Seeking Ways to Extend Progression-Free Survival for Patients with Multiple Myeloma

Nizar J. Bahlis, M.D.

In 2019, more than 30,000 Americans are expected to be diagnosed with multiple myeloma, the second most common blood cancer.^1,2 The introduction of new medicines, including proteasome inhibitors and immunomodulatory agents over the last decade, has led to significant progress for patients.³ However, despite the advancements in treatment, multiple myeloma remains an incurable disease.³ Patients are likely to relapse and become refractory to treatment over time, and physicians seek new treatment options.^3,4

One of the options is DARZALEX^® (daratumumab), a monoclonal antibody that targets CD38.⁵ CD38 is expressed on hematopoietic cells, other cell types and tissues, and is overexpressed on multiple myeloma cells.⁵ DARZALEX inhibits tumor cell growth through direct on-tumor and immunomodulatory mechanisms of actions.⁵ DARZALEX may also have an effect on normal cells.⁵ DARZALEX is approved by the U.S. Food and Drug Administration (FDA) in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy.⁵ The approval of DARZALEX in combination with lenalidomide and dexamethasone (D-Rd) was based on the randomized, Phase 3 POLLUX clinical trial of 569 patients with multiple myeloma who had at least one prior line of therapy.⁵ The D-Rd arm (286 patients) received 25 mg of lenalidomide on days 1-21 of each 28-day Cycle, 40 mg of dexamethasone per week and 16 mg of daratumumab weekly for Cycles 1-2, every 2 weeks for Cycles 3-6 and then every 4 weeks until disease progression.⁵

The results showed:

• At a median follow-up of 13.5 months, D-Rd reduced the risk of disease progression or death by 63% compared to patients in the control arm (Rd) who did not receive DARZALEX.⁵ The median progression-free survival (PFS) for D-Rd had not yet been reached, compared to 18.4 months with Rd alone.⁵
• A significantly higher overall response rate (ORR) (91% vs 75%, respectively) was observed with the DARZALEX combination compared to Rd alone. D-Rd resulted in deeper responses, as 42.3% of patients achieved complete response (CR) or better compared to 18.8% of those in the Rd arm.⁵
• The most frequent adverse reactions (ARs) (>20%) with D-Rd were infusion reactions, diarrhea, nausea, fatigue, pyrexia, upper respiratory tract infection, muscle spasms, cough and dyspnea.⁵ Serious ARs with at least a 2% greater incidence in the D-Rd arm compared to the Rd arm were pneumonia (12% vs 10%), upper respiratory tract infection (7% vs 4%), influenza and pyrexia (3% vs 1% for each), respectively.⁵ Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 28% of patients in the D-Rd arm vs 23% in the Rd arm.⁵ Discontinuation rates due to ARs with D-Rd were similar to Rd alone (7% vs 8%, respectively).⁵

More recently, important longer-term follow-up data have become available from the POLLUX study. In fact, data presented at the American Society of Hematology (ASH) Annual Meeting in December 2018 continued to show positive results for DARZALEX when added to a standard of care of lenalidomide and dexamethasone.⁶

These follow-up data showed that after a median follow-up of 44.3 months in the intent-to-treat (ITT) patient population treated with D-Rd, these patients had a median PFS of 3.7 years (44.5 months) compared with 1.5 years (17.5 months) among patients who received Rd alone (HR 0.44; 95% confidence interval [CI]: 0.35-0.55).⁶ The post-hoc analysis was not adjusted for multiplicity.⁶

“We’ve come a long way in the treatment of multiple myeloma in the past decade. But, for those individuals battling this disease, there’s still much more to be done,” said Nizar Bahlis, M.D., Associate Professor, Arnie Charbonneau Cancer Institute, University of Calgary, and Principal Investigator of the POLLUX study sponsored by Janssen Research & Development, LLC. “The addition of DARZALEX to this current standard of care may offer an important option and a way to attack this disease.”

The follow-up data also showed that D-Rd was associated with higher cumulative response rates (based on best response):

• ORR of 93% vs 76%, respectively⁶
• Very good partial response or better of 80% vs 49%, respectively⁶
• CR or better of 57% vs 23%, respectively⁶
• In the updated analysis the median follow-up time was 44.3 months⁶
• Data are for the response-evaluable population⁶
• The post-hoc analysis was not adjusted for multiplicity⁶

Bone marrow aspirates from subjects who maintained a CR or stringent CR were sent to the central lab for minimal residual disease (MRD) assessment at 3-, 6-, and 12-month intervals using the clonoSEQ assay v2.0 at a sensitivity threshold of 10—⁵.⁶ Results showed 30% of patients achieved MRD-negativity in the D-Rd arm vs 5% of patients in the Rd arm.^6*

The most common (≥5%) Grade 3/4 treatment-emergent adverse events (TEAEs) observed with D-Rd were neutropenia (56%), anemia (18%), thrombocytopenia (15%), lymphopenia (6%), febrile neutropenia (6%), pneumonia (15%), diarrhea (10%), fatigue (7%), cataract (6%), hypokalemia (6%) and hypophosphatemia (6%).⁶ Fifteen percent of patients discontinued treatment due to TEAEs in both the D-Rd and Rd arms.⁶ See Important Safety Information below.

