Subcutaneous Daratumumab Research Articles

Daratumumab As a Treatment for Adult Immune Thrombocytopenia: A Phase II Study with Safety Run-in (the DART Study)

Daratumumab As a Treatment for Adult Immune Thrombocytopenia: A Phase II Study with Safety Run-in (the DART Study)

Evaluation of subcutaneous daratumumab injections in the ambulatory care setting.

Subcutaneous daratumumab is non-inferior to intravenous daratumumab for the treatment of multiple myeloma and significantly reduced incidence of systemic reactions. However, manufacturer for subcutaneous daratumumab has not provided guidance regarding optimal methods for monitoring for hypersensitivity reactions following subcutaneous daratumumab administration. A retrospective analysis was performed in two cohorts of patients who received at least two doses of subcutaneous daratumumab for the treatment of plasma cell disorders: patients with previous exposure to intravenous daratumumab (dara-exposed) and patients without history of intravenous daratumumab (dara-naïve). The primary outcome was incidence of systemic and injection-site reactions following first dose of subcutaneous daratumumab. Secondary analysis included time to systemic and injection-site reactions, grading of adverse reaction, and incidence of second systemic reaction. Thirty-one patients were dara-naïve and 49 patients were dara-exposed. Differences in incidence of systemic (dara-naïve: 9.7% vs dara-exposed: 6.1%, p = 0.67) and injection-site reactions (dara-naïve: 12.9% vs dara-exposed: 14.3%, p = 0.99) did not reach statistical significance. Difference in median time to systemic reaction (dara-naïve: 3 h vs dara-exposed: 12 h, p = 0.18) was clinically important but did not reach statistical significance. Median time to injection-site reactions (dara-naïve: 6 h vs dara-exposed: 24 h, p = 0.03) was shorter in the dara-naïve cohort. No clinically meaningful difference was observed for incidence of second systemic reaction. Most reactions were mild and did not require medical intervention. Following first subcutaneous daratumumab dose, monitoring for 3 h for dara-naïve patients and no monitoring time for dara-exposed patients for hypersensitivity reactions may be a safe and reasonable practice.

P-203: EXCALIBER: a phase 3 study comparing iberdomide, daratumumab, and dexamethasone (IberDd) with daratumumab, bortezomib, and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma

<h3>Background</h3> Despite recent advances, new therapies are needed to deepen and extend remissions in early-line relapsed/refractory multiple myeloma (RRMM). Iberdomide (IBER) is a novel, potent oral cereblon E3 ligase modulator (CELMoD®) compound with enhanced tumoricidal and immune-stimulatory effects when compared with IMiD® agents. Preclinically, IBER overcomes IMiD resistance and has synergy with dexamethasone (DEX), daratumumab (DARA), and bortezomib (BORT). In a phase 1/2 trial in patients (pts) with RRMM, IberDd showed efficacy with favorable tolerability, and pharmacodynamic data demonstrated increased NK and T cell proliferation (Lonial S, et al. HemaSphere 2021; 5(S2):49). The EXCALIBER trial was initiated to compare efficacy and safety of IberDd with that of DVd, a globally approved regimen, in pts with early-line RRMM. <h3>Methods</h3> In this multicenter, open-label, phase 3 study ≈742 pts will be randomized 1:1 to receive IberDd or DVd. Pts will be stratified within each cohort by number of prior lines of therapy (1 vs 2), age (≤70 years vs >70 years), and ISS staging at study entry (I–II vs III). Key eligibility criteria include age (≥18 years), measurable disease treated with 1–2 prior lines of antimyeloma therapy where a partial response or better to ≥1 prior therapy was achieved, and disease progression during or after the last regimen. Prior treatment with anti-CD38 monoclonal antibodies and/or BORT is permitted under stringent conditions. Treatment in the IberDd arm will consist of 28-day (D) cycles (C) with 1.6 mg IBER on D1–21; 1,800 mg subcutaneous (SC) DARA on D1, 8, 15, and 22 of C1–2, D1 and 15 of C3–6, and D1 of ≥C7; and 40 mg oral DEX (20 mg if ≥75 years) on D1, 8, 15, and 22. Treatment in the DVd arm will consist of 21-D cycles for C1–8 and 28-D cycles for ≥C9; 1,800 mg SC DARA on D1, 8, and 15 for C1–3, D1 for C4–8, and D1 for ≥C9; 1.3 mg/m2 SC BORT on D1, 4, 8, and 11 for C1–8; and 20 mg oral DEX (10 mg if ≥75 years) on D1, 2, 4, 5, 8, 9, 11, and 12 for C1–8. Treatment will continue until confirmed progressive disease, unacceptable toxicity, or consent withdrawal. Primary efficacy endpoint is PFS, calculated as the time from randomization to progressive disease, or death. Assuming a decrease in the PFS risk by 25% (HR=0.75) with IberDd, under exponential distribution assumption of PFS (one-sided α=0.025) and adjusted for the 2 interim analyses, 441 PFS events will have 85% power to detect an improvement in treatment effect. Secondary efficacy endpoints include OS, duration of response, time to progression, overall response rate, measurable residual disease, and quality of life. Safety evaluations include treatment-emergent adverse events, laboratory parameters, and vital signs. Two interim analyses are planned for PFS, when ≈134 (30%) and ≈334 (75%) events have been accumulated, to examine futility and superiority, respectively. Enrollment is expected to begin in Q3, 2021. NCT number is pending.

