Pepaxto: A New Peptide-Drug Conjugate for Heavily Pretreated Relapsed and Refractory Multiple Myeloma

Additional Treatment ◽

Cell Transplant ◽

Clinical Trial Registry ◽

Federal Drug Administration ◽

Heavily Pretreated

Objective: The objective of this article was to review existing data of melflufen (Pepaxto) as an additional treatment option for heavily pretreated relapsed and refractory multiple myeloma. Data sources: A PubMed search was completed using the search terms melphalan flufenamide; melflufen; melflufen AND relapsed refractory multiple myeloma; melphalan flufenamide and relapsed refractory multiple myeloma between January 1, 2013, and October 18, 2021. Additional information was obtained from the National Institutes of Health Clinical Trial Registry, Federal Drug Administration (FDA) web updates, and Pepaxto prescribing information. Study selection/data extraction: Clinical trials including melflufen in relapsed refractory multiple myeloma and trials related to safety and clinical pharmacology were included. Data synthesis: The findings of this review show melflufen in combination with dexamethasone can be used as a treatment option for patients with relapsed and refractory multiple myeloma who have previously received greater than 4 previous lines of therapy, and documented resistance to a proteosome inhibitor, an anti-CD38 monoclonal antibody, and an immunomodulator. Relevance to patient care and clinical practice: Melflufen in combination with dexamethasone is a reasonable option for patients with relapsed and refractory multiple myeloma who have received at least 4 previous lines of therapy and considered ineligible for autologous stem cell transplant. Further clinical utilization in earlier lines of therapy is under review, pending the in-depth safety analysis by the FDA. Conclusions: The FDA approval of melflufen in combination with dexamethasone provides an additional therapy option for patients with heavily pretreated relapsed and refractory multiple myeloma.

Daratumumab, Pomalidomide, and Dexamethasone (DPd) for the Treatment of Relapsed/Refractory Multiple Myeloma: A Single Institution Experience

Blood ◽

10.1182/blood-2018-99-117497 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5642-5642 ◽

Cited By ~ 1

Author(s):

Al-Ola Abdallah ◽

Neil Dunavin ◽

Brian McClune ◽

Leyla Shune ◽

Ajoy L. Dias ◽

...

Keyword(s):

