TARGETED THERAPIES
PROTEASOME INHIBITORS
WHAT IS THE FUNCTION OF PROTEASOME ?
The proteasome is responsible for the breakdown of cell proteins. By breaking down these proteins and cell growth factors, it regulates cell growth and apoptosis or programmed cell death. More specifically, the proteasome breaks down denatured or abnormal proteins, such as those in tumours.
WHAT WE KNOW...
A functional proteasome is necessary for the survival of any cell.
Malignant cells are much more sensitive to the proapoptotic effects of proteasome inhibition than normal cells. Due to this property, proteasome inhibition reduces the proliferation as well as the survival of myeloma cells by blocking their progression in the cell cycle and by negatively regulating the expression of inhibitors of apoptosis.
CURRENTLY...
Proteasome inhibitors are indicated in multiple myeloma, their effects are dose-dependent.
Bortezomib was the first proteasome inhibitor developed (reversible inhibitor). Then a second generation proteasome inhibitor was developed, carfilzomib, which differs from bortezomib by its irreversible inhibition of the proteasome.
Although their benefit/risk profile is favorable, these drugs are associated with adverse effects such as neuropathies, and cardiovascular and hematological toxicities which require monitoring.
PROTEASOME INHIBITORS AVAILABLE
BORTEZOMIB (VELCADE™)
In short...
It is the first molecule developed and marketed to inhibit the proteasome. It reduces the proliferation as well as the survival of malignant cells by blocking their progression in the cycle and by negatively regulating the expression of inhibitors of apoptosis.
Experimental studies have confirmed that Velcade™, by altering the stability or activity of these proteins involved in the cell cycle, induces apoptosis of malignant myeloma cells, and seems to spare normal cells.
Inhibition of the proteasome also results in a decrease in the adhesion capacities of myeloma cells, a decrease in DNA repair capacities, accompanied by a potential restoration of sensitivity to DNA degrading agents as well as an anti -angiogenic.
Its approved indications
It is indicated in:
- Monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone, for treatment of adult patients suffering from progressive multiple myeloma, having received at least 1 previous treatment and having already benefited from or being ineligible for a haematopoietic stem cell transplant,
- In combination with melphalan and prednisone, for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for intensive chemotherapy accompanied by haematopoietic stem cell transplantation,
- In combination with dexamethasone (VD), or dexamethasone and thalidomide (VTD), for the induction treatment of adult patients with previously untreated multiple myeloma eligible for intensive chemotherapy plus cell transplantation hematopoietic strains
In practice...
Velcade™ is administered intravenously. The starting dose is 1.3 mg/m². The chemotherapy cycle includes administration on D1, D4, D8 and D11 followed by 10 days without treatment, i.e. a 21-day chemotherapy cycle.
In monotherapy, 4 + 2 cycles are sufficient in the event of a confirmed complete response. Otherwise a total of 8 cycles will be prescribed.
In combination with melphalan and prednisone (VMD), 4 cycles of bortezomib on D1, D4, D8 and D11 followed by 5 cycles on D1 and D8, i.e. 9 cycles in all.
Other protocols that can be used are: Velcade™, Lenalidomide, Dexamethasone (VRD), Velcade™, Endoxan, Dexamethasone (VCD) or Velcade™, Dexamethasone (VD)
His tolerance
The most common side effects, in monotherapy, are digestive disorders, fatigue and most often moderate anorexia.
A decrease in platelets, or thrombocytopenia, is observed in a third of cases with recovery for the next cycle of chemotherapy, it is only rarely accompanied by neutropenia or anemia (< 10%).
The most troublesome toxicity is the usually sensory and painful peripheral neuropathy.
Its use is associated with a risk of shingles.
CARFILZOMIB (KYPROLIS™)
It is also an irreversible proteasome inhibitor active by injection.
It is used in combination, either with lenalidomide and dexamethasone (RevDex), or with dexamethasone alone. It is indicated for the treatment of multiple myeloma in adult patients who have received at least one prior therapy.
IXAZOMIB (NINLARO™)
It is the first an orally active proteasome inhibitor allowing "all-oral" treatments: ixazomib, 4 mg once a week, in combination with RevDex (lenalidomide + dexamethasone) 3 weeks in a row followed by a therapeutic break of a week.
It is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. This medicine is to be taken once a week.