P-216: Daratumumab, Carfilzomib, Lenalidomide, & Dexamethasone for relapsed/refractory Myeloma with salvage autologous hematopoietic cell transplant: interim analysis of the multicenter 2nd chance protocol

Background Despite major advances in multiple myeloma (MM) therapy, most patients relapse after primary treatment. We present the interim analysis of a phase II multicenter trial evaluating the efficacy of daratumumab, carfilzomib (27 mg/m2 twice weekly), lenalidomide, & dexamethasone (Dara-KRD) with high-dose melphalan and autologous hematopoietic cell transplantation (AHCT) in patients after 1-3 prior lines to induce a complete response and provide patients a 2nd chance at long term disease control. Methods Patients received 4 cycles of Dara-KRD followed by AHCT and 4 additional cycles of Dara-KRD followed by maintenance at investigator discretion with a primary endpoint of best overall response by the end of cycle 8. Using a Simon’s two-stage optimal design, 7/22 patients need to achieve a CR to continue. Patient reported outcomes were monitored monthly using the MDASI-MM and NCI PRO-CTCAE. Data cutoff was 7/15/21. Results Between 7/2018 and 7/2020, 23 patients enrolled with 22 evaluable for interim analysis (one did not complete one cycle of treatment and was replaced). Patients had a median age of 65 (range 29-73), with 68% male, 64% white, and 18% black. Time from initial MM diagnosis to enrollment was a median of 4.4 years (range 0.4 -10.6). At initial diagnosis, 36% of patients had ISS stage I disease and 31% had unknown ISS staging. High risk cytogenetics were seen in 36%, with 2 patients having del17p, 2 t(4;14), 1 t(14;16), and 4 gain 1q. Eight-six percent had 1 line of treatment before enrollment with no patients having prior daratumumab, 14% receiving prior carfilzomib, and 86% having had a prior AHCT a median of 3.6 years (range 0.8-9.3) prior to enrollment. Eighty-two percent underwent AHCT and 59% completed all study treatments. Responses deepened post-AHCT prior to the second 4 cycles of Dara-KRD in most cases. Best overall response on study was a CR in 45% (10/22), >VGPR in 77%, and >PR in 82%. Three patients have died, 1 from infection during the pre-HCT cycles and 2 from disease progression. Conclusion Dara-KRD with salvage AHCT induced high overall response rates, meeting the pre-specified cutoff for promising results. Enrollment is ongoing for the second stage of the study using subcutaneous daratumumab and weekly carfilzomib. Full interim analysis and patient reported outcomes will be presented. Despite major advances in multiple myeloma (MM) therapy, most patients relapse after primary treatment. We present the interim analysis of a phase II multicenter trial evaluating the efficacy of daratumumab, carfilzomib (27 mg/m2 twice weekly), lenalidomide, & dexamethasone (Dara-KRD) with high-dose melphalan and autologous hematopoietic cell transplantation (AHCT) in patients after 1-3 prior lines to induce a complete response and provide patients a 2nd chance at long term disease control. Patients received 4 cycles of Dara-KRD followed by AHCT and 4 additional cycles of Dara-KRD followed by maintenance at investigator discretion with a primary endpoint of best overall response by the end of cycle 8. Using a Simon’s two-stage optimal design, 7/22 patients need to achieve a CR to continue. Patient reported outcomes were monitored monthly using the MDASI-MM and NCI PRO-CTCAE. Data cutoff was 7/15/21. Between 7/2018 and 7/2020, 23 patients enrolled with 22 evaluable for interim analysis (one did not complete one cycle of treatment and was replaced). Patients had a median age of 65 (range 29-73), with 68% male, 64% white, and 18% black. Time from initial MM diagnosis to enrollment was a median of 4.4 years (range 0.4 -10.6). At initial diagnosis, 36% of patients had ISS stage I disease and 31% had unknown ISS staging. High risk cytogenetics were seen in 36%, with 2 patients having del17p, 2 t(4;14), 1 t(14;16), and 4 gain 1q. Eight-six percent had 1 line of treatment before enrollment with no patients having prior daratumumab, 14% receiving prior carfilzomib, and 86% having had a prior AHCT a median of 3.6 years (range 0.8-9.3) prior to enrollment. Eighty-two percent underwent AHCT and 59% completed all study treatments. Responses deepened post-AHCT prior to the second 4 cycles of Dara-KRD in most cases. Best overall response on study was a CR in 45% (10/22), >VGPR in 77%, and >PR in 82%. Three patients have died, 1 from infection during the pre-HCT cycles and 2 from disease progression. Dara-KRD with salvage AHCT induced high overall response rates, meeting the pre-specified cutoff for promising results. Enrollment is ongoing for the second stage of the study using subcutaneous daratumumab and weekly carfilzomib. Full interim analysis and patient reported outcomes will be presented.

