Please see MAIA trial design & primary results.
For newly diagnosed, transplant-ineligible MM1,2:
DO YOU START WITH DARZALEX® + Rd FOR THESE TYPES OF PATIENTS?
Examine these patient cases for a deeper understanding of who may be appropriate for frontline DRd.
Age: 73 years old
Job: Retired but still enjoys working part-time as a contract lawyer
Biography:- Hobbies include neighborhood walks and playing bingo
- Married, mother of 3, with 4 college-aged grandchildren
- Motivated and active participant in her treatment
Newly diagnosed and not eligible for transplant
Transplant eligibility of an individual patient is determined based on evaluation by the treating physician.
Clinical condition and disease presentation
ISS disease stage: II
ECOG PS: IECOG PS=Eastern Cooperative Oncology Group Performance Status; ISS=International Staging System.
MAIA trial results relevant for treating patients like Janice
Age: 76 years oldJob: A retired middle school principal with a good support systemBiography:- Married, father of one, with 2 grandchildren
- Presents with back and bone pain, and high symptom burden
- Highly limited in mobility and self-care
Newly diagnosed and not eligible for transplant
Transplant eligibility of an individual patient is determined based on evaluation by the treating physician.
Clinical condition and disease presentation
ISS disease stage: IIIECOG PS: 2
Cytogenetic risk: Presence of high-risk cytogenetics
Additional considerations:- Lower back pain
- Diagnosed with mild dementia 3 years ago (current MMSE score of 22)
ECOG PS=Eastern Cooperative Oncology Group Performance Status; ISS=International Staging System; MMSE=Mini-Mental State Examination.
*Cytogenetic risk was based on fluorescence in situ hybridization (FISH) or karyotype analysis. High-risk cytogenetics were defined as having at least one of the following abnormalities: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], amp[1q21].3
MAIA trial results relevant for treating patients like Luis
Age: 78 years oldJob: History of working in construction but now retiredBiography:- Good support system: not married but in a steady relationship past 20 years
- At times, struggles to stay adherent to treatment
Newly diagnosed and not eligible for transplant
Transplant eligibility of an individual patient is determined based on evaluation by the treating physician.
Clinical condition and disease presentation
ISS disease stage: IIECOG PS: 2Presents with fatigue due to multiple myeloma and reduced lung capacityAdditional considerations: - Presented with diabetes
- Requires assistance to get around, especially up and down stairs
ECOG PS=Eastern Cooperative Oncology Group Performance Status; ISS=International Staging System.
MAIA trial results relevant for treating patients like Samuel
Age: 68 years oldJob: ArchitectBiography:- Married, with 3 adult children
- Enjoys spending time with family and friends
- Looks forward to taking on new projects at work
Newly diagnosed and not eligible for transplant
Transplant eligibility of an individual patient is determined based on evaluation by the treating physician.
Clinical condition and disease presentation
ISS disease stage: IECOG PS: 1Cytogenetic risk: Standard*Additional considerations: Presents with:
- Mild cardiac disease†
- Mild persistent asthma‡
- Chronic kidney disease with moderate renal dysfunction§
CrCl=creatinine clearance; ECOG PS=Eastern Cooperative Oncology Group Performance Status; FEV1=forced expiratory volume in the first second; ISS=International Staging System; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association.
*Cytogenetic risk was based on fluorescence in situ hybridization (FISH) or karyotype analysis. Standard-risk cytogenetics were defined as having none of the following abnormalities: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], amp[1q21].3
†(NYHA class II) with LVEF 50%-55%.
‡(FEV1 >80% predicted) controlled by inhalers.
§(CrCl=35 mL/min).
MAIA trial results relevant for treating patients like Helen
DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); MM=multiple myeloma; Rd=lenalidomide (R) + dexamethasone (d).
When treating newly diagnosed, transplant-ineligible multiple myeloma1:
Reach for DARZALEX® + Rd—a frontline treatment proven over the long term1
The MAIA trial: DARZALEX® approval for adult patients with newly diagnosed, transplant-ineligible multiple myeloma is based on a large, randomized, open-label, multicenter, active-controlled, phase 3 trial.1,2
DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); ECOG PS=Eastern Cooperative Oncology Group Performance Status; IV=intravenous; PD=progressive disease; PO=by mouth; QW=weekly; Q2W=every 2 weeks; Q4W=every 4 weeks; Rd=lenalidomide (R) + dexamethasone (d).
