Saad Usmani, MD, Hematologist-Oncologist at Memorial Sloan Kettering Cancer Center, discusses results from the CEPHEUS clinical trial of daratumumab combination therapy in patients with newly diagnosed multiple myeloma (MM).

MM is a rare blood cancer characterized by the expansion of malignant plasma cells in the bone marrow associated with excessive production of monoclonal immunoglobulins in blood and urine. Individuals with multiple myeloma develop significant osteolytic bone lesions and have immunodeficiency that compromise their longevity and quality of life. The exact underlying cause of disease is currently unknown.

Daratumumab is a monoclonal antibody targeting CD38, being investigated in combination with bortezomib, lenalidomide, and dexamethasone (VRd), an effective and well-tolerated therapy for patients with newly diagnosed MM.

The phase 3 CEPHEUS (NCT03652064) clinical trial established that daratumumab plus bortezomib, lenalidomide, and dexamethasone (DVRd) improved overall minimal residual disease (MRD)-negativity rates and progression-free survival compared to VRd in patients with transplant ineligible or transplant-deferred newly diagnosed MM.

At a median follow-up of 58.7 months, initial analysis of the DVRd transplant ineligible subpopulation showed a complete response or better rate of 80.6% and overall MRD-negativity rate of 60.4%. About 70% of patients were alive and progression free. This final analysis of the CEPHEUS transplant ineligible subpopulation describes a longer median follow-up of 76 months.

Of 395 patients enrolled, 289 with transplant ineligible newly diagnosed MM received either DVRd or VRd. The overall MRD-negativity rate at 10-5 was 61.1% for DVRd and 40.0% for VRd and at 10-6 was 46.5% for DVRd versus 27.6% for VRd. Sustained MRD-negativity rate at 10-5 was 49.3% for DVRd and 29.0% for VRd and at 10-6 was 37.5% for DVRd and 16.6% for VRd. Overall complete response or better rate was 80.6% for DVRd and 61.4% for VRd. Median investigator-assessed progression free survival was not estimable for DVRd and was 50.20 months for VRd, with 59.3% for DVRd versus 38.3% for VRd alive and progression free at 72 months.

Additionally, overall survival favored DVRd over VRd, particularly when censoring for COVID-19, which significantly impacted this study. The treatment effect was consistent across most subgroups.

For more information on MM and other rare cancers, visit https://checkrare.com/diseases/cancers/

CHAPTERS
Introduction 00:00
CEPHEUS Clinical Trial 00:21
Findings From the Final Analysis 1:18
Impact Compared to Standard Treatment 2:20
Notable Safety Findings 3:20
Take Home Message 4:01

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Fatima Scipione, Vice President of Global Patient Affairs at Blueprint Medicines, discusses the Colors of SM program.

Systemic mastocytosis (SM) is a rare disease usually caused by mutations of the KIT D816V gene. The disorder is characterized by uncontrolled mast cell proliferation and activation across multiple organ systems. Indolent SM accounts for approximately 90% of systemic mastocytosis. Common symptoms may include anaphylaxis, maculopapular rash, pruritis, diarrhea, brain fog, fatigue and bone pain. Most adults present with skin lesions, usually in the form of urticaria pigmentosa.

Colors of SM: Expressions of Life with Systemic Mastocytosis is a voluntary program dedicated to highlight the experiences of patients with SM. By partnering patients with artists who interpret a patients’ experiences into pieces of art, the initiative gives insights into what living with this rare disease really looks like. Artists and patients then showcase their work and experiences together at an annual art show.

Colors of SM was launched in partnership with Twist Out Cancer, a nonprofit organization that provides creative arts programs to people living with a variety of health conditions. The program aims to raise awareness about SM and the burden of disease on patients and foster an environment for change and advancement.

Ms. Scipione highlights how powerful it has been to see art communicate emotions, frustrations, resilience, and identity of these patients and how the program has provided visibility, connection, and understanding.

To learn more about SM and other rare autoimmune/anti-inflammatory conditions, visit https://checkrare.com/diseases/autoimmune-autoinflammatory-disorders/

CHAPTERS
Introduction 00:00
SM Overview 1:01
Colors of SM Program 3:29
Getting Involved 8:29

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Eric Lai, MD, Nephrologist at the West Coast Kidney Institute, discusses the importance of early diagnosis in IgA nephropathy (IgAN).