SUBCUTANEOUS DARATUMUMAB + BORTEZOMIB, CYCLOPHOSPHAMIDE, AND DEXAMETHASONE (VCD) IN PATIENTS WITH NEWLY DIAGNOSED LIGHT CHAIN (AL) AMYLOIDOSIS: UPDATED RESULTS FROM THE PHASE 3 ANDROMEDA STUDY

Systemic AL amyloidosis is a plasma cell disease characterized by the deposition of insoluble amyloid fibrils causing organ dysfunction and death. Primary results from the ANDROMEDA study showed that addition of subcutaneous (SC) daratumumab (DARA) to the standard of care combination of bortezomib, cyclophosphamide, and dexamethasone (VCd) was superior to VCd alone, with higher rates of hematologic complete response (CR) and an acceptable safety profile. DARA-VCd was approved for newly diagnosed AL amyloidosis in January 2021. Here we present an update of the primary ANDROMEDA study results with longer follow-up. ANDROMEDA is a randomized, open-label, active-controlled phase 3 study. Adult patients with newly diagnosed AL amyloidosis were randomized 1:1 to DARA-VCd or VCd and were treated for 6 cycles 28 days each. Bortezomib (1.3 mg/m 2 ), cyclophosphamide (300 mg/m 2 ; maximum weekly dose 500 mg), and dexamethasone (40 mg) were given weekly. DARA SC was given weekly (cycle 1–2) and every 2 weeks (cycle 3–6). After cycle 6, patients in the DARA-VCd group received DARA SC alone every 4 weeks for up to 24 cycles from first dose. Disease status was evaluated every 4 weeks in cycle 1–6 and every 8 weeks after cycle 7. The primary endpoint was overall hematologic CR rate in the intent-to-treat population. Secondary endpoints were major organ deterioration progression-free survival (PFS), organ response rate, time to hematologic response, survival, and safety. Of 388 randomized patients, 195 were randomized to DARA-VCd and 193 to VCd. As of November 2020, the median follow-up was 20.3 months (mo), with a median treatment duration of 18.5 mo for DARA-VCd and 5.3 mo for VCd; 78 patients (40%) in the DARA-VCd group were still on treatment. The overall hematologic CR rate continued to be higher with DARA-VCd than VCd (59% vs 19%; odds ratio [OR] 5.9; 95% CI 3.7–9.4; p < 0.0001). More patients achieved a very good partial response or better (≥VGPR) with DARA-VCd than VCd (79% vs 50%; OR 3.7; 95% CI 2.4–5.9; p < 0.0001). Among responders, median time from randomization to ≥VGPR was shorter for DARA-VCd than VCd (0.56 vs 0.82 months). Cardiac response rates were higher with DARA-VCd than VCd at 6 months (42% vs 22%) and at 12 months (57% vs 28%); renal response rates were 54% vs 27% at 6 months and 57% vs 27% at 12 months. A total of 71 deaths occurred (DARA-VCd, n = 31; VCd, n = 40). From cycle 7 onward in the DARA-VCd group, no grade 3/4 treatment-emergent adverse events occurred in ≥5% of patients. There were no systemic administration-related reactions with DARA-VCd after cycle 6. Analysis of major organ deterioration PFS will be updated after ̃200 events have occurred. DARA-VCd (versus VCd alone) demonstrated robust hematologic and organ responses with no new safety concerns with longer follow-up. Updated results from the ANDROMEDA study reinforce the clinical superiority of DARA-VCd over VCd in pts with newly diagnosed AL amyloidosis. Based on its recent approval, DARA-VCd represents a new standard of care in AL amyloidosis. This trial was registered at www.clinicaltrials.gov as NCT03201965.

P-002: Real-world observations and practical considerations of subcutaneous daratumumab administration in multiple myeloma

<h3>Background</h3> Subcutaneous daratumumab (dara-SC) has several advantages over intravenous daratumumab (dara-IV). It has significantly shorter administration time, lower rates of systemic reactions, and smaller administration volume, while maintaining comparable efficacy and safety. Its fixed dosing allows for easier preparation. At our institution, standard approach is to monitor for 4h following the initial dara-SC dose for those at high risk for systemic reactions, defined as no prior dara use, treatment break ≥90d, or any prior history of reactions. We also administer montelukast and fexofenadine for the first 2 doses of dara-SC in addition to the usual standard pre-medications. Herein, we share our experience with dara-SC use in both dara-naive and dara-exposed patients in order to gain practical insight, such as optimal monitoring duration, considerations for transitioning between dara-IV and dara-SC, and the place of therapy for dara-IV based on adverse events (AEs). <h3>Methods</h3> Between June 2020 and June 2021, patients who received at least one dose of dara-SC were identified and their record was reviewed for any systemic reactions, hypersensitivity medication use, and patient reported AEs. <h3>Results</h3> Since June 2020, our dara-SC drug use increased from 38% to 91% of all doses. There were 208 patients who received at least 1 dose of dara-SC. Of 208 patients, 99 (47.6%) were dara-naive and 109 (52.4%) had prior dara exposure – either transitioning from dara-IV on schedule or had dara-IV as a past line of therapy. We identified 124 patients who met the criteria for 4h post dara-SC injection monitoring: dara-naive (79.8%), treatment break ≥90d (18.5%), or prior history of reactions (1.6%). Only 5 experienced systemic reactions, representing 4% among those at high risk. All reactions were mild requiring minimal intervention and occurred following the first dara-SC dose. Onset of reactions and type of intervention during the 4h monitoring window were: hypotension (2h; fluid), nausea/vomiting (2.5h; hypersensitivity medications), and sinus tachycardia (4h), while 2 patients had transient chest pressure/tightness at home (1 within 24h, 1 between 1-6d following the dose). Eleven patients (5%) receiving dara-SC converted back to dara-IV, with AEs being the most common reason. Diarrhea, fatigue, and injection site reactions were among the most frequent patient-reported AEs. When transitioning back to dara-IV, a 90min rapid infusion rate was used if >4 prior dara doses were given. No infusion-related reactions were observed. <h3>Conclusion</h3> The introduction of dara-SC has significantly improved patient experience. We observed a lower rate of systemic reactions compared to previous reports of 10% with first dose of dara-SC. This may be partly due to our strengthened pre-medication strategy. Opportunities exist to further improve and apply practical considerations when administering dara-SC. Based on our results, shortening on-site monitoring time may be feasible.