THALIDOMIDE
AT THE BEGINNING IT IS A HEALTH CATASTROPHE…
Thalidomide was synthesized in 1954 by the German laboratory Grünenthal in Stolberg near Aix-la-Chapelle (Aachen in German).
Thalidomide under the name Contergan™ was introduced in Germany in 1956 as a sleeping pill and then used, at the end of the 1950s, for its antiemetic properties (against vomiting). This drug was then considered to be of low toxicity and one of its main indications was nausea and vomiting in early pregnancy.
From the end of the 1950s to the beginning of the 1960s, 12,000 children were born in Europe with serious malformations of the legs, arms, hands, ears and internal organs which led to its withdrawal from the market in 1961 .
Thalidomide under the name Contergan™ was introduced in Germany in 1956 as a sleeping pill and then used, at the end of the 1950s, for its antiemetic properties (against vomiting). This drug was then considered to be of low toxicity and one of its main indications was nausea and vomiting in early pregnancy.
From the end of the 1950s to the beginning of the 1960s, 12,000 children were born in Europe with serious malformations of the legs, arms, hands, ears and internal organs which led to its withdrawal from the market in 1961 .
IT IS AN ANGIOGENESIS INHIBITOR
As early as 1965 this molecule had been tested in oncology but, at the time, the results of the studies had been disappointing.
In 1964, Prof. J. Sheskin of the Hebrew University of Jerusalem showed that the administration of thalidomide improved patients with erythema nodosum leprosum, a painful complication of leprosy. The discovery of its effectiveness in the treatment of leprosy led to its continued use under the aegis of the WHO.
Hypothesizing that thalidomide-induced absence of fetal limb development (agenesis) may result from inhibition of vascular development, RJ D'Amato, MS Loughnan, E. Flynn and J. Folkman ( Proc. Natl. Acad. Sci. USA 91 (1994), pp. 4082–5 ) laid the groundwork for the hypothesis that led to the use of thalidomide in the treatment of multiple myeloma.
In 1964, Prof. J. Sheskin of the Hebrew University of Jerusalem showed that the administration of thalidomide improved patients with erythema nodosum leprosum, a painful complication of leprosy. The discovery of its effectiveness in the treatment of leprosy led to its continued use under the aegis of the WHO.
Hypothesizing that thalidomide-induced absence of fetal limb development (agenesis) may result from inhibition of vascular development, RJ D'Amato, MS Loughnan, E. Flynn and J. Folkman ( Proc. Natl. Acad. Sci. USA 91 (1994), pp. 4082–5 ) laid the groundwork for the hypothesis that led to the use of thalidomide in the treatment of multiple myeloma.
THE EFFECTIVENESS OF THALIDOMIDE
For the treatment of relapses
The response time is quite fast, between 4 and 12 weeks, with a maximum response observed in the fourth month. The median duration of response is around one year, and about a quarter of patients remain non-progressive under this monotherapy for two years.
The quality of the response, like the intensity of the toxicity, seems to be dose-dependent.
Combination with sequential high-dose dexamethasone increases partial response rates by more than 50%.
The quality of the response, like the intensity of the toxicity, seems to be dose-dependent.
Combination with sequential high-dose dexamethasone increases partial response rates by more than 50%.
In the first line
Since the efficacy of thalidomide in relapsed myeloma has been established, two studies have assessed its first-line use associated with dexamethasone.
The response rates are then around 60 to 70%, including 10 to 15% complete responses.
Other studies have shown the benefit of an association with chemotherapy. The following protocols have thus been developed:
The response rates are then around 60 to 70%, including 10 to 15% complete responses.
Other studies have shown the benefit of an association with chemotherapy. The following protocols have thus been developed:
The MPT protocol (Melphalan + Predinsone + Thalidomide)
It has become a standard protocol and includes the administration of 3 drugs:
- Melphalan (M - Alkéran™) is given four days in a row (D1 to D4), at a daily dose of 0.25 mg/kg, for patients aged 65 to 75, and 0.20 mg/kg, in over the age of 75, and this every six weeks
- Prednisone (P) is administered at a dose of 2 mg/kg/day on the same dates as melphalan (D1 to D4)
- Thalidomide (T) is prescribed at a daily dose of 200 mg continuously, between 65 and 75 years old, and at 100 mg, beyond 75 years old
This is chemotherapy administered orally at home. The duration and rhythm of the cycles is variable depending on the case.