IgAN is a kidney disorder that occurs when IgA protein settles in the kidneys. In the early stages, IgAN has no symptoms. The first sign of this condition may be blood in the urine. End-stage kidney disease may develop. In most instances, the cause of this condition is unknown; however, certain disorders have been linked with IgAN, such as cirrhosis of the liver, celiac disease, and HIV infection. The condition can also often be triggered by a viral illness, such as a head cold or upper respiratory infection, that irritates the mucous membranes throughout the body.

Early diagnosis of IgAN is crucial for patients to receive proper treatment in efforts of preventing severe cirrhosis and end-stage kidney disease, often requiring kidney transplant. Dr. Lai explains that the easiest way to identify early signs of disease is through urine testing at a patient’s yearly physical. This test checks kidney function and signs of disease such as hematuria (blood in the urine) and proteinuria (protein in the urine). While this testing is mandated in other countries, physicians in the US are not required to perform this test.

The risk of progression in IgAN is dependent on the degree of proteinuria, making this marker the most important measure in gauging kidney prognosis and how well disease is being treated. Additionally, estimated glomerular filtration rate (eGFR) is also an important measurement in patients with IgAN.

Current treatment options consist mostly of symptom management. These may include angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, corticosteroids, and liver transplantation.

CHAPTERS
Introduction 00:00
IgAN Overview 00:15
Autoimmune Component 1:54
IgAN Triggers 3:44
Presentation of Disease 5:25
Risk Stratification 8:14
Importance of Urine Testing 14:40
What Physicians Should Know 15:56
Take Home Message 18:30

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Andrew Dauber, MD, Chief of Endocrinology at Children’s National Hospital, discusses results from a phase 3 study of Voxzogo (vosoritide) in children with hypochondroplasia.

Hypochondroplasia is a rare skeletal disease characterized by very short stature, similar to achondroplasia, but with milder features. People with hypochondroplasia usually have very short stature, large head, accentuated lordosis, short arms and legs, and broad, short hands and feet. Other features include a limited range of motion in the elbows, lordosis, and bowed legs. Uncommon symptoms may include learning difficulties and convulsions. Hypochondroplasia is often caused by genetic changes in the FGFR3 gene.

The CANOPY-HCH-3 (NCT06455059) clinical trial is a phase 3, double-blind, placebo-controlled, multicenter, open-label, long-term extension study evaluating the safety and efficacy of vosoritide in children with hypochondroplasia. Vosoritide is a C-type natriuretic peptide (CNP) analog approved by the US Food and Drug Administration (FDA) to promote linear bone growth in children with achondroplasia.

The trial met its primary endpoint, with vosoritide demonstrating a statistically significant increase in the change from baseline at week 52 in annualized growth velocity (AGV) compared to placebo. Treatment with vosoritide also showed a statistically significant increase in standing height and height Z-score versus placebo after one year of treatment. Additionally, significant improvements in arm span were observed.

The safety profile of vosoritide was consistent with the established profile in achondroplasia and no new safety signals were observed.

A supplemental New Drug Application (sNDA) submission to the FDA is planned for the third quarter of 2026.

To learn more about hypochondroplasia and other rare musculoskeletal conditions, visit https://checkrare.com/diseases/musculoskeletal-diseases/

CHAPTERS
Introduction 00:00
Hypochondroplasia Overview 00:24
CANOPY-HCH-3 Clinical Trial 2:07
Normal Growth Rates in Children 4:30
Approval in Achondroplasia 5:36
Potential Use in Other Indications 6:49

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Alaa Hamed, MD, Global Head of Medical Affairs Rare Diseases at Sanofi, discusses results from the phase 2 ElevAATe clinical trial of efdoralprin alfa in patients with alpha-1 antitrypsin deficiency (AATD).

AATD is an inherited disease that causes an increased risk of having chronic obstructive pulmonary disease (COPD), liver disease, skin problems, and vasculitis. Symptoms may include shortness of breath and wheezing, repeated infections of the lungs and liver, yellow skin, fatigue, rapid heartbeat when standing, vision problems, and weight loss. However, some people with AATD do not have any symptoms. AATD is caused by genetic changes in the SERPINA1 gene, resulting in too little or no working alpha-1 antitrypsin protein (AAT) to be made.