*On days when daratumumab was administered, dexamethasone was administered to patients in the DRd arm and served as the treatment dose of steroid for that day, as well as the required pre-infusion medication.1
†For patients older than 75 years of age or with body mass index (BMI) <18.5, dexamethasone was administered at a dose of 20 mg weekly.1
- Primary endpoint was progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria2
- Key secondary endpoints included percentage of patients with complete response (CR), very good partial response (VGPR) rate, minimal residual disease (MRD)–negativity rate (next-generation sequencing [NGS]; 10-5), overall response rate (ORR), overall survival (OS), duration of response, and safety2
- Baseline demographics and disease characteristics were similar between the 2 treatment groups1
Frontline DARZALEX® + Rd—evaluated in a wide range of newly diagnosed, transplant-ineligible patients2,3
MAIA trial included patients of various ages, ECOG PS, and prognostic factors2
ECOG PS=Eastern Cooperative Oncology Group Performance Status; ISS=International Staging System; Rd=lenalidomide (R) + dexamethasone (d).
*Per protocol, cytogenetic tests from bone marrow aspirates were performed by local laboratories at screening and 642 patients had baseline cytogenetic data reported from local laboratories out of the 737 patients who were enrolled in the MAIA trial.4,5
†Cytogenetic risk was based on fluorescence in situ hybridization (FISH) or karyotype analysis; patients who had a high-risk cytogenetic profile had at least one high-risk abnormality (del[17p], t[14;16], or t[4;14]).2
- ~50% of patients were 75 years old or older2
- The trial also included patients with various ECOG PS, cytogenetic profiles, and ISS disease stages2
National Comprehensive Cancer Network® (NCCN®) Category 1, preferred
Daratumumab* (D) in combination with lenalidomide (R) and dexamethasone (d) is recommended by the NCCN as a Category 1 preferred† therapeutic option for patients with newly diagnosed, transplant-ineligible multiple myeloma‡
*Daratumumab includes both daratumumab (DARZALEX®) for intravenous infusion and daratumumab and hyaluronidase-fihj (DARZALEX FASPRO®) for subcutaneous injection. Daratumumab and hyaluronidase-fihj for subcutaneous injection has different dosing and administration instructions compared to daratumumab for intravenous infusion.
†See NCCN.org for definitions of NCCN Categories of Preference and NCCN Categories of Evidence and Consensus.
‡Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma V.2.2024.
© National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed November 2, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
28-month PFS
After 28 months of follow-up:
Frontline DARZALEX® + Rd significantly reduced the risk of progression in patients*1
CI=confidence interval; DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); HR=hazard ratio; PFS=progression-free survival;
Rd=lenalidomide (R) + dexamethasone (d).
*Median follow-up was 28 months (range: 0.0–41.4 months).1,2
†Kaplan-Meier estimate.2
70.6% of patients had not progressed with DRd vs 55.6% with Rd alone at 30 months (DRd: 95% CI: 65.0, 75.4; Rd: 95% CI: 49.5, 61.3)†2
64-month PFS
After 64 months of follow-up:
Patients were progression-free longer with frontline DARZALEX® + Rd vs Rd alone*1
Median PFS was 61.9 months (95% CI: 54.8, NE) with DRd vs 34.4 months (95% CI: 29.6, 39.2) with Rd alone1
CI=confidence interval; DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); HR=hazard ratio; NE=not estimable;
PFS=progression-free survival; Rd=lenalidomide (R) + dexamethasone (d).
*Median follow-up was 64 months.1
Patient case in newly diagnosed, transplant-ineligible MM
Janice, age 73: Active patient who is engaged with her treatment plan
Hypothetical patient case.
- ISS disease stage: II
- ECOG PS: 1
Do you have patients in your practice who may be appropriate for frontline DRd?
Dr. Shain reviews key considerations for treating patients like Janice
DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); ECOG PS=Eastern Cooperative Oncology Group Performance Status; ISS=International Staging System; MM=multiple myeloma.
56-month OS
After 56 months of follow-up:
Frontline DARZALEX® + Rd significantly reduced the risk of death vs Rd alone*1
CI=confidence interval; DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); HR=hazard ratio; IQR=interquartile range; OS=overall survival; Rd=lenalidomide (R) + dexamethasone (d).
*Median follow-up was 56.6 months in the DRd group (IQR: 53.0–60.1 months) and 55.9 months in the Rd group (IQR: 52.5-59.4 months).2
†Kaplan-Meier estimate.2
66% of patients were still alive with DRd vs 53% with Rd alone at 60 months
(DRd: 95% CI: 61, 71; Rd: 95% CI: 47, 59)*†2
(DRd: 95% CI: 61, 71; Rd: 95% CI: 47, 59)*†2
You are now viewing a follow-up analysis of the MAIA study. This information is not included in the current Prescribing Information and has not been evaluated by the FDA. The follow-up analysis was not adjusted for multiplicity and conclusions should not be drawn.
74-month OS
After 74 months of follow-up:
More patients on frontline DARZALEX® + Rd were alive vs Rd alone*3
Median OS was still not reached with DRd vs 64.1 months with Rd alone3
CI=confidence interval; DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); HR=hazard ratio; OS=overall survival; Rd=lenalidomide (R) + dexamethasone (d).