A cautionary tale of the use of lenalidomide and dexamethasone for relapsed/refractory immunoglobulin light chain (AL) amyloidosis.

In this edition of the Journal, Basset et al.1 describe the largest retrospective study to date of the use of lenalidomide and dexamethasone (RD) for the treatment of relapsed/refractory immunoglobulin light chain (AL) amyloidosis. There are a number of key messages that are of substantial clinical value; there is information on predictors of efficacy and also a forensic-like approach to the data that highlight the toxicities of this combination in AL amyloidosis – toxicities that are not prominent in the existing myeloma literature. The authors examined a variety of outcome measures including overall survival (OS), haematological response rate (HRR), very good haematological response (VGHR), haematological event-free survival (haemEFS) and organ response, in particular, renal survival. The 3-month HRR was 31% with an 18% VGHR and a haemEFS of 9 months. Given, the median duration of RD treatment was short at only four cycles, it is imperative to ask – why such a short time on drug? The answer probably lies in the fact that these patients had difficult to treat disease (seemingly a worse patient population than some other previously published studies) along with the observation that the RD combination is associated with substantial toxicity. The authors go to pains to demonstrate that their study population and outcomes do reflect what is observed in the real world and it is reassuring to see that their data is similar to that of a recent meta-analysis of immunomodulatory drugs (IMiDs) for AL amyloidosis.2 So how does one predict who are likely to respond to the RD combination? The authors chose to investigate their predictors of outcome by examining ‘clonal’ and ‘organ’ biomarkers; clonal biomarkers included chromosomal/interphase fluorescence in situ hybridisation (iFISH) abnormalities, light chain (LC) isotype and level of difference in free light chains (dFLC) while organ biomarkers were N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and renal parameters. The major predictors of haematological response were dFLC and LC isotype and not surprisingly, poor OS was predicted by elevated NT-proBNP and dialysis at initiation of RD, as well as dFLC and LC isotype. With respect to gain of 1q21, it predicted for a shorted haemEFS with a trend for poorer OS. Taken together, at baseline, those patients that are predicted to have the best survival are those with low dFLC, low NT-proBNP and absence of clonal risk factors. After 3 and 6 months of RD treatment, those that are predicted to be longer survivors are those with a VGHR with cardiac and renal stability. Cardiac toxicity was a concern, with 21% of patients developing cardiac toxicity with 12% being Grade 3–4. Indeed, we have previously been alerted to the fact that NT-proBNP frequently increases in patients with AL amyloid receiving lenalidomide3, 4 and in this study 83% of patients had substantial increases in NT-proBNP, while cardiac progression at 3 and 6 months was a major predictor of poor survival. Thus, it seems that the NT-proBNP increases are not just a biochemical aberration but seem to predict direct cardiac toxicity of lenalidomide. The authors correctly caution: ‘signs of early cardiac progression should be evaluated carefully and are clinically meaningful’. Indeed, further research into potential mechanisms of any direct cardiac toxicity of lenalidomide in the setting or AL amyloid is warranted. In the same way, renal toxicity is also a concern, and this study provides further evidence that renal toxicity of RD can be problematic particularly in those with pre-existing renal dysfunction.5, 6 Moreover, renal toxicity was also observed in some patients with even minimal renal disease. The authors again provide words of caution: ‘lenalidomide should be avoided in cases of intermediate-advanced renal amyloidosis and careful monitoring of creatinine should be performed during RD treatment’. How does this study help us design better treatments for AL amyloidosis into the future? It is clear that proteasome inhibitors are our most important weapon against AL amyloid. Furthermore, recent data would indicate that anti-CD38 antibodies are also highly effective in AL amyloid. Thus, combining these two agents, seems obvious and indeed the preliminary results of the ANDROMEDA study (ClinicalTrials.gov Identifier: NCT03201965) of bortezomib, dexamethasone, cyclophosphamide and subcutaneous daratumumab for first-line treatment of AL amyloid has recently been published; the overall HRR was 96% and the regimen well tolerated.7 Therefore, we must ask, is there a benefit of adding an IMiD such as lenalidomide to such a triplet? The data from Basset et al. indicates that we need to be cautious. With that in mind, I recommend the reader of this editorial seek out Wikipedia’s definition of a ‘cautionary tale’!

Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis

BackgroundSystemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.MethodsWe randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.ResultsA total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P=0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.ConclusionsAmong patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.)

