® magazine, has been with the team since October 2020 and has covered health care in other specialties before joining MJH Life Sciences. She graduated from Emerson College with a Master’s degree in print and multimedia journalism. In her free time, she enjoys buying stuff she doesn’t need from flea markets, taking her dog everywhere and scoffing at decaf.

Darlene Dobkowski, MA

A treatment combination called D-VRd showed improvements in minimal-residual disease responses in certain patients with newly diagnosed multiple myeloma. 

In patients with transplant-ineligible or -deferred newly diagnosed multiple myeloma, adding Darzalex (daratumumab) to Velcade (bortezomib), Revlimid (lenalidomide) and dexamethasone (VRd) demonstrated improved minimal-residual disease (MRD) responses.

These findings were based on an analysis of MRD outcomes from the phase 3 CEPHEUS trial, presented at the 

In addition, the combination led to improved progression-free survival (PFS), regardless of MRD negative or positive status.

Minimal-residual disease (MRD): microscopic traces of cancer that remain in the body after receiving treatment. MRD-negativity means there are no detectable traces of cancer in the body.

Progression-free survival (PFS): time patients live without their cancer worsening or spreading.

Complete response (CR): patients fully responded to treatment, meaning they no longer show signs or symptoms of cancer.

Partial response (PR): patients respond to treatment but not completely, meaning their tumors shrunk after receiving treatment.

End point: the main goal of a study measured at the end to see if the treatment worked.

Subcutaneous: treatment given beneath the skin.

ECOG performance status: a measurement of how independently patients can complete daily tasks. A score of 0 means patients can perform tasks fully independently and a score of 4 means they cannot perform tasks independently.

“These data support the use of [Darzalex] in combination with VRd as a normal standard of care in patients with newly diagnosed multiple myeloma who are transplant ineligible or when transplant is deferred,” Dr. Sonja Zweegman from the Department of Hematology at Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Netherlands, said during a presentation of the data.

After a median follow-up of 58.7 months, at a 10

sensitivity, the overall MRD-negativity rate was 60.9% for patients treated with Darzalex plus VRd (197 patients) versus 39.4% for those given VRd alone (198 patients). At a 10

 sensitivity, the overall MRD-negativity rates were 46.2% for patients in the daratumumab plus VRd group versus 27.3% for the VRd group.

“It can be appreciated … that adding [Darzalex] to VRd led to a 50% increase in MRD negativity,” Zweegman said.

The 54-month PFS rates were 68.1% and 49.5%, respectively, reducing the risk for disease progression or death by 43%. Zweegman noted that the MRD negativity rates were generally consistent across prespecified subgroups.

When evaluating cumulative MRD negative complete response (CR) rates from the sensitivity level 10

, patients reached MRD negativity faster, with higher rates at all time points. “And the difference of the MRD negativity rates between the [two treatment groups] is increasing up to three years,” Zweegman added.

This same effect was seen at the sensitivity level 10

, which is even more related to PFS, she noted. “And importantly… [Darzalex] almost doubles the MRD negative CR rates that sustained for more than 12, 24 and 36 months.”

, MRD-negative patients experienced superior PFS, compared with MRD-positive patients in both treatment groups. Further, the 54-month PFS rates for MRD-negative patients treated with Darzalex plus VRd or VRd alone were 86.2% and 79.0%, respectively. In MRD-positive patients, these rates were 51% and 36.5%.

“So [Darzalex] provides PFS benefit regardless of the MRD negativity CR status,” Zweegman said.

The CR or better rate was 81.2% in the Darzalex group versus 61.6% in the VRd group. In the Darzalex plus VRd group, the stringent CR, CR, very good partial response (PR), and PR rates were 65.0%, 16.2%, 11.7% and 4.1%, respectively. In the VRd group, these respective rates were 44.4%, 17.2%, 25.3% and 6.1%.

Regarding safety, grade 3 or 4 (severe or life-threatening) treatment-emergent side effects occurred in 92.4% of patients in the Darzalex group versus 85.6% of patients in the VRd group. Treatment-emergent side effects led to discontinuation of all study drugs in 7.6% and 15.9% of patients, respectively.