*Median follow-up was 73.6 months.3
Patient case in newly diagnosed, transplant-ineligible MM
Janice, age 73: Active patient who is engaged with her treatment plan
Hypothetical patient case.
- ISS disease stage: II
- ECOG PS: 1
Do you have patients in your practice who may be appropriate for frontline DRd?
Dr. Shain reviews key considerations for treating patients like Janice
DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); ECOG PS=Eastern Cooperative Oncology Group Performance Status; ISS=International Staging System; MM=multiple myeloma.
28-month response rates
After 28 months of follow-up:
Deep responses for a strong start. Durable responses to keep your patients’ treatment journeys moving forward*1,2
93% ORR was achieved with DARZALEX® + Rd after 28 months of follow-up*1,2
CR=complete response; ORR=overall response rate; PR=partial response; Rd=lenalidomide (R) + dexamethasone (d); sCR=stringent complete response; VGPR=very good partial response.
*Median follow-up was 28 months (range: 0.0–41.4 months).1,2
‡sCR is CR plus normal free light chain ratio and the absence of clonal cells in bone marrow as assessed by immunohistochemistry or immunofluorescence.2
DEPTH
DRd nearly doubled the number of patients who achieved CR† or better vs Rd alone.1
- More than doubled sCR‡: 30% with DRd vs 13% with Rd alone
DURABILITY
Median duration of response had not yet been reached with DRd vs 34.7 months (95% CI: 30.8, not estimable) for Rd alone.1
SPEED OF RESPONSE
Median time to response was 1.05 months with DRd (range: 0.2-12.1 months) and with Rd alone (range: 0.3-15.3 months).1
After 28 months of follow-up:
Patients experienced MRD negativity with frontline DARZALEX® + Rd at a rate 3x greater than Rd alone*†1,2
CI=confidence interval; DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); MRD=minimal residual disease; Rd=lenalidomide (R) + dexamethasone (d).
*Median follow-up was 28 months (range: 0.0-41.4 months).1,2
†MRD negativity was defined as undetectable levels of multiple myeloma cells by bone marrow aspirate at any time point after the randomization and before disease progression or start of subsequent therapy, and in the trial was assessed by means of next-generation sequencing assay at a sensitivity threshold of 10-5 via bone marrow aspirate, collected at initial trial screening, at the time of confirmation of complete response or stringent complete response, and thereafter at 12, 18, 24, and 30 months.2
Superior MRD rates vs Rd alone
- 24% of patients were minimal residual disease (MRD)-negative with DRd (95% CI: 19.9, 28.9)
- 7% of patients were MRD-negative with Rd (95% CI: 4.9, 10.5)1
MRD was based on a sensitivity threshold of 10-5 using a next-generation sequencing assay (clonoSEQ®).2
You are now viewing a follow-up analysis of the MAIA study. This information is not included in the current Prescribing Information and has not been evaluated by the FDA. The follow-up analysis was not adjusted for multiplicity and conclusions should not be drawn.
64-month response rates
Cumulative response rates after 64.5 months of follow-up*3
93% ORR was achieved with DARZALEX® + Rd after 64.5 months of follow-up*3
CI=confidence interval; CR=complete response; ORR=overall response rate; PR=partial response; Rd=lenalidomide (R) + dexamethasone (d); sCR=stringent complete response; VGPR=very good partial response.
*Median follow-up was 64.5 months.3
‡sCR is CR plus normal free light chain ratio and the absence of clonal cells in bone marrow as assessed by immunohistochemistry or immunofluorescence.2
DEPTH3
1.7x more patients receiving DRd achieved CR or better vs Rd alone
- More than doubled sCR‡: 35% with DRd vs 15% with Rd alone
The follow-up analysis was not adjusted for multiplicity and no conclusions should be drawn.
These analyses are not included in the Prescribing Information for DARZALEX®. These analyses were not adjusted for multiple comparisons. There are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.
28-month PFS by subgroup
PFS numerically favored frontline DARZALEX® + Rd in most subgroups vs Rd alone after 28 months of follow-up*1
CI=confidence interval; DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); ECOG PS=Eastern Cooperative Oncology Group Performance Status; IgG=immunoglobulin G; ISS=International Staging System; NE=not estimable; PFS=progression-free survival; Rd=lenalidomide (R) + dexamethasone.
*Median follow-up was 28 months (range: 0.0-41.4 months).1
†Per protocol, cytogenetic tests from bone marrow aspirates were performed by local laboratories at screening and 642 patients had baseline cytogenetic data reported from local laboratories out of the 737 patients who were enrolled in MAIA.2,3
‡Cytogenetic risk was based on fluorescence in situ hybridization (FISH) or karyotype analysis; patients who had a high-risk cytogenetic profile had at least one high-risk abnormality (del[17p], t[14;16], or t[4;14]).1
56-month PFS by subgroup
Regardless of age, performance status or cytogenetic profile:
PFS continued to numerically favor patients on frontline DARZALEX® + Rd vs Rd alone after 56 months of follow-up*4,5
CI=confidence interval; CrCI=creatinine clearance; DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); ECOG PS=Eastern Cooperative Oncology Group Performance Status; IgG=immunoglobulin G; IQR=interquartile range; ISS=International Staging System; NE=not estimable; PFS=progression-free survival; Rd=lenalidomide (R) + dexamethasone (d).