Multiple Myeloma ◽

Proteasome Inhibitor ◽

Research Funding ◽

Median Number ◽

Cell Transplant ◽

Duration Of Treatment ◽

Effective Treatment Option ◽

Overall Response

Abstract Background: Daratumumab triplet regimens containing dexamethasone and lenalidomide or bortezomib are an effective treatment option for patients with relapsed/refractory multiple myeloma (RRMM). Daratumumab was recently FDA-approved in combination with the second-generation immunomodulatory drug, pomalidomide, and dexamethasone based (DPd) on results of the EQUULEUS study where overall response rates (ORR) of 60% were seen. The goal of this retrospective study was to analyze clinical outcomes of the DPd triplet regimen in either a daratumumab and pomalidomide naïve or refractory population of heavily pretreated RRMM patients at our institution. Methods: Thirty-two patients with RRMM treated with DPd at the University of Kansas Health System between November 2015 and July 2018 were included in our analysis. DPd consisted of 28-day cycles of daratumumab 16 mg/kg intravenously (weekly for cycles 1 and 2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter until disease progression); pomalidomide 4 mg orally (PO)on Days 1-21 and adjusted for cytopenia or toxicities; and dexamethasone 40 mg PO weekly adjusted based on tolerance. based on age. Responses were evaluated using IMWG criteria. Patient characteristics, disease course, and outcomes were summarized with descriptive statistics. Kaplan-Meier analyses were used to estimate progression-free (PFS) and overall survival (OS). Results:The median age was 64 years (range 44-83). Twenty-three patients (72%) had IgG isotype, 11 patients (34 %) had ISS stage III disease at diagnosis, 13 patients (41%) had high risk cytogenetics, and 13 patients (41%) had extramedullary disease. Median number of previous lines of therapy was 4 (1-9). Twenty-two patients (69%) received ≥3 prior therapies. Twenty-three patients (72%) were proteasome inhibitor refractory, 28 patients (88%) were immunomodulator refractory, 9 patients (28%) were daratumumab refractory, and 3 patients (15%) were double refractory to daratumumab and pomalidomide. Twenty-eight patients (88%) had received autologous stem cell transplant (ASCT) prior to DPd; 12 patients (38%) had ≥2 prior transplants. Median number of DPd cycles received was 6 (2-30) and the median duration of treatment was 5 months (2-30). At a median follow-up of 8.4 months (range: 2-29), the overall response rate (ORR) for all patients was 72% which compares favorably to the ORR of 60% in the EQUULEUS study. However, about half of the responses were partial responses (PR) (47%). The ORR rate for those who were refractory to either pomalidomide or daratumumab was 65%. The PFS was 8.3 months, while the median OS was not reached. Conclusion: DPd was recently approved for the treatment of RRMM. Our ORR compares favorably to the EQUULEUS study, however about half of responses were partial responses or better. Surprisingly, our analysis shows an impressive ORR in patients with previous exposure to proteasome inhibitor and immunomodulatory therapies in RRMM population, suggesting a benefit of DPd even in patients who received prior pomalidomide or daratumumab. Disclosures McGuirk: Astellas Pharma: Research Funding; Gamida Cell: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding; Pluristem Ltd: Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Fresenius Biotech: Research Funding; Bellicum Pharmaceuticals: Research Funding. Ganguly:Daiichi Sankyo: Research Funding; Janssen: Consultancy; Amgen: Consultancy; Seattle Genetics: Speakers Bureau.

A phase I study of the addition of high-dose lenalidomide to melphalan conditioning for autologous stem-cell transplant in relapsed or refractory multiple myeloma

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2015.07.596 ◽

2015 ◽

Vol 15 ◽

pp. e291-e292 ◽

Cited By ~ 1

Author(s):

P. Forsberg ◽

D. Guarneri ◽

A. Rossi ◽

R. Pearse ◽

A. Perry ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Phase I ◽

Phase I Study ◽

Stem Cell Transplant ◽

High Dose ◽

Cell Transplant ◽

Refractory Multiple Myeloma

Survival and treatment patterns of patients with relapsed or refractory multiple myeloma in France — a cohort study using the French National Healthcare database (SNDS)

Annals of Hematology ◽

10.1007/s00277-021-04522-y ◽

2021 ◽

Author(s):

Cyrille Touzeau ◽

Nadia Quignot ◽

Jie Meng ◽

Heng Jiang ◽

Artak Khachatryan ◽

...

Keyword(s):

Multiple Myeloma ◽

Real World ◽

Unmet Need ◽

Treatment Patterns ◽

Cell Transplant ◽

Healthcare Database ◽

National Healthcare ◽

Patient Groups

AbstractOver the past decade, several drugs have been approved for the treatment of relapsed or refractory multiple myeloma (RRMM). This retrospective study, using the French National Healthcare database (SNDS), describes the treatment patterns and outcomes of patients with RRMM treated in real-world clinical practice in France. Patients were adults, with a diagnosis of multiple myeloma, who initiated second-line (2L) treatment approved for use in France between 2014 and 2018; this included bortezomib, carfilzomib, daratumumab, ixazomib, lenalidomide, or pomalidomide. Data were analyzed overall, by first-line (1L) autologous stem cell transplant (ASCT) status and by lenalidomide treatment status at 2L. In total, 12987 patients with RRMM were included in the study (mean age 69.5 years); 27% received an ASCT at 1L, and 30% received a lenalidomide-sparing regimen at 2L. Overall, and among the ASCT and non-ASCT subgroups, most patients received a bortezomib-based regimen at 1L, whereas lenalidomide-based regimens were most common at 2L. Among patients who received a lenalidomide-sparing regimen at 2L, this was most often a proteasome inhibitor-based regimen. Mortality rate was 26.1/100 person-years, and median (95% confidence interval) survival from 2L initiation was 32.4 (31.2–33.6) months. Survival differed by various factors, shorter survival was reported in the non-ASCT group, those receiving a lenalidomide-sparing regimen at 2L, older patients (≥ 70 years), and those with multiple comorbidities. This analysis provides insight into the real-world use of approved novel MM treatments and highlights an ongoing unmet need to improve outcomes, particularly for selected patient groups.