The most common any-grade treatment-emergent side effects included blood and lymphatic disorders (Darzalex group, 82.7%; VRd group, 64.6%), including neutropenia (55.8%; 39.0%), thrombocytopenia (46.7%; 33.8%) and anemia (37.1%; 31.8%). Gastrointestinal disorders occurred (79.7%; 81.5%), including diarrhea (56.9%; 59%) and constipation (38.1%; 42.1%); general disorders and administration-site conditions (80.7%; 75.4%), including peripheral edema (42.1%; 39%) and fatigue (32%; 30.8%). Psychiatric disorders occurred (46.2%; 49.2%), including insomnia (32%; 32.3%); infections (91.9%; 85.6%), including upper respiratory tract infection (39.6%; 32.8%) and COVID-19 (38.1%; 24.6%); and second primary malignancies (7.6%; 9.2%).

More About MRD-Negativity in Multiple Myeloma

“We all know that MRD negativity is associated with longer survival, and it's a strong prognostic for clinical end points in multiple myeloma and a key goal of multiple myeloma therapy,” Zweegman explained. “And therefore, MRD negativity was supported by the [FDA Oncologic Drugs Advisory Committee] as an early end point for accelerated approval in multiple myeloma.”

The phase 3 CEPHEUS trial was the first phase 3 study of Darzalex with MRD as a primary end point. In the trial, investigators demonstrated that the addition of subcutaneous Darzalex with VRd in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma led to superior rates of overall and sustained MRD negativity, as well as more CR, and it significantly improved PFS.

At the 2024 ASH Annual Meeting, Zweegman reported on an expanded analysis of MRD outcomes from the CEPHEUS trial.

In the trial, investigators randomly assigned patients evenly to receive Darzalex at 1,800 milligrams (mg) once per week, then once every three weeks, plus 1.3 mg per square meter of Velcade; 25 mg of Revlimid and 20 mg of dexamethasone; or VRd alone at the same dosing schedule. Starting in cycle 9, patients in the experimental group received 1,800 mg of Darzalex once every 4 weeks plus 25 mg of Revlimid and 40 mg of dexamethasone; patients in the control group received Rd at the same dosing schedule.

The overall MRD-negativity rate with a CR or better served as the trial’s primary end point. Secondary end points included PFS; the proportion of patients with sustained MRD negativity with a CR or better for at least 12 months; and CR or better rate.

Patients were required to have an ECOG performance status (PS) of 0 to 2 and a frailty score of 0 or 1.

“Phase 3 Randomized Study of Daratumumab (DARA) + Bortezomib, Lenalidomide and Dexamethasone (VRd) Versus Alone in Patients with Transplant-Ineligible Newly Diagnosed Multiple Myeloma or for Whom Transplant Is Not Planned As Initial Therapy: Analysis of Minimal Residual Disease in the Cepheus Trial” by Dr. Sonja Zweegman, et al. Presented at: 2024 ASH Annual Meeting; December 7-10, 2024; San Diego, California.

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Articles

The addition of Darzalex (daratumumab) to the VRd regimen (Velcade, Revlimid, and dexamethasone) in transplant-ineligible or deferred newly diagnosed multiple myeloma patients significantly improved minimal-residual disease (MRD) negativity and progression-free survival (PFS). The phase 3 CEPHEUS trial demonstrated a 50% increase in MRD negativity with Darzalex, with consistent benefits across subgroups. Despite higher rates of severe side effects, the combination therapy showed superior MRD-negative complete response rates and PFS, supporting its use as a standard care option for this patient population.

Patients newly diagnosed with multiple myeloma who are transplant ineligible or deferred may benefit from receiving a Darzalex treatment combination. 

Darzalex Regimen May Improve MRD Responses in Multiple Myeloma

The FDA approved Braftovi plus Erbitux and mFOLFOX6 to treat patients with metastatic colorectal cancer with a BRAF V600E mutation.

The Food and Drug Administration (FDA) approved Braftovi (encorafenib) plus Erbitux (cetuximab) and mFOLFOX6 to treat patients with metastatic colorectal cancer with a BRAF V600E mutation.

mFOLFOX6 is a chemotherapy regimen consisting of oxaliplatin plus leucovorin plus fluorouracil, according to the FDA.

