patients with relapsed or refractory myeloma.

BVd increased progression-free survival (PFS) by 59% compared to DVd. PFS is the time patients live until their disease worsens.

More data is needed to confirm the overall survival benefit of BVd.

The researchers concluded that BVd is a potential new standard of care for relapsed/refractory myeloma patients.

The median progression-free survival (PFS; time patients live until disease worsening) with BVd was 36.6 months compared with 13.4 months for DVd, representing a 59% reduction in the risk of progression or death.

Data for overall survival (OS; time from treatment until death of any cause) were not ready at the time that the researchers collected data, meaning that not enough patients had died for them to calculate an average. At 18 months, 84% of patients remained alive in the BVd group compared with 73% in the DVd arm, indicating an early, but not yet statistically significant, reduction of 43% in the risk of death. When an outcome difference between two datapoints is not statistically significant, it means that the researchers could not be certain that one regimen performed better than the other.

“There was a statistically significant and clinically meaningful progression-free survival benefit, with a strong and clinically meaningful overall survival benefit favoring BVd over DVd. All the response as well as the different response categories were also in favor of BVd,” lead investigator Dr. María-Victoria Mateos, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Centro de Investigación del Cáncer (IBMCC-USAL, CSIC), said during a presentation of the results. “These trials support the potential for BVd as a potential new standard of care for relapsed/refractory myeloma patients.”

In the study, 494 patients were randomly assigned to receive BVd (243 patients) or DVd (251 patients).

The median age of patients in the BVd arm was 65 years and was 64 years in the DVd arm. The ECOG performance score was 1 or less for 96% of patients, meaning that the patients could independently perform all of their daily tasks. Most had stage 1 or 2 disease (95%). The median time from diagnosis in the BVd arm was 4.3 years compared with 3.9 years in the control group. Two-thirds of patients had standard cytogenetic risk, meaning that they did not have genetic mutations associated with poor prognosis (72% and 70% in the BVd and DVd arms, respectively). The most common high-risk cytogenetic characteristics was t(4;14), which was present in 17% of participants. This was followed by a deletion in 17p13 for 12% in the BVd group and for 14% in the DVd arm.

Extramedullary disease (myeloma located outside of the bone marrow) was present for 5% of those in the BVd arm compared with 10% of those in the DVd group. Half of patients had received one prior line of therapy, and 12% in the BVd arm and 11% in the DVd group had received four or more lines of therapy. Prior therapies were similar between groups and the time to relapse after the most recent therapy was the same for each group, with 20% having relapsed in 12 or less months. There were 2% of patents in the DVd arm who had received prior Darzalex. Rates of prior chemotherapy and autologous stem cell transplantation were similar.

In a pre-specified subgroup analysis, Mateos noted that BVd was superior to DVd across all subgroups, including those with disease that did not respond to prior Revlimid (lenalidomide) and those with high-risk cytogenetics.

Deeper responses were noted with BVd versus DVd, Mateos noted. The objective response rate (ORR; percentage of patients whose disease shrunk or disappeared) with BVd was 82.7%, which consisted of a stringent complete response (sCR; when there are no myeloma cells or proteins detected in the bone marrow or urine) rate of 14% and a complete response (CR; no disease detected in the bone marrow) rate of 20.6%, for a CR or better rate of 34.6%.

The CR or better rate with DVd was 17.1% and consisted of a sCR rate of 5.2% and a CR rate of 12%. The ORR in the DVd arm was 71.3%. Minimal residual disease (MRD)-negative (no cancer detected in the blood) CRs were experienced by 24.7% of those in the BVd arm versus 9.6% in the DVd arm. Very good partial responses (VGPR; 90% or more decrease in blood M protein, associated with myeloma) were seen in 31.3% of those treated with BVd and for 29.1% of those treated with DVd. MRD-negative VGPR or better rates were 38.7% and 17.1% for BVd and DVd, respectively.

“The CR rate or better was doubled with BVd and it is important to note the superiority of MRD negativity rate, which in myeloma is one of the most important factors predicting outcome,” Mateos said.