Researchers found that DARZALEX continued to show higher rates of PFS over time and higher cumulative response rates with longer-term follow-up.⁶ We continue to explore the addition of DARZALEX to standard of care treatment regimens across stages of the disease.

*Patients with an MRD-positive test or patients who had not undergone MRD testing were considered to be MRD positive. Sustained MRD-negativity were defined as maintenance of MRD negativity at the 10-5 threshold for >= 6 months or >= 12 months.

IMPORTANT SAFETY INFORMATION⁵

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (e.g., anaphylactic reactions) to daratumumab or any of the components of the formulation.Infusion Reactions — DARZALEX^® can cause severe and/or serious infusion reactions, including anaphylactic reactions. In clinical trials, approximately half of all patients experienced an infusion reaction. Most infusion reactions occurred during the first infusion and were grade 1-2. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX^® infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Interference with Serological Testing — Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX^®. Type and screen patients prior to starting DARZALEX^®.

Neutropenia — DARZALEX^® may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. DARZALEX^® dose delay may be required to allow recovery of neutrophils. No dose reduction of DARZALEX^® is recommended. Consider supportive care with growth factors.

Thrombocytopenia — DARZALEX^® may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. DARZALEX^® dose delay may be required to allow recovery of platelets. No dose reduction of DARZALEX^® is recommended. Consider supportive care with transfusions.

Interference with Determination of Complete Response — Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Adverse Reactions — The most frequently reported adverse reactions (incidence ≥20%) in clinical trials were: infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy and upper respiratory tract infection.

In patients who received DARZALEX^® in combination with bortezomib, melphalan, and prednisone (DVMP), the most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory tract infection (48%), infusion reactions (28%), and peripheral edema (21%). Serious adverse reactions (≥2% compared to the VMP arm) were pneumonia (11%), upper respiratory tract infection (5%), and pulmonary edema (2%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were lymphopenia (58%), neutropenia (44%), and thrombocytopenia (38%).

In patients who received DARZALEX^® in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions (≥2% compared to Rd) were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%), and pyrexia (3%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were neutropenia (53%) and lymphopenia (52%).

In patients who received DARZALEX^® in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse reactions was 42%. Serious adverse reactions (≥2% compared to Vd) were upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were lymphopenia (48%) and thrombocytopenia (47%).

In patients who received DARZALEX^® in combination with pomalidomide and dexamethasone, the most frequent adverse reactions (>20%) were fatigue (50%), infusion reactions (50%), upper respiratory tract infection (50%), cough (43%), diarrhea (38%), constipation (33%), dyspnea (33%), nausea (30%), muscle spasms (26%), back pain (25%), pyrexia (25%), insomnia (23%), arthralgia (22%), dizziness (21%), and vomiting (21%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% patients included pneumonia (7%). Treatment-emergent hematology Grade 3-4 laboratory abnormalities ≥20% were anemia (30%), neutropenia (82%), and lymphopenia (71%).

DRUG INTERACTIONS

In patients who received DARZALEX^® as monotherapy, the most frequently reported adverse reactions (incidence ≥20%) were: infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). The overall incidence of serious adverse reactions was 33%. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were lymphopenia (40%) and neutropenia (20%).Effect of Other Drugs on Daratumumab: The coadministration of lenalidomide, pomalidomide or bortezomib with DARZALEX^® did not affect the pharmacokinetics of daratumumab.

Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX^® with bortezomib or pomalidomide did not affect the pharmacokinetics of bortezomib or pomalidomide.

For the full U.S. Prescribing Information, please click here.

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References

1. American Cancer Society. What are the key statistics about multiple myeloma? http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-key-statistics. Accessed February 2019.
2. Multiple Myeloma Research Foundation. About Multiple Myeloma. https://themmrf.org/multiple-myeloma. Accessed February 2019.
3. Larocca, Alexxandra et al. Emerging drugs and combinations to treat multiple myeloma. Oncotarget 2017; 8(36): 60656-60672.
4. Bahlis, NJ et al. Benefit of continuous treatment for responders with newly diagnosed multiple myeloma in the randomized FIRST trial. Leukemia 2017;31:2435-2442.
5. DARZALEX® [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.
6. Bahlis, Nizar et al. Three-year follow up of the Phase 3 POLLUX study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) alone in relapsed or refractory multiple myeloma (RRMM). Paper presented at: Annual Meeting of the American Society of Hematology. December 2018; San Diego, CA.

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