The accelerated approval, which was announced by an alert from the FDA, was based on findings from the BREAKWATER trial. The trial included patients with treatment naïve BRAF V600E mutation-positive metastatic colorectal cancer detected by an FDA-approved test, particularly the Qiagen therascreen BRAF V600E RGQ polymerase chain reaction kit.

Objective response rate: the percentage of patients with a partial or complete response to treatment.

Progression-free survival: the time during and after treatment when a patient with cancer lives with the disease without worsening.

Overall survival: the time from diagnosis or start of treatment when a patient with cancer is still alive.

Decreased neutrophil counts: lower than normal number of neutrophils, a type of white blood cell, which, when decreased, can impact the body’s ability to fight off infections.

Increased lipase counts: a higher level of an enzyme in the blood that is produced by the pancreas. Increased levels may indicate pancreatitis or other gastrointestinal problems.

Initially, patients were randomly assigned to receive either Braftovi with Erbitux every two weeks; Braftovi with Erbitux and mFOLFOX6 every two weeks; or mFOLFOX6, FOLFOXIRI (both every two weeks) or CAPOX (every three weeks). The last arm’s treatment was administered either with or without Avastin (bevacizumab). Eventually the trial was updated to only include the first two treatment assignments.

Patients were treated until unacceptable toxicity, disease progression, lost to follow-up, consent withdrawal or death, according to the alert. The approval was mainly based on results in patients assigned Braftovi with Erbitux and mFOLFOX6 compared with those treated with mFOLFOX6, FOLFOXIRI or CAPOX, which defined the control arm.

The main area of interest was objective response rate. In the trial, the objective response rate was 61% in patients treated with Braftovi with Erbitux and mFOLFOX6 compared with 40% in those in the control arm. The median duration of response was 13.9 months in the treatment arm and 11.1 months in the control arm.

Researchers will also be assessing overall survival and progression-free survival in the ongoing BREAKWATER trial as part of the post-marketing confirmatory evidence for this accelerated approval, according to the alert.

The most common side effects, which occurred in at least 25% of patients, included nausea, peripheral neuropathy, rash, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, bleeding and fever. In addition, the most common grade 3 (severe) or 4 (life-threatening) laboratory abnormalities, occurring in at least 20% of patients, were decreased neutrophil counts and increased lipase counts.

The FDA noted that the recommended dose of Braftovi is 300 milligrams, administered orally (via four 75-milligram capsules) once per day plus Erbitux and mFOLFOX6 until disease progression or unacceptable toxicity.

The FDA has granted accelerated approval for the combination of Braftovi (encorafenib), Erbitux (cetuximab), and mFOLFOX6 to treat metastatic colorectal cancer with a BRAF V600E mutation. This decision is based on the BREAKWATER trial, which demonstrated a 61% objective response rate for the treatment group compared to 40% for the control group. The trial also reported a median response duration of 13.9 months. Common side effects include nausea, peripheral neuropathy, and severe laboratory abnormalities like decreased neutrophil counts.

Braftovi received accelerated approval with Erbitux and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. 

FDA Approves Braftovi Plus Erbitux and Chemo for Metastatic Colorectal Cancer Subset

Targeting the estrogen receptor and HER2 pathways improved progression-free survival in patients with HR-positive, HER2-positive metastatic breast cancer.  

Targeting Multiple Pathways Improves Outcomes in Some With Metastatic Breast Cancer

Findings from a recent clinical trial demonstrated a meaningful improvement in progression-free survival when Ibrance (palbociclib) was added to anti-HER2 therapy plus endocrine therapy in patients with HR-positive, HER2-positive metastatic breast cancer.

Results from the AFT-38 PATINA trial, which were presented at the 

 (SABCS), also showed that finding these biomarkers by genetic testing can help identify patients best suited for particular treatments.

After SABCS, we spoke with CURE’s Editor-in-Chief, Dr. Debu Tripathy, about the potentially practice-changing data presented at the conference, one of which were from this trial. Tripathy is professor of medicine and chair of the department of breast medical oncology at The University of Texas MD Anderson Cancer Center in Houston.