Side effects of any grade was experienced by all patients enrolled in the trial. Moderate to severe (grade 3/4) side effects that were related to treatment occurred in 90% of those enrolled in the BVd arm compared with 67% in the DVd group. Side effects led to treatment discontinuation for 31% of patients in the BVd arm compared with 19% in the DVd group. Side effects led to a dose reduction for 75% of patients in the BVd group compared with 59% in the DVd group. Treatment-related serious side effects were seen in 19% of those in the BVd group and for 12% in the DVd group. Fatal side effects related to study drug were experienced by seven patients in the BVd arm compared with two in the DVd arm.

Changes in baseline correct visual acuity were the most unique side effects, Mateos noted. Overall, 34% of patients experienced a worsening in visual acuity from 20/20 to 20/50, or blurred vision, Mateos said. There were 2% of patients who experienced a shift to 20/200 vision, or impaired vision.

“With dose adjustments and delays, a majority of patients resolved these ocular events, and only 9% of patients had to discontinue treatment due to ocular events,” said Mateos.

An analysis was conducted to examine whether dose interruptions and delays impacted PFS. For those with one or more dose delays that lasted 12 weeks or longer, the median PFS was 36.6 months, which matched the overall median for the trial. Moreover, quality was not different between groups, Mateos noted.

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Articles

Belamaf plus bortezomib and dexamethasone lengthened the time patients with relapsed or refractory myeloma lived before their disease got worse. 

Belamaf Regimen Improves Progression-Free Survival in Myeloma 

Neoadjuvant (primary cancer treatment) Opdivo (nivolumab) plus Yervoy (ipilimumab) followed by therapeutic lymph node dissection (surgical removal of the lymph nodes) and response-driven adjuvant therapy (additional cancer treatment after the primary treatment to reduce the risk for the cancer to return) reduced the risk of progression, recurrence or death by 68% compared with therapeutic lymph node dissection and adjuvant Opdivo alone for patients with macroscopic stage 3 node-positive melanoma, study findings demonstrated.

Findings from the phase 3 NADINA study were presented at the 2024 ASCO Annual Meeting.

The combination of neoadjuvant Opdivo (nivolumab) and Yervoy (ipilimumab) followed by response-driven adjuvant therapy significantly reduced the risk of progression, recurrence or death by 68% compared to therapeutic lymph node dissection and adjuvant Opdivo alone in patients with stage 3 node-positive melanoma.

The NADINA phase 3 study demonstrated that 12-month event-free survival (EFS) was 83.7% for patients receiving the combination therapy, versus 57.2% for those receiving adjuvant therapy alone, with consistent benefits across various subgroups and a correlation between pathologic complete response and EFS.

Subgroup analyses indicated improved EFS for both BRAF-mutant and BRAF wild-type melanoma patients with neoadjuvant Opdivo/Yervoy compared to adjuvant therapy alone, with significant pathologic complete response rates observed.

The neoadjuvant combination therapy was associated with higher rates of severe side effects, but overall quality of life was similar to that of the adjuvant therapy group, highlighting the benefit of immunotherapy prior to surgery as a new standard of care for stage 3 melanoma.

At an analysis conducted after a median 9.9 months’ of follow-up, the estimated 12-month event-free survival (the time after primary treatment ends when a patient is free from the complications or events that treatment was meant to delay or prevent; EFS) rate with the neoadjuvant combination of Opdivo and Yervoy plus response-drive adjuvant therapy was 83.7% compared with 57.2% for adjuvant therapy alone. This benefit remained consistent across key subgroups, and a correlation was seen between pathologic complete response rates (the lack of the signs of cancer in tissue samples that are removed during surgery or after treatment) and EFS.

"This was at once the interim and the final analysis, because it was highly statistically significantly positive," lead investigator Dr. Christian U. Blank, Netherlands Cancer Institute (NKI-AVL), Amsterdam, Netherlands, said during a press briefing on the results. "I think NADINA defines now in melanoma that neoadjuvant immunotherapy is the new standard of care for macroscopic stage 3 melanoma. It is a new template for other malignancies implementing an immunotherapy regimen followed by response driven activities."

