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PEPAXTO + dexamethasone showed a clinically meaningful response in the indicated population1

The HORIZON study was a multicenter, single-arm study in 157 patients with RRMM1

  • The approval of PEPAXTO + dexamethasone was based on the 97 patients who received at least 4 prior lines and were refractory to at least one PI, IMiD, and CD38‑directed monoclonal antibody, and were therefore considered triple‑class refractory

97 patients in the indicated population had received a median of 6 prior lines of treatment1

EFFICACY RESULTS IN TRIPLE-CLASS REFRACTORY
PATIENTS WHO HAD RECEIVED AT LEAST 4 PRIOR LINES1,2

ORR was 23.7% with a 95% confidence interval ranging from 15.7 to 33.4
Median DOR was 4.2 months with a 95% confidence interval ranging from 3.2 to 7.6.
  • PR and VGPR were achieved by 14.4% and 9.3% of patients, respectively1
  • Median time to response was 2.1 months (range: 1.0 to 6.1 months)1
  • Median PFS was 3.8 months (95% CI: 3.0, 4.6)2
  • Median OS was 9.1 months (95% CI: 6.4, 11.5)2

Responses in subset patients with EMD (n=40)2

  • ORR was 15.0% (95% CI: 5.7, 29.8)
  • Median DOR was 3.9 months (95% CI: 1.8, not estimable)
  • Median PFS was 2.9 months (95% CI: 1.9, 3.7)

The statistical analysis plan of the EMD patient population was not prespecified. It does not control for Type I error.

PEPAXTO + dexamethasone was evaluated in the HORIZON study1

PEPAXTO was studied in a multicenter, single-arm study in 157 patients with RRMM, of whom 97 received at least 4 prior lines and were triple-class refractory1

Inclusion Criteria
(selected)3,4
  • Adult patients
    (≥18 years) with RRMM
  • Refractory to
    pomalidomide or
    CD38‑directed monoclonal antibody or both
  • ≥2 prior lines of therapy, including an IMiD and PI
  • ECOG PS 0-2
N=1571
28-Day Cycle1

PEPAXTO
(40 mg IV)
on Day 1
+ + dexamethasone
(40 mg POa ) on
Days 1, 8, 15, and 22

Endpoints1,4,5

Primary Endpoint

  • ORR
    (sCR, CR, VGPR, PR)

Secondary Endpoints

  • PFS
  • DOR
  • OS
  • CBR
  • TTNT
  • TTR
  • TTP
  • QoL
  • Safety

Follow-up for PFS and OS for up to 24 months.3

Patients continued PEPAXTO until disease progression or unacceptable toxicity.1

aPatients aged ≥75 years received 20 mg.1

The HORIZON study included heavily pretreated triple-class refractory patients with poor prognostic factors1,6

Demographics and disease characteristics of the HORIZON study population

Parameter
Intent to treat (N=157)1
Indicated population
(n=97)1
Median age, y (range)2,7
65
(35-86)
65
(35-86)
Male sex, n (%)2,7
89
(57%)
56
(58%)
Median time since initial diagnosis, y (range)2
6.5
(0.7-24.6)
6.4
(2.1-24.6)
Baseline ECOG PS, n (%)2,7,b,c
 
 
0
39
(25%)
22
(23%)
1
93
(59%)
63
(65%)
2
25
(16%)
12
(12%)
ISS stage, n (%)2,7
 
 
I
63
(40%)
29
(30%)
II
49
(31%)
31
(32%)
III
39
(25%)
33
(34%)
High-risk cytogenetics, n (%)2,7,d
59
(38%)
32
(33%)
Extramedullary disease, n (%)2,7
55
(35%)
40
(41%)
  • 41% of the indicated population also had extramedullary disease, an aggressive and resistant entity associated with poor prognosis1,8

bBaseline was defined as the most recent assessment prior to administration of the first dose of study drug.7

cECOG PS scores range from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability and were established at baseline (most recent assessment before administration of the first dose of study drug).7

dBased on FISH at study entry.7

Heavily pretreated patients were evaluated in the HORIZON study1
Median6prior lines of therapye

eRange: 4-12 lines.

Prior treatment1

Parameter
Indicated population
(n=97)
Documented refractory status, %
Lenalidomide
Pomalidomide
Bortezomib
Carfilzomib
Daratumumab
 
94%
92%
74%
63%
93%
Previous stem cell transplant, %
70%
Refractory to prior alkylator therapy, %
75%

CBR, clinical benefit rate; CR, complete response; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; EMD, extramedullary disease; FISH, fluorescence in situ hybridization; IMiD, immunomodulatory agent; ISS, International Staging System; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PI, proteasome inhibitor; PO, orally; PR, partial response; QoL, quality of life; RRMM, relapsed refractory multiple myeloma; sCR, stringent complete response; TTNT, time to next treatment; TTP, time to progression; TTR, time to response; VGPR, very good partial response.