Progression-free survival: the time during and after treatment when a patient with cancer lives without the disease worsening.

Well, you know, we're making incremental progress. I think the main lesson for all of us that are in practice is to make sure that we are obtaining biomarkers on all of our patients, not only receptor status, but now using genomics. I think this is going to be an important aspect of the future.

I think the one immediately practice-changing area is going to be that we should be treating our patients by blockading all the accessible pathways. And in the PATINA study, in particular, it became clear that targeting both the HER2 pathway and the estrogen receptor pathway is important in patients who express both of those receptors.

We've hypothesized that for a long time. We've never done a randomized trial to prove it, but now we have randomized data that when you add the CDK inhibitor component to endocrine therapy, you do get a signal. So the first thing is, at least use the endocrine therapy, and then maybe the standard will change to use the CDK inhibitor therapy too.

That will be really up to the [Food and Drug Administration] to see if the data in the PATINA trial is robust enough to do that. I believe it is. It was a well-powered study. The signal is clear. It does help. The only downside is that we did see more diarrhea in that group, in the patients that got both the [Herceptin (trastuzumab) and Perjeta (pertuzumab)] along with CDK inhibitor therapy. So I think that that's an important thing to recognize.

And we need to continue to put patients on clinical trials. That's the big message, too. Open trials and put patients on it, because the field is moving quickly, and we need everybody's engagement in that.

So there are more granular things that I can share, but I think those are the big main messages.

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FDA approves Ryoncil for children with GVHD.

The Food and Drug Administration (FDA) approved Ryoncil (remestemcel-L-rknd) for the treatment of steroid-refractory acute graft versus host disease in children aged two months and older.

This marks the first FDA-approved mesenchymal stromal cell therapy, according to an alert from the agency.

The approval was based on findings from the MSB-GVHD001 study, which analyzed data from 54 children with steroid-refractory acute graft versus host disease. In particular, participants enrolled on the study had grade B to D (moderate to very severe) steroid-refractory acute graft versus host disease. For purposes of this study, steroid-refractory acute graft versus host disease was defined as advanced graft versus host disease that progressed within three days or that has not improved within seven days of treatment with methylprednisolone, a corticosteroid medication.

Mesenchymal stromal cell therapy: the use of stem cells that develop in blood vessels, connective tissue and lymphatic tissue to treat a disease.

Overall response rate: the percentage of patients with a significant reduction or complete disappearance of a disease from treatment.

Complete response: the disappearance of all signs of a condition from treatment.

Partial response: a decrease in the extent of a disease in the body from treatment.

Edema: swelling from excess fluid in the body.

In the study, the researchers measured overall response rate at Day 28, which included complete and partial response rates, and duration of overall response, according to the alert. The median duration of response was calculated from response at Day 28 to either new systemic therapy for advanced graft versus host disease, progression or all-cause death.

At Day 28, the overall response rate was 70%, including a complete response rate of 30% and a partial response rate of 41%. The median duration of response was 54 days, and ranged from seven days to at least 159 days, the FDA noted

The most common side effects, which occurred in at least 20% of patients, included bacterial infectious disorders, viral infectious disorders, fever, infection with an unidentified pathogen, edema, bleeding, high blood pressure and abdominal pain.

The FDA explained that the recommended dose of Ryoncil is 2 x 106 MSC/kg body weight, to be administered intravenously twice a week for four consecutive weeks, totaling eight infusions. Of note, the infusions are delivered at least three days apart. Patients may continue treatment with Ryoncil based on the disease’s response at 28 days after initial treatment.

This marks the first mesenchymal stromal cell therapy approved by the FDA for children with acute graft versus host disease.

Darlene Dobkowski, MA

Darzalex Regimen May Improve MRD Responses in Multiple Myeloma

FDA Approves Braftovi Plus Erbitux and Chemo for Metastatic Colorectal Cancer Subset

Targeting Multiple Pathways Improves Outcomes in Some With Metastatic Breast Cancer

Ryoncil Receives FDA Approval for Children With GVHD

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