In the study, 423 patients were randomly assigned to the neoadjuvant arm (212 patients) or the standard-of-care adjuvant group (211 patients). Most patients in the study were male (65%), and ages were mixed between those over and under the age of 60. All patients had at least 1 PET-positive lymph node at diagnosis, with 19.6% having 2 to 3 nodes and 3.5% with more than 3 positive nodes. There were 11.3% of patients with metastases in transit (when cancer cells travel from the original tumor but may have gotten stuck in between the tumor and the lymph nodes).

For those with BRAF-mutant melanoma (which may lead to uncontrolled cell division and growth leading to cancer), the EFS rate was 83.5% with neoadjuvant Opdivo/ Yervoy compared with 52.1% for those treated with adjuvant therapy alone. In the BRAF wild-type group (when the BRAF gene is found in its natural, non-mutated state), the EFS with neoadjuvant Opdivo/Yervoy was 83.9% compared with 62.4% with adjuvant therapy alone.

By local assessment (the evaluation of a patient’s response to treatment by an oncologist directly involved in their care), the major pathologic response rate (how to measure how the disease has responded to treatment) with neoadjuvant Opdivo/Yervoy was 56.6% and by central review (independent of biopsies, scans, or other measurements typically performed during a trial), it was 59%. The pathological complete response rate (lack of all signs of cancer) was 45.8% by local assessment and 47.2% by central review. A minority of patients had a pathological partial response (decrease in tumor size or extent of cancer in the body) of 9.4% by local assessment and 8% by central review. For those with a pathological complete response, the probability of relapse-free survival (the time after treatment when a patient survives without symptoms or signs of that cancer; RFS) at 12 months was 95.4%. For those with a near-pathological complete response (minimal amount of cancer remaining), which was included in the major pathologic response criteria, the 12-month RFS rate was 94.1%. Those with a partial response had a 12-month RFS rate of 76.1%.

Subgroup analyses favored Opdivo and Yervoy across all subgroups.

"The study confirms and shows for the first time in a phase 3 study that giving immunotherapy before surgery results in superior outcomes to giving immunotherapy only after surgery," said ASCO commentator Dr. Michael Lowe, from Emory University in Atlanta. "The study also confirms that giving two immunotherapy drugs before surgery results in excellent responses."

The most observed grade 3 or higher (severe or worse) side effects in the neoadjuvant arm were infection, diarrhea, abnormal blood counts, rash, fever and fatigue. Overall, serious side effects were observed in 29.7% of patients in the neoadjuvant group compared with 14.7% in the standard therapy arm. There was one death in the adjuvant only arm related to pneumonitis (inflammation of the lungs). Surgery-related side effects were reported in 14.6% of patients in the neoadjuvant Opdivo/Yervoy arm and in 14.4% of the adjuvant group.

"The quality of life was equal for the neoadjuvant arm and for the adjuvant arm, despite the difference in grade 3 or 4 (severe or life-threatening) toxicities in these patients," said Blank. "The majority of toxicity or quality of life reduction for the patients comes from the surgery and not from the immunotherapy."

Opdivo plus Yervoy in the neoadjuvant setting reduced the risk for recurrence, progression or death, potentially offering patients with stage 3 melanoma a new standard of care. 

Neoadjuvant Opdivo Plus Yervoy Provides ‘Excellent Responses’ in Stage 3 Melanoma

Enlarged spleen is a common symptom of myelofibrosis, but a new regimen of navitoclax and Jakafi may help, recent findings showed.

The combination of navitoclax with Jakafi (ruxolitinib) reduced spleen volume by 35% or more at week 24 when being compared with Jakafi in combination with placebo for patients with myelofibrosis, according to findings from the phase 3 TRANSFORM-1 study that were presented at the 2023 

American Society of Hematology (ASH) Annual Meeting and Exposition

After a median follow-up of 14.9 months, navitoclax and Jakafi resulted in a spleen volume reduction of 35% or more by week 24 for 63.2% of patients compared with 31.5% for placebo plus Jakafi, marking a significant overall difference of 31%. At week 24, there was an average -9.7 change in TSS (total symptom score) with navitoclax/ Jakafi from baseline compared with a change of -11.1 for placebo plus Jakafi, which was not statistically significant.