Daratumumab Is Safe and Highly Effective in AL Amyloidosis

Introduction: AL amyloidosis remains a challenge to treat due to relapse even with the use of novel agents as well as high dose melphalan and autologous hematopoietic cell transplant (HCT). Daratumumab (DARA), an anti-CD38 human monoclonal antibody, is highly effective in patients with multiple myeloma and has been approved for that purpose.Given that there are only 27 patient reports on safety and efficacy of DARA in AL amyloidosis (Kaufman et al. Blood 2017 and Sher et al. Blood 2016), we report on our experience with DARA in pretreated AL amyloidosis patients.Methods:Patients were identified through our IRB-approved plasma cell disorder patient registry and their medical records reviewed to confirm treatment safety and response. DARA was administered at the standard dosing of 16 mg/kg weekly for 8 doses, then every 2 weeks for 8 doses, then every 4 weeks until disease progression.Results: We conducted a retrospective analysis which identified 15 adult patients with AL amyloidosis treated at the Cleveland Clinic with DARA monotherapy. DARA was initiated at any time between December 2015 and February 2017 upon evidence of biochemical or organ relapse. The median age was 61 years (range, 40-88) with 53% of the patients being male. One of the patients had symptomatic myeloma by the current International Myeloma Working Group (IMWG) criteria. The median number of prior lines of therapy was 4. Sixty percent of our patient cohort had previously undergone high dose melphalan and autologous HCT. Prior to DARA, 53% had achieved at least a hematologic partial response (PR) with 40% having achieved a hematologic very good partial response (VGPR). Five patients had either cardiac or renal involvement only. Two patients had tongue involvement only and three had both cardiac and renal involvement.The overall hematologic response rate to DARA was 82% (9 patients achieved at least a VGPR out of 11 patients assessable for hematologic response). A VGPR was achieved in 8 patients (73%) and one patient attained a complete remission (CR). The median time to hematologic response was 4 weeks. The median time of exposure to DARA was 10 weeks. Organ response was measured according to consensus guidelines (Comenzo et al. Leukemia 2012, Palladini et al. JCO 2012). Half of the patients with cardiac involvement (4 out of 8) had a cardiac response while 3 out of the 5 patients with renal involvement had a renal response (60%).Most of the reported toxicities were grade 1 and 2. The drug was discontinued in two patients due to safety issues (debilitating fatigue after 3 months of DARA in one patient and a facial rash after one a single DARA infusion in the other). Table 1 below shows the safety data.Conclusion: Our analysis shows that DARA is safe and highly effective in most patients with AL amyloidosis who have undergone previous treatment. It can induce rapid hematologic as well as meaningful organ response. There is hope for regulatory authority approval of DARA in AL amyloidosis with an upcoming randomized trial in newly diagnosed patients. There is also an expectation of less risk of volume overload in cardiac patients as subcutaneous DARA use moves toward approval. [Display omitted] DisclosuresValent:Celgene Corporation: Speakers Bureau; Takeda: Speakers Bureau.

Results of a Time and Motion Survey Regarding Subcutaneous versus Intravenous Administration of Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma.

PurposeDaratumumab (DARA) is a humanized anti-CD38 monoclonal antibody and approved as monotherapy or in combination with standard of care regimens for the treatment of multiple myeloma (MM). DARA intravenous (IV) administration is time-consuming; availability of DARA subcutaneous (SC) is expected to reduce this burden. A time and motion survey was undertaken to elicit healthcare providers’ (HCPs’) understanding of the workflow and time estimates for administration of DARA IV and SC (beyond treatment time) in patients with relapsed/refractory MM.Patients and MethodsThis web-based, prospective survey collected data from HCPs at sites that actively enrolled patients in the phase 3 COLUMBA trial, a multicenter, noninferiority study of DARA IV versus DARA SC. Data collection included time actively spent on pre-specified drug preparation and drug administration/patient care activities; active HCP and chair time were extrapolated for first and subsequent treatments.ResultsCompared with DARA IV, DARA SC reduced median total active HCP time by 63.8% (from 265.9 to 96.3 minutes) and 49.5% (from 179.2 to 90.4 minutes) for first and subsequent treatments, respectively. When extrapolated to the anticipated number of treatments per year (23 in Year 1 and 13 in Year 2, per label), estimated active HCP time per patient was reduced by 50% in Years 1 (from 70.1 to 34.8 hours) and 2 (from 38.8 to 19.6 hours) for DARA SC versus DARA IV. Estimated chair time for DARA SC was decreased by 97% versus DARA IV for first (from 456.9 to 13.3 minutes) and subsequent treatments (from 238.0 to 8.1 minutes).ConclusionThese results suggest that DARA SC is associated with less active HCP involvement during drug preparation and drug administration/patient care compared with DARA IV, potentially reducing burdens on patients and caregivers and creating efficiencies for HCPs and healthcare facilities, allowing more patients access to care.

Subcutaneous daratumumab + bortezomib, cyclophosphamide, and dexamethasone (VCd) in patients with newly diagnosed light chain (AL) amyloidosis: Updated results from the phase 3 ANDROMEDA study.