*Median follow-up was 56 months in the DRd group (IQR: 53.0-60.1 months) and in the Rd group (IQR: 52.5-59.4 months).4,5
†Per protocol, cytogenetic tests from bone marrow aspirates were performed by local laboratories at screening and 642 patients had baseline cytogenetic data reported from local laboratories out of the 737 patients who were enrolled in MAIA.2,3
‡Cytogenetic risk was based on fluorescence in situ hybridization (FISH) or karyotype analysis; patients who had a high-risk cytogenetic profile had at least one high-risk abnormality (del[17p], t[14;16], or t[4;14]).1
After 56 months of follow-up, the median PFS was not reached with DARZALEX® + Rd vs 34.4 months with Rd alone among the overall MAIA patients (hazard ratio=0.53, 95% CI: 0.43, 0.66).*4,5
The follow-up analysis was not adjusted for multiplicity and no conclusions should be drawn.
Primary safety analysis
Frontline DARZALEX® + Rd provides a demonstrated safety profile*1
Most frequent adverse reactions reported in ≥20% of patients and with at least 5% greater frequency in DARZALEX® + Rd arm†1
DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); Rd=lenalidomide (R) + dexamethasone (d).
*Median duration of study treatment was 25.3 months (range: 0.1–40.44 months) in the DRd group and 21.3 months (range: 0.03–40.64 months) in the Rd group.1
†Adverse reactions that occurred with a frequency of ≥10% and <20%, and with at least a 5% greater frequency in DARZALEX® + Rd arm were headache, urinary tract infection, hyperglycemia, hypocalcemia, vomiting, chills, paresthesia, and hypertension.1
Serious adverse reactions with a 2% greater incidence in the DRd arm compared with the Rd arm were pneumonia (DRd 15% vs Rd 8%), bronchitis (DRd 4% vs Rd 2%), and dehydration (DRd 2% vs Rd <1%).1
Most frequent hematologic laboratory abnormalities1
Rd=lenalidomide (R) + dexamethasone (d).
- Discontinuation rates due to any adverse event: 7% with DRd vs 16% with Rd2
- Infusion-related reactions (IRRs) with DRd occurred in 41% of patients; 2% were Grade 3 and <1% were Grade 41
- IRRs of any grade or severity may require management by interruption, modification, and/or discontinuation of the infusion1
- Most IRRs occurred during the first infusion1
You are now viewing a follow-up analysis of the MAIA study. This information is not included in the current Prescribing Information and has not been evaluated by the FDA. TEAEs are reported as observed. The follow-up analysis was not adjusted for multiplicity and conclusions should not be drawn.
Long-term safety analysis
DARZALEX® + Rd offers your patients a frontline treatment that’s supported by 64.5 months of safety evaluation*†3
Most frequent TEAEs as observed (any grade reported in ≥30% of patients and/or Grade 3/4 reported in ≥20% of patients) in DARZALEX® + Rd arm†3
Rd=lenalidomide (R) + dexamethasone (d); TEAE=treatment-emergent adverse event.
*Median follow-up was 64.5 months.3
†Safety analysis set. TEAEs are defined as any adverse event (AE) that occurs after the start of the first study treatment through 30 days after the last study treatment; or the day prior to start of subsequent antimyeloma therapy, whichever is earlier; or any AE that is considered related (very likely, probably, or possibly related) regardless of the start date of the event; or any AE that is present at baseline but worsens in toxicity grade or is subsequently considered drug related by the investigator.
- Cumulative Grade 3/4 infection rates were 43% for DRd vs 30% for Rd†3
- Cumulative rates of discontinuation due to TEAEs were 15% for DRd vs 24% for Rd3
- Hematologic adverse events included in the follow-up analyses are investigator-reported TEAEs and not investigator-reported treatment-emergent laboratory abnormalities
DARZALEX® can cause severe and/or serious infusion-related reactions (IRRs) including anaphylactic reactions. In clinical trials (monotherapy and combination: N=2,066), IRRs occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 IRR at Week 2 or subsequent infusions.1
DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); Rd=lenalidomide (R) + dexamethasone (d); TEAE=treatment-emergent adverse event.
Frequency of IRRs (any grade) across clinical trials (N=2,066)1
IRR=infusion-related reaction.