Prednisone and melphalan are given the first 4 days of the cycle in the morning. Thalidomide is to be taken continuously, once every day in the evening. Thalidomide is only available from hospital pharmacies.
Antithrombotic prophylaxis to prevent the occurrence of possible phlebitis and/or pulmonary embolism is systematically associated in the form of subcutaneous injection of low molecular weight heparin or oral intake of vitamin K antagonist, or, in patients without a history of thrombosis, aspirin.
Other protocols are being evaluated, for example:
- CDT: Cyclophosphamide + Dexamethasone + Thalidomide
- DT-PACE: Dexamethasone + Thalidomide + cisPlatine + Adriamycin™ + Cyclophosphamide + Etoposide
- DVD-T: Doxorubicin + Vincristine + Dexamethasone + Thalidomide
Possible side effects….
As thalidomide is a potent teratogen, it should under no circumstances be used in women who are or may be pregnant unless all conditions of the Pregnancy Prevention Program are met. Pregnancy Prevention Program requirements must be met by all patients, and apply to both men and women.
One of the most troublesome effects is the risk of neuropathies with sensory disturbances. Precise monitoring will be organized by the healthcare team.
An increased risk of venous thrombosis (phlebitis) when used in combination with chemotherapy, in particular anthracyclines, may lead to the use of anticoagulant drugs being discussed.
The other toxicities observed are mainly related to fatigue, drowsiness, depression or behavioral changes, fluid retention, constipation. These risks increase with age and are not significantly influenced by the dose.
One of the most troublesome effects is the risk of neuropathies with sensory disturbances. Precise monitoring will be organized by the healthcare team.
An increased risk of venous thrombosis (phlebitis) when used in combination with chemotherapy, in particular anthracyclines, may lead to the use of anticoagulant drugs being discussed.
The other toxicities observed are mainly related to fatigue, drowsiness, depression or behavioral changes, fluid retention, constipation. These risks increase with age and are not significantly influenced by the dose.
INDICATIONS
For thalidomide (50 and 100 mg tablets)
It is indicated, in combination with melphalan and prednisone (MPT protocol), for the first-line treatment of patients over 65 years of age with untreated multiple myeloma or with a contraindication to high-dose chemotherapy.
The initial dose is 200 mg/day for 2 to 3 weeks. If the peak of the monoclonal component begins to decrease, it is possible to continue the treatment at this dosage, guided by the evolution of the peak. Depending on tolerance, if the monoclonal peak remains stable or drops only very slightly, it is possible to increase the dosage up to 400 mg/day. It is a continuous treatment.
The initial dose is 200 mg/day for 2 to 3 weeks. If the peak of the monoclonal component begins to decrease, it is possible to continue the treatment at this dosage, guided by the evolution of the peak. Depending on tolerance, if the monoclonal peak remains stable or drops only very slightly, it is possible to increase the dosage up to 400 mg/day. It is a continuous treatment.
For thalidomide 100 mg
This dosage has been the subject of a temporary authorization for use (ATU) since 2002 for the 100 mg dosage form and can, under certain conditions, be prescribed. Thalidomide is indicated for:
- Untreated myeloma, in combination with melphalan and prednisone, in patients over 65 or with a contraindication to high-dose chemotherapy.
- When there is no therapeutic alternative: refractory and/or relapsing myeloma after at least one line of therapy that included alkylating agents.
LENALIDOMIDE (REVLIMID™), THE NEW REFERENCE
A NEW GENERATION IMID
Lenalidomide is an immuno-modulating drug, similar to thalidomide . It is active orally, in combination with dexamethasone, for the treatment of multiple myeloma.
Its efficacy
In relapsed patients, the time without progression of the disease was 11.3 months in the therapeutic trials compared with 4.7 months in the control group. Overall survival was increased by 34%.
Its tolerance is acceptable with, however, a marked neutropenia rate of 29.5% versus 2.3% and thrombocytopenia of 11.5% versus 5.7%.
LENALIDOMIDE (REVLIMID™), THE NEW REFERENCE
A NEW GENERATION IMID
Lenalidomide is an immuno-modulating drug, similar to thalidomide . It is active orally, in combination with dexamethasone, for the treatment of multiple myeloma.
Its efficacy
In relapsed patients, the time without progression of the disease was 11.3 months in the therapeutic trials compared with 4.7 months in the control group. Overall survival was increased by 34%.