8003 Background: Systemic AL amyloidosis is a plasma cell disease characterized by the deposition of insoluble amyloid fibrils causing organ dysfunction and death. Primary results from the ANDROMEDA study showed that addition of subcutaneous (SC) daratumumab (DARA) to the standard of care combination of bortezomib, cyclophosphamide, and dexamethasone (VCd) was superior to VCd alone, with higher rates of hematologic complete response (CR) and an acceptable safety profile. DARA-VCd was approved for newly diagnosed AL amyloidosis in January 2021. Here we present an update of the primary ANDROMEDA study results with longer follow-up. Methods: ANDROMEDA is a randomized, open-label, active-controlled phase 3 study. Adult patients (pts) with newly diagnosed AL amyloidosis were randomized 1:1 to DARA-VCd or VCd and were treated for 6 28-day Cycles (Cyc). Bortezomib (1.3 mg/m2), cyclophosphamide (300 mg/m2 maximum weekly dose 500 mg), and dexamethasone (40 mg) were given weekly. DARA SC was given weekly (Cyc 1–2) and every 2 weeks (wk) (Cyc 3–6). After Cyc 6, pts in the DARA-VCd group received DARA SC alone every 4 wk for up to 24 Cyc from first dose. Disease status was evaluated every 4 wk in Cyc 1–6 and every 8 wk after Cyc 7. The primary endpoint was overall hematologic CR rate in the intent-to-treat population. Secondary endpoints were major organ deterioration progression-free survival (PFS), organ response rate, time to hematologic response, survival, and safety. Results: Of 388 randomized pts, 195 were randomized to DARA-VCd and 193 to VCd. As of November 2020, the median treatment duration was 18.5 months (mo) for DARA-VCd and 5.3 mo for VCd; 78 pts (40%) in the DARA-VCd group were still on treatment. The overall hematologic CR rate continued to be higher with DARA-VCd than VCd (59% vs 19%; odds ratio [OR] 5.9; 95% CI 3.7–9.4; P&lt; 0.0001). More pts achieved a very good partial response or better (≥VGPR) with DARA-VCd than VCd (79% vs 50%; OR 3.7; 95% CI 2.4–5.9; P&lt; 0.0001). Among responders, median time from randomization to ≥VGPR was shorter for DARA-VCd than VCd (0.56 vs 0.82 mo). Cardiac response rates were higher with DARA-VCd than VCd at 6 mo (42% vs 22%) and at 12 mo (57% vs 28%); renal response rates were 54% vs 27% at 6 mo and 57% vs 27% at 12 mo. A total of 71 deaths occurred (DARA-VCd, n = 31; VCd, n = 40). From Cyc 7 onward in the DARA-VCd group, no grade 3/4 treatment-emergent adverse events occurred in ≥5% of pts. There were no systemic administration-related reactions with DARA-VCd after Cyc 6. Analysis of major organ deterioration PFS will be updated after ̃200 events have occurred. Conclusions: Updated results from the ANDROMEDA study reinforce the clinical superiority of DARA-VCd over VCd in pts with newly diagnosed AL amyloidosis. Based on its recent approval, DARA-VCd represents a new standard of care in AL amyloidosis. Clinical trial information: NCT03201965.

Health-related quality of life (HRQoL) in patients with relapsed/refractory multiple myeloma (RRMM) treated with pomalidamide and dexamethasone ± subcutaneous daratumumab: Patient-reported outcomes (PROs) in APOLLO.

8046 Background: APOLLO (NCT03180736) is a phase 3 trial of pomalidomide and dexamethasone (Pd) ± subcutaneous daratumumab (1800 mg, co-formulated with recombinant human hyaluronidase PH20 in 15 mL) in patients with RRMM and ≥1 prior line of therapy including lenalidomide and a proteasome inhibitor. After 16.9 months (mo) median follow-up, D-Pd significantly reduced the rate of progression or death by 37% relative to Pd. Patients with RRMM have reduced HRQoL compared with age- and sex-matched populations. Here, we present PROs from the APOLLO trial. Methods: Patients were randomized 1:1 to D-Pd or Pd and treated in 28-day cycles until disease progression/unacceptable toxicity. PROs were assessed on Day 1 of each cycle using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30), EORTC QLQ Multiple Myeloma Module 20-item (MY20), and EuroQol 5-dimensional descriptive system. PRO analyses were performed on patients from the intent-to-treat population with a baseline (BL) and ≥1 post-BL assessment. Treatment effect was assessed by a mixed effects model with repeated measures. Time to worsening was estimated using the Kaplan-Meier method. Results: A total of 304 patients were included (151 D-Pd, 153 Pd). Median treatment duration was 11.5 mo with D-Pd vs 6.6 mo with Pd. At Cycle 16 (Cyc 16), 63 and 40 patients remained on treatment in the D-Pd and Pd groups, respectively. Compliance rates for PRO instruments were high and comparable between groups. Patients treated with D-Pd had a reduction in pain (maximum improvement: 6.8 points at Cyc 12) measured with the EORTC QLQ-C30 and no mean change in disease symptoms or the treatment side effects subscales of the EORTC QLQ-MY20. Group mean physical and emotional functioning were unchanged from BL with D-Pd but worsened in the Pd group (maximum worsening: 6.4 at Cyc 4 and 9.1 points at Cyc 14). The proportion of patients with a meaningful improvement from BL was 55.0% vs 49.0% for disease symptoms, 43.0% vs 35.3% for physical functioning, and 41.7% vs 31.4% for emotional functioning with D-Pd vs Pd, respectively. Median time to worsening was ̃4 mo, except for the disease symptoms subscale (̃10 mo); there were no differences between groups. Conclusions: When daratumumab was added to Pd, patients did not experience any decrements in HRQoL while on treatment, but some patients experienced reductions in pain as well as clinically meaningful improvements in symptoms and emotional/physical function. These findings complement the clinical benefits of D-Pd in RRMM patients and further support its use in this RRMM population. Clinical trial information: NCT03180736.

Subcutaneous daratumumab (DARA SC) plus lenalidomide versus lenalidomide alone as maintenance therapy in patients (pts) with newly diagnosed multiple myeloma (NDMM) who are minimal residual disease (MRD) positive after frontline autologous stem cell transplant (ASCT): The phase 3 AURIGA study.