IMPORTANT SAFETY INFORMATION

PEPAXTO is contraindicated in patients with a history of serious allergic reaction to melphalan flufenamide or melphalan.

PEPAXTO may cause thrombocytopenia, which may lead to hemorrhage. Monitor platelets at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first 2 months of treatment with PEPAXTO. Do not administer PEPAXTO if the platelet count is less than 50 x 109/L. Withhold PEPAXTO until platelet count is 50 x 109/L or greater and resume at same or reduced dose based on duration of interruption. Adjust dose and/or dose schedule based on signs and symptoms of bleeding.

PEPAXTO may cause neutropenia, which may lead to infection. Monitor neutrophil counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first 2 months of treatment with PEPAXTO. Do not administer PEPAXTO if absolute neutrophil count is less than 1 x 109/L. Withhold PEPAXTO until absolute neutrophil count is 1 x 109/L or greater and resume at same or reduced dose based on duration of interruption. Consider leukocyte growth factor as clinically appropriate.

PEPAXTO may cause anemia. Monitor red blood cell counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first 2 months of treatment with PEPAXTO. Treat anemia as clinically indicated. Dosage modification and dose delay of PEPAXTO may be required to allow for recovery of red blood cells.

Patients taking PEPAXTO experienced infections, including fatal infections. Consider antimicrobials as clinically appropriate.

Nonclinical safety studies with melphalan flufenamide at dosages exceeding the recommended dose for PEPAXTO were associated with mortality. The safety and efficacy of PEPAXTO has not been established for use as a conditioning regimen in patients receiving transplant.

Secondary malignancies such as myelodysplastic syndromes or acute leukemia have been reported in patients with multiple myeloma who were treated with PEPAXTO. Monitor patients long term for the development of secondary malignancies.

Based on its mechanism of action, PEPAXTO can cause fetal harm when administered to a pregnant woman because it is genotoxic and targets actively dividing cells. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with PEPAXTO and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEPAXTO and for 3 months after the last dose.

The most common adverse reactions (20%; Grades 1‑4) were fatigue (55%), nausea (32%), diarrhea (27%), pyrexia (24%), and respiratory tract infection (24%).

Special Considerations
Use in Pregnancy

Based on the mechanism of action, PEPAXTO can cause fetal harm when administered to a pregnant woman. There are no available data on PEPAXTO use in pregnant women to evaluate for a drug-associated risk. PEPAXTO is a genotoxic drug. Advise a woman of childbearing potential of the potential risks to the fetus.

Lactation

There is no information regarding the presence of melphalan flufenamide or its metabolites in human breast milk, or the effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with PEPAXTO and for 1 week after the last dose.

Females and Males of Reproductive Potential

PEPAXTO can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with PEPAXTO and for 6 months after the last dose.

PEPAXTO may damage the developing male germ cells, resulting in possible genetic fetal abnormalities. Advise males with a female partner of reproductive potential to use effective contraception during treatment with PEPAXTO and for 3 months after the last dose.

PEPAXTO can cause amenorrhea in premenopausal women and result in infertility. Based on findings of melphalan flufenamide in animals, PEPAXTO may impair male fertility. Alkylating drugs, such as PEPAXTO, can also cause irreversible testicular suppression in patients.

INDICATION

PEPAXTO is indicated in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38‑directed monoclonal antibody. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Limitation of Use

PEPAXTO is not indicated and is not recommended for use as a conditioning regimen for transplant outside of controlled clinical trials.

Please click here for full Prescribing Information.

IMPORTANT SAFETY INFORMATION

PEPAXTO is contraindicated in patients with a history of serious allergic reaction to melphalan flufenamide or melphalan.

PEPAXTO may cause thrombocytopenia, which may lead to hemorrhage. Monitor platelets at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first 2 months of treatment with PEPAXTO. Do not administer PEPAXTO if the platelet count is less than 50 x 109/L. Withhold PEPAXTO until platelet count is 50 x 109/L or greater and resume at same or reduced dose based on duration of interruption. Adjust dose and/or dose schedule based on signs and symptoms of bleeding.