Most IRRs occurred during the first infusion across clinical trials (N=2,066)1
- For 37% of patients, IRRs (any grade) occurred with the Week 1 (16 mg/kg) infusion; for 2% of patients, with the Week 2 infusion; and cumulatively, for 6% of patients with subsequent infusions
- Median time to onset of an IRR was 1.5 hours (range: 0–73 hours)
- Incidence of infusion modification due to reactions was 36%
- DARZALEX® can cause severe IRRs. Severe IRRs included bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. 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, hypotension, and blurred vision
- Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX® infusion. If ocular symptoms occur, interrupt DARZALEX® infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX®
Management of IRRs1
For IRRs of any grade/severity, immediately interrupt the DARZALEX® infusion and manage symptoms. Management of IRRs may further require reduction in the rate of infusion or treatment discontinuation of DARZALEX® as outlined below.
IRR=infusion-related reaction.
Interference with serological testing1
DARZALEX® binds to CD38 found on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test) that may persist for up to 6 months after the last DARZALEX® infusion.
Reminders
- Type and screen patients before starting DARZALEX®
- Inform blood banks when a patient is on DARZALEX®
- Identify any blood samples of patients treated with DARZALEX®
- Ask patients to tell other healthcare professionals that they've taken DARZALEX®
Neutropenia and thrombocytopenia1
DARZALEX® may increase neutropenia and thrombocytopenia 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. Consider withholding DARZALEX® until recovery of neutrophils or for recovery of platelets.
Interference with determination of complete response1
Daratumumab is a human immunoglobulin G (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.
Embryo-fetal toxicity1
Based on the mechanism of action, DARZALEX® can cause fetal harm when administered to a pregnant woman. DARZALEX® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX® and for 3 months after the last dose.
The combination of DARZALEX® with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.
Brochure on daratumumab and serological testing
Identification card to give to patients taking daratumumab
This analysis is not included in the Prescribing Information for DARZALEX®. This analysis was conducted post hoc, and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.
Please see MAIA trial design & primary results.
Methodology
After 64.5 months of follow-up:
Post hoc analysis of MAIA evaluating long-term outcomes in patients with high-risk cytogenetics*1
High-risk cytogenetics defined as having at least 1 of the following 3 abnormalities: t[4;14], t[14;16], or del[17p].1
Post hoc PFS analysis of evaluable patients from the MAIA study by cytogenetics subgroups after 64.5 months of follow-up*†1
DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); PFS=progression-free survival; Rd=lenalidomide (R) + dexamethasone (d).
*Median follow-up was 64.5 months.1
†Per protocol, cytogenetic tests from bone marrow aspirates were performed by local laboratories at screening and 642 patients had baseline cytogenetic data reported from local laboratories out of the 737 patients who were enrolled in MAIA.1,2
At the time of MAIA study initiation, the International Myeloma Working Group (IMWG) defined high-risk cytogenetics as presence of at least 1 of the following abnormalities: t[4;14], t[14;16], or del[17p], determined by fluorescence in situ hybridization (FISH) analysis. Standard risk was defined as the absence of these 3 abnormalities.2-6
Biomarkers collection per MAIA Clinical Study Protocol: Biomarker samples were evaluated to determine the clinical benefit of DRd in high-risk molecular subtypes. Prespecified biomarkers were t[4;14], t[14;16], del[17p], specific gene signatures, and specific mutations. Samples for biomarker evaluations were collected as specified per the Time and Events Schedule and could be used for additional biomarker testing at a later time.7
Cytogenetic abnormalities, t[4;14], t[14;16], or del[17p], were detected based on FISH or karyotype analysis.1
PFS results
In a subgroup analysis of patients with high-risk cytogenetics:
Median PFS was 45.3 months with frontline DARZALEX® + Rdvs 29.6 months with Rd alone*1
High-risk cytogenetics defined as having at least 1 of the following 3 abnormalities: t[4;14], t[14;16], or del[17p].1
PFS among patients with high-risk cytogenetics1
CI=confidence interval; DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); HR=hazard ratio; PFS=progression-free survival; Rd=lenalidomide (R) + dexamethasone (d).
*Median follow-up was 64.5 months.1
†HR and 95% CI from a Cox proportional hazards model with treatment as the sole explanatory variable. HR <1 indicates an advantage for DRd.1
This analysis was conducted post hoc and no conclusions should be drawn.
Patient case in newly diagnosed, transplant-ineligible MM
Luis, age 76: Patient with high-risk cytogenetics*
Hypothetical patient case.
- ISS disease stage: III
- ECOG PS: 2
Do you have patients in your practice who may be appropriate for frontline DRd?
Dr. Shain reviews key considerations for treating patients like Luis
DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); ECOG PS=Eastern Cooperative Oncology Group Performance Status; ISS=International Staging System; MM=multiple myeloma.
*Cytogenetic risk was based on fluorescence in situ hybridization (FISH) or karyotype analysis. High-risk cytogenetics were defined as having at least one of the following abnormalities: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], amp[1q21].1
This analysis is not included in the Prescribing Information for DARZALEX®. This analysis was conducted post hoc, and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.