TPS8054 Background: DARA, a human anti-CD38 IgGκ monoclonal antibody, is approved in many countries as monotherapy in relapsed/refractory MM (RRMM) and in combination with standard of care (SoC) in RRMM and NDMM. However, no clinical studies have yet compared DARA maintenance versus SoC maintenance. The ongoing phase 3 AURIGA study will evaluate the addition of DARA to lenalidomide maintenance among pts with NDMM who are MRD positive after SoC induction and ASCT. The primary endpoint is the conversion rate to MRD negativity after 1 year of maintenance therapy. Methods: This open-label, multicenter, randomized phase 3 study will enroll approximately 214 pts in the United States aged 18-79 years with NDMM who receive ≥4 cycles of induction followed by ASCT. Pts must enroll within 6 months of ASCT, be naïve for anti-CD38 treatment, have a very good partial response or better per IMWG criteria, and be MRD positive at a threshold of 10–5 by next generation sequencing (NGS) within 30 days of screening. Pts will be stratified by cytogenetic risk (high vs standard/unknown) and randomized 1:1 to 28-day cycles of lenalidomide maintenance (10 mg PO; D1-28 [dose increasing to 15 mg if tolerated]) ± DARA SC (DARA 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE® drug delivery technology, Halozyme, Inc., San Diego, CA, USA; QW Cycle 1-2, Q2W Cycles 3-6, Q4W C7+). Treatment will continue for up to 36 cycles or until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint is MRD conversion rate after 12 months of maintenance treatment, defined as the proportion of pts who achieve MRD negativity (10–5) by NGS. Additional MRD assessments occur after 18, 24, and 36 months of maintenance. While MRD negativity is associated with improved long-term outcomes for pts with MM and is an emerging, validated prognostic factor, this study is among the first to use MRD negativity as a primary study endpoint. Importantly, MRD negativity allows for earlier efficacy assessment than traditional endpoints such as progression-free survival (PFS) and overall survival (OS). Secondary endpoints include overall MRD conversion rate at any time, sustained MRD negativity lasting ≥12 months, PFS, OS, response rates, duration of complete response, changes in health-related quality of life, and safety. Due to the COVID-19 pandemic, this study has been amended to improve enrollment access by allowing up to 12 months from start of induction therapy to ASCT to mitigate against ASCT delays and to allow greater flexibility for screening and laboratory assessments. Clinical trial information: NCT03901963.

Safety of subcutaneous daratumumab in the treatment of plasma-cell disorders: A single-center experience.

e20007 Background: Daratumumab (Dara) is a CD38-directed monoclonal antibody approved for the treatment of patients with multiple myeloma (MM) and light-chain amyloidosis (AL). Infusion-related reactions (IRRs) have been reported in 28-56% of individuals receiving the conventional intravenous (IV) formulation, necessitating slow infusions and frequent use of rescue medications to mitigate complications. Recently subcutaneous (SC) Dara received approval in MM, and randomized data suggests a lower rate of IRRs compared to IV Dara. Guidelines regarding post-injection monitoring with SC Dara are not well established. This retrospective study aims to evaluate the safety of SC Dara in patients with MM and AL, and to suggest guidelines for monitoring following SC Dara administration. Methods: This single-center retrospective study included patients treated with MM or AL receiving SC Dara between June 2020 and December 2020. The primary outcome of the study was incidence of IRRs. Secondary outcomes include timing and severity of IRRs based on CTCAE version 4.0. Results: A total of 82 patients received SC Dara during the study period. Of these 82, forty-nine (60%) had previously received Dara (Dara-exposed), and 33 patients (40%) were Dara-naïve. Eight of the 82 patients (9.8%) experienced an IRR. All were grade 1 (n=5, 63%) or grade 2 (n=3, 38%) in severity. Seven patients in the Dara-naïve group experienced an IRR (21%), and one patient in the Dara-exposed group (2%) experienced injection-site erythema with the second SC dose after transitioning from IV. Three patients experienced reactions immediately after SC Dara administration, and four patients experienced delayed reactions &gt;4 hours after SC Dara administration (median 11.9 hours; range 5-24). Among those with delayed reactions, three experienced reactions after being discharged from the treatment area but symptoms resolved without any intervention. Conclusions: In this single-center study of patients receiving SC Dara, IRRs occurred in about 10% of patients, and were more likely with a patient’s first dose of SC Dara. All reactions were mild to moderate in severity and could be managed in the outpatient setting. We suggest that Dara-naïve patients receiving their 1st SC Dara dose be monitored for one hour after SC Dara administration. Monitoring does not appear necessary for patients transitioning from IV to SC Dara or receiving subsequent doses of SC Dara. [Table: see text]

ASH Highlights and Commentary: Multiple Myeloma

Dr. Faiman considers the use of qualitative interviews to understand the patient perspective on the clinical benefits and tolerability of belamaf. She also highlights the safety profile and noninferiority of subcutaneous daratumumab compared with IV daratumumab, as described in the APOLLO trial. Finally, Dr. Faiman emphasizes the importance of achieving MRD negativity measured by multiparameter flow cytometry and next-generation sequencing.