Sequential CD38 monoclonal antibody retreatment leads to deep remission in a patient with relapsed/refractory multiple myeloma

International Journal of Immunopathology and Pharmacology ◽

10.1177/2058738420980258 ◽

2020 ◽

Vol 34 ◽

pp. 205873842098025

Author(s):

Maximilian Johannes Steinhardt ◽

Xiang Zhou ◽

Franziska Krummenast ◽

Katharina Meckel ◽

Katharina Nickel ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell Transplant ◽

Residual Disease ◽

Progression Free Survival ◽

Cell Transplant ◽

Free Survival ◽

Heavily Pretreated ◽

Multi Agent ◽

Minimal Residual

We report on a currently 76-year-old female patient with relapsed/refractory (RR) multiple myeloma (MM) treated at our institution. This patient had received six lines of therapy including tandem autologous stem cell transplant, proteasome inhibitor, immunomodulatory drugs and CD38 antibody MOR202. At the last relapse, she progressed during treatment with pomalidomide and MOR202. In an individualized therapy concept, we started a multi-agent salvage therapy with pomalidomide, bortezomib, doxorubicin, dexamethasone, and CD38 antibody daratumumab (“Pom-PAD-Dara”), which resulted in a stringent complete remission with minimal residual disease (MRD) negativity after nine cycles. So far, our patient shows a progression free survival of more than 12 months. Our case demonstrates the feasibility of successful CD38 antibody retreatment in a patient with heavily pretreated CD38 antibody resistant MM.

Pomalidomide (CC4047) Plus Low-Dose Dexamethasone (Pom/dex) Is Highly Effective Therapy in Relapsed Multiple Myeloma

Blood ◽

10.1182/blood.v112.11.866.866 ◽

2008 ◽

Vol 112 (11) ◽

pp. 866-866 ◽

Cited By ~ 4

Author(s):

Martha Q. Lacy ◽

Suzanne R. Hayman ◽

Morie A. Gertz ◽

Jacob B. Allred ◽

Sumithra J. Mandrekar ◽

...

Keyword(s):