Please see MAIA trial design & primary results.
Methodology
After 64.5 months of follow-up:
Post hoc analysis of MAIA evaluating long-term outcomes in patients with revised high-risk cytogenetics*1
Revised high-risk cytogenetics defined as having at least 1 of the following 6 abnormalities: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], or amp[1q21].1
Post hoc PFS analysis of evaluable patients from the MAIA study by cytogenetics subgroups after 64.5 months of follow-up*†1
DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); PFS=progression-free survival; Rd=lenalidomide (R) + dexamethasone (d).
*Median follow-up was 64.5 months.1
†Per protocol, cytogenetic tests from bone marrow aspirates were performed by local laboratories at screening and 642 patients had baseline cytogenetic data reported from local laboratories out of the 737 patients who were enrolled in MAIA. At a later date, additional tests were performed by a central laboratory and assay cutoffs assigned at the central laboratory were used to detect gain[1q21] and amp[1q21], which identified additional high-risk patients. This included patients with no cytogenetic data from local laboratories whose status was revised as high risk, increasing the number of patients with cytogenetic data to 671 patients.1,2
At the time of MAIA study initiation, the International Myeloma Working Group (IMWG) defined high-risk cytogenetics as presence of at least 1 of the following abnormalities: t[4;14], t[14;16], or del[17p], determined by fluorescence in situ hybridization (FISH) analysis. An updated IMWG consensus statement in 2016 advised on including additional cytogenetic abnormalities, such as t[14;20] and gain[1q21], in clinical trials. These abnormalities, t[14;20] and gain[1q21], are also included in the Mayo Stratification for Myeloma and Risk-Adapted Therapy (mSMART) guidelines for classifying high-risk cytogenetics. Standard-risk cytogenetics was defined as the absence of these cytogenetic abnormalities.2-9
Biomarkers collection per MAIA Clinical Study Protocol: Biomarker samples were evaluated to determine the clinical benefit of DRd in high-risk molecular subtypes. Prespecified biomarkers were t[4;14], t[14;16], del[17p], specific gene signatures, and specific mutations. Samples for biomarker evaluations were collected as specified per the Time and Events Schedule and could be used for additional biomarker testing at a later time. As part of the post hoc analysis presented, a retrospective evaluation of additional biomarkers that represent high-risk cytogenetics, t[14;20], gain[1q21], and amp[1q21], was conducted.2,10
Cytogenetic abnormalities, t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], or amp[1q21], were detected based on FISH or karyotype analysis.1
PFS results
In a subgroup analysis:
PFS with frontline DARZALEX® + Rd vs Rd alone in patients with revised high-risk cytogenetics*1
Revised high-risk cytogenetics defined as having at least 1 of the following 6 abnormalities: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], or amp[1q21].1
Median PFS was 61.4 months with frontline DRd vs 31.2 months with Rd alone among patients with 1 high-risk cytogenetic abnormality*1
CI=confidence interval; DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); HR=hazard ratio; HRCA=high-risk cytogenetic abnormality; NR=not reached; PFS=progression-free survival; Rd=lenalidomide (R) + dexamethasone (d).
*Median follow-up was 64.5 months.1
- Among patients with revised standard cytogenetic risk (0 HRCA), median PFS was not reached with DRd vs 35.1 months with Rd alone (HR=0.50; 95% CI: 0.37, 0.66)*1
This analysis was conducted post hoc and no conclusions should be drawn.
Median PFS was 24.9 months with frontline DRd vs 24.0 months with Rd alone among patients with ≥2 high-risk cytogenetic abnormalities*1
CI=confidence interval; DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); HR=hazard ratio; HRCA=high-risk cytogenetic abnormality; PFS=progression-free survival; Rd=lenalidomide (R) + dexamethasone (d).
*Median follow-up was 64.5 months.1
This analysis was conducted post hoc and no conclusions should be drawn.
Patient case in newly diagnosed, transplant-ineligible MM
Luis, age 76: Patient with high-risk cytogenetics*
Hypothetical patient case.
- ISS disease stage: III
- ECOG PS: 2
Do you have patients in your practice who may be appropriate for frontline DRd?
Dr. Shain reviews key considerations for treating patients like Luis
DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); ECOG PS=Eastern Cooperative Oncology Group Performance Status; ISS=International Staging System; MM=multiple myeloma.
*Cytogenetic risk was based on fluorescence in situ hybridization (FISH) or karyotype analysis. High-risk cytogenetics were defined as having at least one of the following abnormalities: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], amp[1q21].1
This analysis is not included in the Prescribing Information for DARZALEX®. This analysis was conducted post hoc, and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy or safety among the subgroups.
Please see MAIA trial design & primary results.