Its tolerance is acceptable with, however, a marked neutropenia rate of 29.5% versus 2.3% and thrombocytopenia of 11.5% versus 5.7%.
THE RevDEX IN PRACTICE…
Its current indications in France
In first line, it is indicated for the treatment of previously untreated multiple myeloma in adult patients not eligible for a transplant
In second line, it is indicated, in combination with dexamethasone, for the treatment of multiple myeloma in adult patients who have received at least one prior treatment. Its dosage The recommended initial dose of lenalidomide is 25 mg orally every day for 21 consecutive days followed by a week off. Dexamethasone at a dose of 40 mg once a day is administered orally, in sequence over a few days or as a single weekly dose.
Possible side effects...
Treated patients often complain of fatigue, skin rashes, muscle cramps and musculoskeletal pain, fluid retention, diarrhea and erectile dysfunction Precautions to be taken take Treatment should not be initiated if the neutrophil count is < 1,000 and/or if the platelet count is < 75,000. Prevention of venous thrombosis is generally initiated by anticoagulant drugs. For women likely to procreate, the prescription is limited to 1 month of treatment, a pregnancy test must be carried out every month, within 3 days preceding the prescription.
POMALIDOMIDE (IMMOVID/POMALYST™)
MEDICATION
His characteristics
Pomalidomide is a second- generation immunomodulator (IMiD) belonging to the thalidomide and lenalidomide family.
Pomalidomide has, with the other IMiDs, a direct antitumor effect, interaction with the medullary microenvironment and an immunomodulatory action. The action of pomalidomide is strongly synergistic with dexamethasone.
Its efficiency
Experimental data suggests that this molecule may be more potent than other marketed "IMiDs".
The response rate obtained in patients refractory to thalidomide, lenalidomide or bortezomib, in combination with dexamethasone is significantly higher in Phase 3 trials.
His tolerance
Pomalidomide has a better tolerance profile than other products in this class.
Nevertheless, there is hematological toxicity and a thromboembolic risk requiring prophylaxis.
It is teratogenic like all drugs of this class.
IN PRACTICE
"PomDex" indications...
Pomalidomide is approved in combination with dexamethasone, in the treatment of relapsed and refractory multiple myeloma in patients who have already received at least two previous treatments including lenalidomide (Revlimide™) and bortezomib (Velcade™) and whose disease progressed during the last treatment. Its oral dosage
The recommended dose is 4 mg 21 days per month. Dexamethasone is given at a dose of 40 mg/d on D1, D8, D15, D22.
Its tolerance
Haematological side effects
They essentially consist of myelosuppression which may be associated with an increased risk of infections. That is why doctors recommend flu and pneumococcal vaccinations for all patients and their relatives. In addition, antibiotic prophylaxis during the first cycles of treatment with pomalidomide or for the entire duration of treatment is recommended for patients at risk of infection.
Other possible problems
They are common with drugs of this class are, an increased risk of thrombosis, neuropathies.
PCD
It is also a validated combination which corresponds to Pomalidomide 4 mg/day 21 days per month + Cyclophosphamide 50 mg 21 days per month + Dexamethasone 40 mg/day D1, D8, D15, D22.
NEW TREATMENT PROTOCOLS
TPM
This is now the treatment protocol, entirely orally, for patients over the age of 65. The treatment consists of 6 cures of 4 weeks and includes:
- Melphalan [ M (4 mg/m²)] from D1 to D4
- P rednisolone [ 40 mg/m² (P)] D1 to D4
- T halidomide [200 or 100 mg/d (T)] at a dose of 100 mg
VMP
The bortezomib ( Velcade ™) -Melphalan -Prednisone combination is also approved for first-line treatment for patients of any age who cannot benefit from intensive treatment. In subjects under 65 years of age, treatment is continued until a maximum response is obtained, generally for 2 to 4 months. Then a sample of autologous hematopoietic stem cells in the blood for an autograft. Finally, chemotherapy intensification followed by reinjection of autologous hematopoietic stem cells (autograft) is carried out.
In subjects over 65, the treatment protocol is continued until a maximum response is achieved (usually after several cycles) and may be continued for 12 to 18 months.
The response to treatment is assessed on the decrease in the monoclonal immunoglobulin peak from the first cycles and at the end of treatment.
In the absence of a response, a second line protocol will be offered.
THE CURRENT THERAPEUTIC PANOPLY
| Proteasome inhibitors | imids | Monoclonal antibodies | Alkylants |
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