PEPAXTO may cause neutropenia, which may lead to infection. Monitor neutrophil counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first 2 months of treatment with PEPAXTO. Do not administer PEPAXTO if absolute neutrophil count is less than 1 x 109/L. Withhold PEPAXTO until absolute neutrophil count is 1 x 109/L or greater and resume at same or reduced dose based on duration of interruption. Consider leukocyte growth factor as clinically appropriate.

PEPAXTO may cause anemia. Monitor red blood cell counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first 2 months of treatment with PEPAXTO. Treat anemia as clinically indicated. Dosage modification and dose delay of PEPAXTO may be required to allow for recovery of red blood cells.

Patients taking PEPAXTO experienced infections, including fatal infections. Consider antimicrobials as clinically appropriate.

Nonclinical safety studies with melphalan flufenamide at dosages exceeding the recommended dose for PEPAXTO were associated with mortality. The safety and efficacy of PEPAXTO has not been established for use as a conditioning regimen in patients receiving transplant.

Secondary malignancies such as myelodysplastic syndromes or acute leukemia have been reported in patients with multiple myeloma who were treated with PEPAXTO. Monitor patients long term for the development of secondary malignancies.

Based on its mechanism of action, PEPAXTO can cause fetal harm when administered to a pregnant woman because it is genotoxic and targets actively dividing cells. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with PEPAXTO and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEPAXTO and for 3 months after the last dose.

The most common adverse reactions (20%; Grades 1‑4) were fatigue (55%), nausea (32%), diarrhea (27%), pyrexia (24%), and respiratory tract infection (24%).

Special Considerations
Use in Pregnancy

Based on the mechanism of action, PEPAXTO can cause fetal harm when administered to a pregnant woman. There are no available data on PEPAXTO use in pregnant women to evaluate for a drug-associated risk. PEPAXTO is a genotoxic drug. Advise a woman of childbearing potential of the potential risks to the fetus.

Lactation

There is no information regarding the presence of melphalan flufenamide or its metabolites in human breast milk, or the effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with PEPAXTO and for 1 week after the last dose.

Females and Males of Reproductive Potential

PEPAXTO can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with PEPAXTO and for 6 months after the last dose.

PEPAXTO may damage the developing male germ cells, resulting in possible genetic fetal abnormalities. Advise males with a female partner of reproductive potential to use effective contraception during treatment with PEPAXTO and for 3 months after the last dose.

PEPAXTO can cause amenorrhea in premenopausal women and result in infertility. Based on findings of melphalan flufenamide in animals, PEPAXTO may impair male fertility. Alkylating drugs, such as PEPAXTO, can also cause irreversible testicular suppression in patients.

INDICATION

PEPAXTO is indicated in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38‑directed monoclonal antibody. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Limitation of Use

PEPAXTO is not indicated and is not recommended for use as a conditioning regimen for transplant outside of controlled clinical trials.

Please click here for full Prescribing Information.

  1. REFERENCES:
  2. 1. PEPAXTO. Prescribing information. Oncopeptides, Inc.; 2021.
  3. 2. Data on file, 2021. Oncopeptides, Inc. DOF-0008.
  4. 3. Mateos MV, Oriol A, Larocca A, et al. Clinical activity of melflufen in patients with triple-class refractory multiple myeloma and poor-risk features in an updated analysis of HORIZON (OP-106), a Phase 2 study in patients with relapsed/refractory multiple myeloma. Poster presented at: 61st Annual Meeting of the American Society of Hematology; December 7-10, 2019; Orlando, FL.
  5. 4. A study of melphalan flufenamide (melflufen) in combination with dexamethasone in relapsed refractory multiple myeloma patients (HORIZON). ClinicalTrials.gov identifier: NCT02963493. Updated July 7, 2020. Accessed August 2, 2020. https://clinicaltrials.gov/ct2/show/NCT02963493
  6. 5. Richardson PG, Oriol A, Larocca A, et al. HORIZON (OP-106): melflufen plus dexamethasone in relapsed/refractory multiple myeloma refractory to pomalidomide and/or an anti-CD38 monoclonal antibody — primary and subgroup analysis. Poster presented at: 25th Congress of the European Hematology Association (EHA25 Virtual); June 11-21, 2020.
  7. 6. Mikhael J. Treatment options for triple-class refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2020;20(1):1-7. doi: 10.1016/j.clml.2019.09.621
  8. 7. Richardson PG, Oriol A, Larocca A, et al. Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol. 2020;JCO2002259. doi: 10.1200/JCO.20.02259
  9. 8. Sevcikova S, Minarik J, Stork M, et al. Extramedullary disease in multiple myeloma – controversies and future directions. Blood Rev. 2019;36:32-39. doi: 10.1016/j.blre.2019.04.002