Methodology
Post hoc subgroup analysis of MAIA by frailty status score
Frailty assessment was performed retrospectively using age, CCI, and baseline ECOG PS1
CCI=Charlson Comorbidity Index; DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); ECOG PS=Eastern Cooperative Oncology Group Performance Status; Rd=lenalidomide (R) + dexamethasone (d).
- The median age in frail subgroup was 77 years (range: 57-90 years), with 88% of patients having ECOG PS ≥11
- CCI was calculated based on retrospective review of each patient’s medical history1
Limitations: The retrospective assessment of frailty score was a limitation of this study. Retrospective CCI calculations were based on reported medical history, which may contain missing data and result in underestimating or overestimating the number of patients in each frailty subgroup. The ECOG PS score parameter used for frailty score calculations in the study is more subjective, with susceptibility to intra- and inter-observer bias, compared with the ADL and IADL scales used in the IMWG scoring system. While the frailty scale used in the study is based on parameters that are routinely assessed in clinical practice for clinical use, the use of comprehensive frailty assessments that more accurately reflect biological or functional frailty will remain important for the further optimization of treatment strategies for frail patients. Patients with an ECOG PS score ≥3 and patients with comorbidities that may interfere with the study procedures were excluded from MAIA; the inclusion and exclusion criteria for the study limit the generalizability of these results to more frail patients seen in clinical practice.1
ADL=activities of daily living; CCI=Charlson Comorbidity Index; ECOG PS=Eastern Cooperative Oncology Group Performance Status; IADL=instrumental activities of daily living; IMWG=International Myeloma Working Group.
PFS results
In a subgroup analysis of frail patients after 36.4 months of follow-up:
61.5% of patients had not progressed with frontline DARZALEX® + Rd vs 39.5% of patients with Rd alone*1
CI=confidence interval; DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); HR=hazard ratio; NR=not reached; PFS=progression-free survival; Rd=lenalidomide (R) + dexamethasone (d).
*Median follow-up was 36.4 months.1
In frail patients, the risk reduction for disease progression or death was 38% with DRd vs Rd alone (HR=0.62; 95% CI: 0.45, 0.85)1
This analysis was conducted post hoc and no conclusions should be drawn.
Most frequent Grade 3/4 TEAEs (≥10%) in frail patients1
DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); Rd=lenalidomide (R) + dexamethasone (d); TEAE=treatment-emergent adverse event.
All TEAEs are reported as observed. This analysis was conducted post hoc and no conclusions should be drawn.
Additional safety information: results from Prescribing Information
Of the 2,459 patients who received DARZALEX® at the recommended dose, 38% were 65 to 74 years of age, and 15% were 75 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. The incidence of serious adverse reactions was higher in older patients than in younger patients. Among patients with relapsed and refractory multiple myeloma (n=1,213), the serious adverse reactions that occurred more frequently in patients 65 years and older were pneumonia and sepsis. Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplant (n=710), the serious adverse reaction that occurred more frequently in patients 75 years and older was pneumonia.2
Of the 214 patients who received DARZALEX FASPRO® as combination therapy with pomalidomide and dexamethasone or DARZALEX FASPRO® as combination therapy with lenalidomide and low-dose dexamethasone for relapsed and refractory multiple myeloma, 43% were 65 to <75 years of age, and 18% were 75 years of age or older.3
Adverse reactions occurring at a higher frequency (≥5% difference) in patients ≥65 years of age included fatigue, pyrexia, peripheral edema, urinary tract infection, diarrhea, constipation, vomiting, dyspnea, cough, and hyperglycemia. Serious adverse reactions occurring at a higher frequency (≥2% difference) in patients ≥65 years of age included neutropenia, thrombocytopenia, diarrhea, anemia, COVID-19, ischemic colitis, deep vein thrombosis, general physical health deterioration, pulmonary embolism, and urinary tract infection.3
No clinically meaningful differences in the pharmacokinetics of daratumumab were observed in geriatric patients compared to younger adult patients.3
Patient case in newly diagnosed, transplant-ineligible MM
Samuel, age 78: Elderly patient with comorbidities
Hypothetical patient case.
- ISS disease stage: II
- ECOG PS: 2
Do you have patients in your practice who may be appropriate for frontline DRd?
Dr. Birhiray reviews key considerations for treating patients like Samuel
DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); ECOG PS=Eastern Cooperative Oncology Group Performance Status; ISS=International Staging System; MM=multiple myeloma.
This analysis is not included in the Prescribing Information for DARZALEX®. This analysis was conducted post hoc, and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy or safety among the subgroups.
Please see MAIA trial design & primary results.
Methodology
After 64 months of follow-up:
Post hoc analysis of MAIA evaluating long-term outcomes in age subgroups*1,2
Post hoc PFS analysis of the MAIA study population by 3 age subgroups after 64.5 months of follow-up*1,2
Patient age was defined at randomization. The median age for the overall MAIA population was 73 (range: 50–90) years for the DRd arm and 74 (range: 45–89) years for the Rd arm.3
DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); PFS=progression-free survival; Rd=lenalidomide (R) + dexamethasone (d).