“The spleen volume reduction was doubled and highly statistically significant. There’s no question there, but for the secondary end point, the total symptom score, both groups have the reduction, but it was not statistically significant,” said lead investigator Dr. Naveen Pemmaraju, Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “There may be multiple reasons for that. (Jakafi) alone is a nice drug for symptom improvement, but when you add in a second drug, you're improving the outcomes for the patient but maybe introducing a bit more toxicity. The statistical significance may not have come out because of that.”

Oral Jakafi is a drug that inhibits certain proteins (BCL-XL, BCL-2 and BCL-W), which may impart unique efficacy for myeloproliferative neoplasms (MPN).

“It turns out in MPN and myelofibrosis that the BCL-XL pathway appears to be a bit more important than the BCL-2,” said Pemmaraju. “In myelofibrosis, BCL-XL appears to be upregulated and so in vitro studies showed that either the Jakafi by itself or even better in combination with the Jakafi can overcome JAK resistance and add benefit.”

The median TSS in the combination arm was 21 compared with 24 in the control group. A minority of patients were transfusion dependent at baseline, at 4% in the combination group and 3% in the control arm. The most common risk score was intermediate-2, at 83% in the combination group and 87% in the control. JAK2 V617F was the most common driver mutation, with approximately two-thirds having this mutation in each group. Nearly half of patients had mutations associated with high molecular risk. “These high molecular risk mutations are very important,” said Pemmaraju. “Earlier studies may not have captured this, and we were fortunate to capture this in the majority of patients.”

There was a significantly higher rate of spleen volume reduction of 35% or more with the combination at all time points throughout the study. Across the full-time scale of the study, 76.8% of those in the combination arm experienced a spleen volume reduction of at least 35% compared with 41.7% with Jakafi in combination with placebo, which was a meaningful 34.6% reduction.

The median time to first spleen volume reduction of 35% response was similar between groups, at 12.3 vs 12.4 weeks, for the combination and control arms, respectively. Fewer patients lost spleen volume reduction of 35%, in the combination group (18.8%) compared with the control arm (26.4%). Nearly three-fourths of patients had a 12-month duration of spleen volume reduction of 35% in each arm (76.7% vs 76.9%, combination and control, respectively).

The rate of any-grade side effect was similar between arms, with more patients in the combination arm having a grade 3 or higher side effect (85% vs 70%). The most common grade 3 or higher side effects in the combination vs control arms, respectively, were thrombocytopenia (51% vs 15%), anemia (46% vs 39%) and neutropenia (38% vs 4%). For all grade events, diarrhea was more commonly seen with the combination vs control (34% vs 14%). Serious side effects were less common with the combination at 26% compared with 32% for the control arm. Side effects that led to dose reduction or dose interruption were twice as common in the combination arm.

“Importantly, dose reductions and interruptions were mostly due to the thrombocytopenia, but importantly none of those were due to clinical bleeding,” said Pemmaraju.

In 2022, AbbVie, the company developing navitoclax noted plans for a submission to the FDA in 2023, pending pivotal study results.

The recent phase 3 TRANSFORM-1 study concluded that navitoclax combined with Jakafi showed significant spleen volume reductions in patients with myelofibrosis.

Navitoclax Plus Jakafi Improves Spleen Volume Reductions in Myelofibrosis

Patients with grade 2 IDH-mutant glioma experienced a 61% reduced risk of progression or desk when treated with vorasidenib. 

Patients with grade 2 IDH-mutant glioma (a type of brain cancer) experienced a 61% reduced risk of progression or desk when treated with vorasidenib (AG-881) compared with placebo, according to results from the phase 3 INDIGO clinical trial, presented at the 2023 

Progression-free survival (time from treatment until disease progression) with vorasidenib was 27.7 months compared with 11.1 months for those treated with placebo. Treatment in the study was given during a “watch and wait” period used to delay the start of debilitating chemoradiation therapy, which is standard following glioma resection. In addition to improvements in progression-free survival, vorasidenib also resulted in a significant lengthening in the interval to receipt of another treatment.

 mutations with vorasidenib significantly delays tumor growth and the need for more toxic therapies,” lead author Dr. Ingo Mellinghoff, of Memorial Sloan Kettering Cancer Center, said in a statement. “This is clinically meaningful because patients diagnosed with grade 2 glioma with 

 mutations are typically young, otherwise healthy individuals. The results of this trial offer a chance to change the treatment paradigm for this type of glioma and could bring the first new targeted therapy for low-grade glioma.”