Efdoralprin alfa is a recombinant human AAT-Fc fusion protein, designed to achieve a longer half-life than plasma-derived augmentation therapy, restore and maintain functional AAT levels to the normal range, and inhibit neutrophil elastase and other proteases that can cause lung tissue damage.

The ElevAATe clinical trial (NCT05856331) is a phase 2 double-blind, randomized, active-control, parallel group study evaluating the pharmacokinetics, pharmacodynamics, immunogenicity, and safety of efdoralprin alfa compared to standard of care in adults with AATD emphysema. Results from this study were presented at the 2026 American Thoracic Society (ATS) International Conference.

Efdoralprin alfa, dosed every three weeks, was observed to achieve mean increases in functional alpha-1 antitrypsin (fAAT) trough levels more than three times greater than plasma-derived protein (pdAAT) dosed weekly. All key secondary endpoints in the study were also met. In patients dosed every three weeks, fAAT levels remained above the normal threshold (23.8 μM) for 100% of days during the 32 week study compared to 41% of days in patients on a standard of care augmentation therapy.

Efdoralprin alfa was also well tolerated, with no participants experiencing treatment-emergent adverse events leading to permanent discontinuation of study intervention. The most common adverse events were COPD exacerbations, headache, and COVID-19 infection. The incidence of grade 2 or greater COPD exacerbations, considered an adverse event of special interest in the ElevAATe study, were lower for the efdoralprin alfa every three weeks arm versus the efdoralprin alfa every four weeks and pdAAT arms.

CHAPTERS
Introduction 00:00
Early Signs and Symptoms 00:10
Unmet Needs in Guidance 1:15
Efdoralprin Alfa Overview 1:45
ElevAATe Clinical Trial 3:58
Next Steps 6:24

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Yi Lin, MD, PhD, Hematologist/Oncologist at Mayo Clinic, discusses immune effector cell-associated enterocolitis (IEC-EC) in patients with relapsed/refractory multiple myeloma (R/R MM) treated with ciltacabtagene autoleucel (cilta-cel).

MM is a rare blood cancer characterized by the expansion of malignant plasma cells in the bone marrow associated with excessive production of monoclonal immunoglobulins in blood and urine. Individuals with multiple myeloma develop significant osteolytic bone lesions and have immunodeficiency that compromise their longevity and quality of life. The exact underlying cause of disease is currently unknown.

Cilta-cel is a B-cell maturation antigen-directed genetically modified autologous T cell immunotherapy. IEC-EC, an uncommon adverse reaction, is characterized by severe and persistent diarrhea, typically 1 to 3 months following CAR-T cell infusion. This study analyzed the incidence and features of IEC-EC in the CARTITUDE clinical studies of cilta-cel for RRMM.

A total of 483 patients across the CARTITUDE-1, -2, -4, and CARTIFAN-1 studies were evaluated for evidence of IEC-EC. Across these studies, six patients presented with IEC-EC, 12 to 214 days after receiving cilta-cel, and with a median onset 67 days post infusion.

Four patients experienced symptom resolution within 123 to 227 days, while two had persistent symptoms until death. Patients with IEC-EC had lower levels of B cells and higher levels of CAR+ T cells and inflammatory cytokines at onset compared to a GI symptom-free control group at comparable time. While all patients treated with cilta-cel experienced B cell depletion, patients with IEC-EC had more prolonged deficiency.

Histological analyses of GI biopsies from five patients with IEC-EC revealed the absence of plasma cells. CAR-T cells were detected and localized to the lamina propria and were not observed juxtaposed with epithelia. Histologic damage was greater in the small intestine (mainly the duodenum) than the colon.

To learn more about MM and other rare cancers, visit https://checkrare.com/diseases/cancers/

CHAPTERS
Introduction 00:00
R/R Multiple Myeloma Treatment Options 00:11
IEC-EC in CARTITUDE Trials 2:05
Side Effects in Other Treatments 7:29
Informing Patients on Side Effects 9:41
Take Home Message 12:02

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Mitchell Geffner, MD, Co-Director, Congenital Adrenal Hyperplasia Clinic, and Ron Burkle Chair, Center for Endocrinology, Diabetes, and Metabolism, Children’s Hospital of Los Angeles, discusses the etiology, diagnosis, and management of pediatric adrenocortical insufficiency.