*Median follow-up was 64.5 months.1,2
PFS for ages <70 years
In a subgroup analysis of patients under 70 years of age:
Median PFS was not reached with frontline DARZALEX® + Rd vs 39.2 months with Rd alone*1
CI=confidence interval; DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); HR=hazard ratio; NR=not reached; PFS=progression-free survival; Rd=lenalidomide (R) + dexamethasone (d).
*Median follow-up was 64.5 months.1
†Kaplan-Meier estimate.1
At 60 months, 67% of patients had not progressed with DRd vs 29% with Rd alone†1
PFS for ages ≥70 to <75 years
In a subgroup analysis of patients ≥70 to <75 years of age:
Median PFS was 61.9 months with frontline DARZALEX® + Rd vs 37.5 months with Rd alone*1
CI=confidence interval; DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); HR=hazard ratio; PFS=progression-free survival; Rd=lenalidomide (R) + dexamethasone (d).
*Median follow-up was 64.5 months.1
PFS for ages ≥75 years
In a subgroup analysis of patients 75 years of age or older:
Median PFS was 54.3 months with frontline DARZALEX® + Rd vs 31.4 months with Rd alone*2
CI=confidence interval; DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); HR=hazard ratio; PFS=progression-free survival; Rd=lenalidomide (R) + dexamethasone (d).
*Median follow-up was 64.5 months.2
This analysis was conducted post hoc and no conclusions should be drawn.
Safety
Safety in patients aged ≥75 years4
In an analysis of safety among patients aged ≥75 years, Grade 3 or 4 treatment-emergent adverse events (TEAEs) occurred in 95.5% of patients on DRd and 95.0% of patients on Rd.
The most common (≥20%) Grade 3 or 4 TEAEs were neutropenia (DRd, 62.4%; Rd, 41.5%), lymphopenia (DRd, 21.0%; Rd, 12.6%), anemia (DRd, 20.4%; Rd, 25.2%), and pneumonia (DRd, 20.4%; Rd, 14.5%).
Serious TEAEs occurred in 80.9% of patients on DRd and 79.2% of patients on Rd, the most common of which was pneumonia (19.7% and 12.6%, respectively).
TEAEs led to study treatment discontinuation in 15.3% of patients on DRd and 27.7% of patients on Rd. TEAEs with an outcome of death occurred in 11.5% of patients on DRd and 13.2% of patients on Rd.
All TEAEs are reported as observed. These analyses were conducted post hoc and no conclusions should be drawn.
Additional safety information: results from Prescribing Information
Of the 2,459 patients who received DARZALEX® at the recommended dose, 38% were 65 to 74 years of age, and 15% were 75 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. The incidence of serious adverse reactions was higher in older patients than in younger patients. Among patients with relapsed and refractory multiple myeloma (n=1,213), the serious adverse reactions that occurred more frequently in patients 65 years and older were pneumonia and sepsis.5
Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplant (n=710), the serious adverse reaction that occurred more frequently in patients 75 years and older was pneumonia.5
Of the 214 patients who received DARZALEX FASPRO® as combination therapy with pomalidomide and dexamethasone or DARZALEX FASPRO® as combination therapy with lenalidomide and low-dose dexamethasone for relapsed and refractory multiple myeloma, 43% were 65 to <75 years of age, and 18% were 75 years of age or older.6
Adverse reactions occurring at a higher frequency (≥5% difference) in patients ≥65 years of age included fatigue, pyrexia, peripheral edema, urinary tract infection, diarrhea, constipation, vomiting, dyspnea, cough, and hyperglycemia. Serious adverse reactions occurring at a higher frequency (≥2% difference) in patients ≥65 years of age included neutropenia, thrombocytopenia, diarrhea, anemia, COVID-19, ischemic colitis, deep vein thrombosis, general physical health deterioration, pulmonary embolism, and urinary tract infection.6
No clinically meaningful differences in the pharmacokinetics of daratumumab were observed in geriatric patients compared to younger adult patients.6
Patient case in newly diagnosed, transplant-ineligible MM
Helen, age 68: Younger transplant-ineligible patient
Hypothetical patient case.
- ISS disease stage: I
- ECOG PS: 1
Do you have patients in your practice who may be appropriate for frontline DRd?
DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); ECOG PS=Eastern Cooperative Oncology Group Performance Status; ISS=International Staging System; MM=multiple myeloma; Rd=lenalidomide (R) + dexamethasone (d).
References:
- DARZALEX® [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.
- Facon T, Kumar SK, Plesner T, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(11):1582-1596.
- Moreau P, Facon T, Usmani SZ, et al. Daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): clinical assessment of key subgroups of the phase 3 MAIA study. Poster presented at the 64th American Society of Hematology (ASH) Annual Meeting & Exposition; December 10-13, 2022; New Orleans, LA.