Transition from Intravenous to Subcutaneous Daratumumab Formulation in Clinical Practice

IntroductionDaratumumab is an anti-CD38 monoclonal antibody widely used for treating patients with newly diagnosed or relapsed/refractory multiple myeloma. The subcutaneous formulation of daratumumab was developed with the purpose of minimizing the treatment burden (to patients and health care system) associated with intravenous daratumumab. Given its recent approval, there is a knowledge gap regarding the best practices that should be instituted for safe administration of subcutaneous daratumumab. MethodsA retrospective chart review was performed from August 2020 until November 2020 to identify patients either switched to or treated upfront (daratumumab naive) with any subcutaneous daratumumab-based treatment regimen. All patients received appropriate premedications per institutional standards of care. The study end points were to report real-world data regarding administration-related reaction rates (at or following discharge from infusion center), as well as compare their incidence rates to those noted in the COLUMBA study (historical cohort). ResultsThe study included 58 patients, of whom 38% (n = 22) were daratumumab naive. The majority (84%, n = 49) received subcutaneous daratumumab in combination with various antimyeloma regimens. There were no cases of administration-related reactions at infusion center or after discharge irrespective of previous exposure to intravenous daratumumab. None of the patients included herein required rescue home medications or visited the emergency department within 24 to 48 hours after subcutaneous daratumumab administration. These translated into a significant difference in incidence of administration-related reactions compared with historical cohort (0% vs. 13%, P = .003). ConclusionSubcutaneous daratumumab was extremely well tolerated and could be safely administered without need for monitoring or rescue home medications.

Subcutaneous daratumumab in Asian patients with heavily pretreated multiple myeloma: subgroup analyses of the noninferiority, phase 3 COLUMBA study

The phase 3 COLUMBA study demonstrated noninferiority of subcutaneous daratumumab (DARA SC) to intravenous daratumumab (DARA IV) in relapsed or refractory multiple myeloma. We present a subgroup analysis of Asian patients from COLUMBA. Eligible patients had ≥ 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or were double refractory. Co-primary endpoints were overall response rate (ORR) and maximum trough concentration (Ctrough). Secondary endpoints included rates of infusion-related reactions, progression-free survival, and patient-reported satisfaction with therapy. Sixty-seven Asian patients (DARA SC, n = 30; DARA IV, n = 37) were randomized, including 42 Japanese patients (DARA SC, n = 18; DARA IV, n = 24). Comparable ORRs for DARA SC versus DARA IV were seen in the Asian cohort (66.7% vs 43.2%) and Japanese-only cohort (61.1% vs 54.2%), including patients weighing ≤ 65 kg. Similarity of Ctrough was seen in both Asian and Japanese-only cohorts; the ratio of the geometric mean of the Ctrough concentrations for DARA SC/DARA IV was 143.96% (90% confidence interval (CI), 112.03–185.00%) and 148.02% (90% CI, 113.32–193.34%), respectively. The Asian cohort (both treatment groups) and Japanese-only cohort (DARA SC group) experienced higher rates of grade 3/4 cytopenias compared with the global COLUMBA population, occurring predominantly in patients of low bodyweight; no patients discontinued treatment due to cytopenias. The Cancer Therapy Satisfaction Questionnaire results generally favored DARA SC. In the Asian and Japanese-only cohorts, DARA SC was comparable to DARA IV. The efficacy, pharmacokinetic, safety, and satisfaction results were generally consistent with the global COLUMBA population regardless of patient bodyweight. ClinicalTrials.gov Identifier: NCT03277105

Subcutaneous daratumumab and hyaluronidase-fihj in newly diagnosed or relapsed/refractory multiple myeloma.

Daratumumab, a human immunoglobulin G1 kappa monoclonal antibody that targets CD38, is currently approved as monotherapy and in varying combinations with approved anti-myeloma regimens in both newly diagnosed multiple myeloma and relapsed refractory multiple myeloma. Originally developed for intravenous administration, the subcutaneous formulation of daratumumab (daratumumab and hyaluronidase-fihj) was recently approved by the US Federal Drug Administration and European Commission in 2020. In clinical trials, compared with the intravenous formulation, subcutaneous daratumumab (Dara-SC) has significantly shorter administration time (median first dose 7 h versus 3–5 min, respectively), lower rates of infusion-related reactions (median first dose 50% versus less than 10%, respectively), and lower volume of infusion (median 500–1000 ml versus 15 ml, respectively). Otherwise, the pharmacokinetics, safety profile, and efficacy are comparable. This review summarizes the pivotal trials that led to the approval of Dara-SC, highlights important clinical considerations for the use of Dara-SC, and provides practical guidelines for the administration of Dara-SC in the clinic.

A comprehensive overview of daratumumab and carfilzomib and the recently approved daratumumab, carfilzomib and dexamethasone regimen in relapsed/refractory multiple myeloma

ABSTRACT Introduction: Novel, effective regimens are needed in patients with relapsed and refractory myeloma (RRMM) who inevitably relapse after PI and IMID containing treatment. Areas covered: Pre-clinical data, early clinical and pivotal trials relevant to the development of the two backbone drugs of carfilzomib and daratumumab, and the two important recent trials, EQUULEUS and CANDOR leading to the FDA approval of the combination regimen of daratumumab, carfilzomib, and dexamethasone (DKd) for RRMM are detailed in this review. Expert opinion: EQUULEUS and CANDOR have established the efficacy of the DKd regimen in the landscape of bortezomib and lenalidomide refractory patients. The split dosing schedule of the first dose of daratumumab was approved by the FDA based on EQUULEUS, significantly improving patient convenience. Subcutaneous daratumumab is being evaluated in this combination to further improve tolerance and convenience. Further studies are needed to evaluate and optimally sequence the many effective and potent drugs available in RRMM.

PCN82 Budget Impact Analysis of Subcutaneous Daratumumab for the Treatment of Patients with Multiple Myeloma in Sweden

PCN82 Budget Impact Analysis of Subcutaneous Daratumumab for the Treatment of Patients with Multiple Myeloma in Sweden