Pediatric adrenal insufficiency manifests as inadequate production of cortisol (also called hydrocortisone) and sometimes of aldosterone, two essential hormones. The most common cause is primary dysfunction in the adrenal cortex, usually from congenital adrenal hyperplasia. It can also result from a pituitary or hypothalamic disorder, where adrenocorticotropic hormone fails to prompt the adrenal glands to produce cortisol.

In terms of diagnosis, Dr. Geffner explained that its early signs and features are vague and mimic other clinical problems (e.g, fatigue, nausea, weight loss, and headaches). “Unless one has a very high clinical suspicion, the diagnosis will be missed or delayed, and that can be life threatening,” he said. Patients can wind up in the emergency room because of hypoglycemia or hyponatremia, and it is important that first responders and critical care doctors are aware of the patient’s condition.

A simple lab test for electrolyte levels—low sodium concentrations and high potassium levels (associated with aldosterone deficiency)—can help point to the correct diagnosis, said Dr. Geffner. A finding of morning serum cortisol concentrations below 3 mcg/dL is definitive for pediatric adrenal insufficiency.

Adrenoleukodystrophy, another potential cause of pediatric adrenal insufficiency, is part of the newborn screening panel in some but not in the majority of states, according to Dr. Geffner.

Historically, the treatment of pediatric adrenal insufficiency was based on hydrocortisone replacement. Normally, a child’s daily production of cortisol is around 8 mg/m2/day, and this varies throughout the day (i.e., more is produced in the morning, upon awakening) and with higher levels of stress (such as fever, trauma, or surgery). The goal of management is to use the lowest oral corticosteroid dose possible to address the physiologic deficiency throughout the day and account for episodes of stress, while avoiding potential side effects, like stunted growth. Episodes of adrenal insufficiency caused by stress are addressed with intramuscular injections of hydrocortisone. Therefore, all patients with adrenal insufficiency should have ready access to an injectable form of cortisol, said Dr. Geffner.

Children with adrenal insufficiency have no restrictions on activities, like sports, to avoid an unforeseen, stressful event, like a broken bone. “We do recommend that the school knows about the child’s medical condition,” he commented. “Nurses are not always available at the school. Parents should also meet with local EMS personnel, so if the EMS gets a call, they’ll know the child’s condition, also perhaps what medicine is available at home.”

One unmet need is to make an easy-to-administer hydrocortisone injection. “Several companies are looking at autoinjectors, needle-less injectors, that don’t require mixing,” noted Dr. Geffner.

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Mitchell Geffner, MD, Co-Director, Congenital Adrenal Hyperplasia Clinic, and Ron Burkle Chair, Center for Endocrinology, Diabetes, and Metabolism, Children’s Hospital of Los Angeles, discusses the etiology, diagnosis, and management of pediatric adrenocortical insufficiency.

Pediatric adrenal insufficiency manifests as inadequate production of cortisol (also called hydrocortisone) and sometimes of aldosterone, two essential hormones. The most common cause is primary dysfunction in the adrenal cortex, usually from congenital adrenal hyperplasia. It can also result from a pituitary or hypothalamic disorder, where adrenocorticotropic hormone fails to prompt the adrenal glands to produce cortisol.

In terms of diagnosis, Dr. Geffner explained that its early signs and features are vague and mimic other clinical problems (e.g, fatigue, nausea, weight loss, and headaches). “Unless one has a very high clinical suspicion, the diagnosis will be missed or delayed, and that can be life threatening,” he said. Patients can wind up in the emergency room because of hypoglycemia or hyponatremia, and it is important that first responders and critical care doctors are aware of the patient’s condition.

A simple lab test for electrolyte levels—low sodium concentrations and high potassium levels (associated with aldosterone deficiency)—can help point to the correct diagnosis, said Dr. Geffner. A finding of morning serum cortisol concentrations below 3 mcg/dL is definitive for pediatric adrenal insufficiency.