In the study, 331 patients were randomly assigned to receive oral vorasidenib (168 patients) at 40 mg once daily or matched placebo (163 patients) in 28-day cycles.

Histologic subtypes of low-grade glioma were evenly distributed between oligodendroglioma and astrocytoma. The location of the tumor at primary diagnosis was frontal for two-thirds of patients. The longest diameter of tumor was 2 or more centimeters for most patients (82.7% vs 84.0%, for vorasidenib and placebo, respectively). The median interval from last glioma surgery to randomization was 2.4 years and 21.5% had received 2 or more tumor surgeries before enrollment.

 alteration, which was present in 97% of those in the vorasidenib arm and for 93.3% in the placebo group. More than half of patients also had a codeletion in chromosome 1p/19q.

The median follow-up was 14 months for vorasidenib and was 14.3 months for placebo. Progression occurred in 28% of those in the vorasidenib arm compared with 54% for those in the placebo group. Investigator-assessed results were similar to those reported in the primary analysis, with vorasidenib remaining superior.

There was an 85.6% likelihood of not requiring another intervention at 18 months in the vorasidenib arm compared with 47.4% in the placebo arm. At the 24-month assessment, 83.4% of patients in the vorasidenib arm still had not required another intervention compared with 27% in the placebo group. Following initial results, the study was unblinded and patients were allowed to cross over. There were 52 patients initially in the placebo arm (31.9%) who crossed over to receive vorasidenib.

“Second interim analysis was so clear and showed efficacy so clearly that the data monitoring board recommended that we unblind,” Mellinghoff noted.

The 18-month progression-free survival rate was 60.4% in the vorasidenib group compared with 26.7% in the placebo group. The 24-month progression-free survival rates were 50.7% in the vorasidenib arm compared with 17.6% in the placebo group.

The objective response rate (percentage of patients whose disease shrunk as a result of treatment) was 10.7% with vorasidenib compared with 2.5% for placebo. In the vorasidenib group, this included two partial responses (1.2%) and 16 minor responses (9.5%). The placebo arm was all minor responses. Most patients had stable disease, with progressive disease seen in 6.0% and 8.6% of those in the vorasidenib and placebo arms, respectively.

An ASCO Expert commenting on the results, Dr. Glenn Lesser, said “These results are quite striking and they’re statistically highly significant, and more important, they’re clinically very important. In select patients with low-grade glioma, we can potentially delay the use of these toxic chemotherapy and radiation for years, perhaps many years, and delay the toxicity.”

Side effects of any grade occurred in 94.6% of those in the vorasidenib group and for 93.3% of those in the placebo group. Grade 3 or higher (moderate to severe) side effects occurred in 22.8% of patients in the vorasidenib arm compared with 13.5% of those in the placebo arm. The most common side effects in the vorasidenib arm were related to liver enzyme increases, including increases in alanine aminotransferase (ALT; 38.9%; 9.6% was grade 3 or higher), aspartate aminotransferase (AST; 28.7%; 4.2%), and gamma-glutamyl transferase (GGT; 15.6%; 3.0%).

There were 3 serious side effects reported in the vorasidenib arm that were reported to be associated with the treatment, specifically ALT increase, liver failure and hepatitis. All serious side effects were considered resolved at the time of the analysis in September 2022. Side effects led to discontinuation for 3.6% of patients in the vorasidenib arm compared with 1.2% in the placebo arm. Dose reductions were needed for 10.8% of those in the vorasidenib arm compared with 3.1% in the placebo group. Dose interruptions occurred for approximately one-quarter of patients in both arms.

Vorasidenib reduced the risk of disease progression or death for certain patients with low-grade brain cancer, recent study results showed. 

Silas Inman

Belamaf Regimen Improves Progression-Free Survival in Myeloma

Neoadjuvant Opdivo Plus Yervoy Provides ‘Excellent Responses’ in Stage 3 Melanoma

Navitoclax Plus Jakafi Improves Spleen Volume Reductions in Myelofibrosis

Vorasidenib May ‘Change the Treatment Paradigm’ for Low-Grade Glioma

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