Multiple Myeloma ◽

Low Dose ◽

Single Agent ◽

Objective Response ◽

Response To Therapy ◽

Cell Transplant ◽

Prior Therapy ◽

Grade 3

Abstract Background: Thalidomide and its analogue lenalidomide have high response rates among patients with newly diagnosed as well as previously treated myeloma. Pomalidomide (CC4047) is the newest immunomodulatory (IMiD) agent that has shown single-agent activity in phase I studies. We report on the first Phase 2 trial of pomalidomide combined with low dose dexamethasone (Pom/dex) in patients with relapsed or refractory multiple myeloma. Methods: 37 patients (21 male and 16 female) were enrolled. Pomalidomide was given orally 2 mg daily on days 1–28 of a 28-day cycle. Dexamethasone was given orally at a dose of 40 mg daily on days 1, 8, 15 and 22 of each cycle. Response was assessed by the International Myeloma Working Group Uniform Response criteria. All patients received aspirin 325 mg daily as prophylaxis against DVT. Results: The median age was 66 years (range, 40 – 88). All patients were evaluable for response and toxicity, and all analysis were done on intent to treat basis. All patients had received prior therapy; 38% had 3 prior regimens; 35% had 2 prior regimens and 27% had one prior regimen. 76% had previous autologous stem cell transplant (ASCT) and 24% had 2 prior ASCT. 62% had previous IMiD therapy. Toxicity was mild and consisted primarily of myelosuppression. Grade 3 neutropenia occurred in 31%; grade 3 thrombocytopenia 3%; grade 3 anemia 3 %. Other grade 3/4 toxicities seen in less than 5% pts included: diarrhea, atrial fibrillation, pneumonia, dehydration and renal insufficiency. 16 % had grade 1/2 neuropathy. No grade 3 neuropathy was seen and there have been no thromboembolic events. Thirty (81%) patients are continuing study treatment. Seven patients have discontinued treatment due to: disease progression (5), died on study (1) and the medical doctor’s discretion (1). Twenty three of 37 patients (62%) achieved an objective response to therapy; including 9 (24%) with VGPR; 14 patients (38%) with PR; 6 (16%) with stable disease. Objective responses were seen in 4 of 13 patients (29%) who were refractory to lenalidomide. Conclusions: Pomalidomide plus dexamethasone (Pom/dex) is highly active and well tolerated for treatment of relapsed/refractory multiple myeloma with an objective responserate of 62%, including a 29% response rate among patients who are lenalidomiderefractory.

Phase I/II, open-label, 2-arm study to evaluate safety, tolerability, and clinical activity of GSK2857916 in combination with 2 standard-of-care (SoC) regimens in relapsed/refractory multiple myeloma: (DREAMM 6).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.tps8053 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. TPS8053-TPS8053 ◽

Cited By ~ 3

Author(s):

Luciano J. Costa ◽

Hang Quach ◽

Keith Stockerl-Goldstein ◽

Bradley Augustson ◽

Geraldine Ferron-Brady ◽

...

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibody ◽

Dose Escalation ◽

Standard Of Care ◽

Clinical Activity ◽

Cell Transplant ◽

Open Label ◽

Heavily Pretreated ◽

Line Of Therapy

TPS8053 Background: B-cell maturation antigen (BCMA) is a validated therapeutic target in Multiple Myeloma (MM). GSK2857916 is a humanized (IgG1) anti-BCMA monoclonal antibody conjugated to monomethyl auristatin-F via protease resistant maleimidocaproyl linker and produced in afucosylated form to enhance antibody-dependent cellular cytotoxicity. In FTIH study BMA117159, GSK2857916 was well tolerated and showed unprecedented clinical activity [ORR=60%; mPFS 7.9 months (95% CI, 3.1–not estimable)] as monotherapy in heavily pretreated MM patients. GSK2857916 in combination with SoC regimens, could potentially further improve outcomes for patients with relapsed/refractory (RR) MM. Methods: DREAMM 6 is a 2-part study: Part 1 (dose escalation) is evaluating safety and tolerability of 2 doses (2.5 mg/kg and 3.4 mg/kg) of GSK2857916, in combination with SoC regimens in two independent arms: Arm A with Lenalidomide/Dexamethasone, and Arm B with Bortezomib/Dexamethasone. Modified Toxicity Probability Interval design will guide dose escalation and RP2D of GSK2857916 in each arm for Part 2 (cohort expansion). Part 2 will confirm safety, evaluate clinical activity of GSK2857916 RP2D with either combination and collect pharmacokinetic information on GSK2857916, Lenalidomide and bortezomib. Up to 90 subjects previously treated with at least 1 prior line of therapy who have undergone autologous stem cell transplant or are transplant-ineligible will be enrolled; up to 24 in Part 1 and up to 66 in Part 2. Subjects in Arm A will continue combination treatment until progression, intolerance, consent withdrawal or death. Subjects in Arm B will receive up to 8 cycles of GSK2857916 in combination with Bor/Dex and then continue GSK2857916 monotherapy until progression, intolerance, consent withdrawal, or death. Enrolment on study started in October 2018 and is ongoing. Study funded by GlaxoSmithKline; drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. ClinicalTrials.gov Identifier: NCT03544281.