Adrenoleukodystrophy, another potential cause of pediatric adrenal insufficiency, is part of the newborn screening panel in some but not in the majority of states, according to Dr. Geffner.

Historically, the treatment of pediatric adrenal insufficiency was based on hydrocortisone replacement. Normally, a child’s daily production of cortisol is around 8 mg/m2/day, and this varies throughout the day (i.e., more is produced in the morning, upon awakening) and with higher levels of stress (such as fever, trauma, or surgery). The goal of management is to use the lowest oral corticosteroid dose possible to address the physiologic deficiency throughout the day and account for episodes of stress, while avoiding potential side effects, like stunted growth. Episodes of adrenal insufficiency caused by stress are addressed with intramuscular injections of hydrocortisone. Therefore, all patients with adrenal insufficiency should have ready access to an injectable form of cortisol, said Dr. Geffner.

Children with adrenal insufficiency have no restrictions on activities, like sports, to avoid an unforeseen, stressful event, like a broken bone. “We do recommend that the school knows about the child’s medical condition,” he commented. “Nurses are not always available at the school. Parents should also meet with local EMS personnel, so if the EMS gets a call, they’ll know the child’s condition, also perhaps what medicine is available at home.”

One unmet need is to make an easy-to-administer hydrocortisone injection. “Several companies are looking at autoinjectors, needle-less injectors, that don’t require mixing,” noted Dr. Geffner.

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Mitchell Geffner, MD, Co-Director, Congenital Adrenal Hyperplasia Clinic, and Ron Burkle Chair, Center for Endocrinology, Diabetes, and Metabolism, Children’s Hospital of Los Angeles, discusses the etiology, diagnosis, and management of pediatric adrenocortical insufficiency.

Pediatric adrenal insufficiency manifests as inadequate production of cortisol (also called hydrocortisone) and sometimes of aldosterone, two essential hormones. The most common cause is primary dysfunction in the adrenal cortex, usually from congenital adrenal hyperplasia. It can also result from a pituitary or hypothalamic disorder, where adrenocorticotropic hormone fails to prompt the adrenal glands to produce cortisol.

In terms of diagnosis, Dr. Geffner explained that its early signs and features are vague and mimic other clinical problems (e.g, fatigue, nausea, weight loss, and headaches). “Unless one has a very high clinical suspicion, the diagnosis will be missed or delayed, and that can be life threatening,” he said. Patients can wind up in the emergency room because of hypoglycemia or hyponatremia, and it is important that first responders and critical care doctors are aware of the patient’s condition.

A simple lab test for electrolyte levels—low sodium concentrations and high potassium levels (associated with aldosterone deficiency)—can help point to the correct diagnosis, said Dr. Geffner. A finding of morning serum cortisol concentrations below 3 mcg/dL is definitive for pediatric adrenal insufficiency.

Adrenoleukodystrophy, another potential cause of pediatric adrenal insufficiency, is part of the newborn screening panel in some but not in the majority of states, according to Dr. Geffner.

Historically, the treatment of pediatric adrenal insufficiency was based on hydrocortisone replacement. Normally, a child’s daily production of cortisol is around 8 mg/m2/day, and this varies throughout the day (i.e., more is produced in the morning, upon awakening) and with higher levels of stress (such as fever, trauma, or surgery). The goal of management is to use the lowest oral corticosteroid dose possible to address the physiologic deficiency throughout the day and account for episodes of stress, while avoiding potential side effects, like stunted growth. Episodes of adrenal insufficiency caused by stress are addressed with intramuscular injections of hydrocortisone. Therefore, all patients with adrenal insufficiency should have ready access to an injectable form of cortisol, said Dr. Geffner.

Children with adrenal insufficiency have no restrictions on activities, like sports, to avoid an unforeseen, stressful event, like a broken bone. “We do recommend that the school knows about the child’s medical condition,” he commented. “Nurses are not always available at the school. Parents should also meet with local EMS personnel, so if the EMS gets a call, they’ll know the child’s condition, also perhaps what medicine is available at home.”

One unmet need is to make an easy-to-administer hydrocortisone injection. “Several companies are looking at autoinjectors, needle-less injectors, that don’t require mixing,” noted Dr. Geffner.

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