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Chromosome 17p Deletion

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Daratumumab

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Angiogenesis Inhibitors

Growth Inhibitors

Therapy consists in cycles of the DPd combination as follows:

* Pomalidomide 4 mg once daily on days 1-21;
* Oral or intravenous dexamethasone 40 mg/day (≤ 75 years old) or 20 mg/ day (\>75 years old) on days 1, 8, 15 and 22;
* Daratumumab 16 mg/kg intravenously at following schedule:
* cycle 1 and 2: days 1, 8, 15, and 22
* cycle 3 through 6: days 1, and 15
* from cycle 7 until disease progression: day 1.

* Daratumumab 16 mg/kg intravenously at following schedule:
* cycle 1 and 2: days 1, 8, 15, and 22
* cycle 3 through 6: days 1, and 15
* from cycle 7 until disease progression: day 1.

Oral or intravenous dexamethasone 40 mg/day (≤ 75 years old) or 20 mg/ day (\>75 years old) on days 1, 8, 15 and 22

Vittorio Montefusco

Multiple myeloma (MM) with chromosome 17 deletion (del(17p) represents one of the most dangerous genetic variant of this disease, since it is associated with a high level of genomic instability. Del(17p) is present in approximately 10% of patients at diagnosis, and its frequency increases with disease evolution. The adverse prognosis of del(17p) has been observed in patients treated with conventional chemotherapy and new drugs. Only very few studies have suggested an advantage in treating del(17p) MM patients with specific therapies. In particular, several recent trials combining lenalidomide plus dexamethasone with a new agent, suggested that high risk cytogenetics patients may benefit from newest generation drugs. Yet, in all studies, outcome of patients with high risk genetic features have been derived from subgroup analyses, with all the limitations of this approach. To date no trial has been designed with the specific aim to test genotype-adapted therapies.

The objective of the present study is to evaluate the combination of daratumumab-pomalidomide-dexamethasone (DPd) in relapsed or relapsed/refractory MM patients harboring del(17p).

Treatment of relapsed or relapsed/refractory MM patients harbouring del(17p) is a relevant unmet medical need. A clinical trial designed to test a tailored treatment for this patient population would be a major improvement. In this perspective the combination DPd seems attractive since:

* both daratumumab and pomalidomide are therapies not interfering with DNA replication, thus not increasing the intrinsic genomic instability of del(17p) plasma cells.
* the POLLUX study has shown that daratumumab in combination with lenalidomide is highly effective in relapsed and relapsed/refractory MM patients.10
* the IFM 2010-02 trial has suggested that pomalidomide may be effective in del(17p) patients.
* the DPd combination has been successfully tested in MM patients with advanced disease.

Patients will undergo screening for protocol eligibility within 28 days (4 weeks) of enrolment.

After providing written informed consent to participate in the study, patients will be evaluated for study eligibility. It is to note that patients can be enrolled based on the presence of del(17p), as per center evaluation. However, the presence of del(17p) should be confirmed by the central laboratory (University of Torino laboratory), which will perform the test in 5 working days.

After registration, subjects who meet all the inclusion criteria will be treated according to the protocol, only after the presence of del(17p) has been confirmed by the central laboratory.

Treatment period includes administration of 28-day cycles of treatment with DPd until any sign of progression or intolerance.

The response will be assessed after each cycle. The LTFU period will start after development of confirmed progressive disease (PD) or treatment interruption due to toxicity. All patients are to be followed for survival during the LTFU period every 3 months via telephone or office visit.

A Trial for Relapsed and Relapsed/Refractory Multiple Myeloma Patients

Daratumumab, Pomalidomide and Dexamethasone for Del(17p) Positive Relapsed and Relapsed/Refractory Multiple Myeloma Patients [DEDALO]

Molecular minimal residual disease (MRD) 10-5 negativity rate assessed by means of next-generation sequencing (ClonoSEQ assay) in patients attaining a complete remission in the first year of treatment.

Number of months from the date of randomization to the date of first observation of PD, or death from any cause as an event.

Overall response rate will include complete response (CR), very good partial response (VGPR) and partial response (PR) using the International Response Criteria. Responders are defined as subjects with at least a PR.

Time from randomization to objective tumor progression on next-line treatment or death from any cause.

Time between first documentation of response and PD. Responders without disease progression will be censored either at the time of lost to FU, at the time of death due to other cause than PD, or at the end of the study.

Time between randomization and death. Subjects who die will be censored at time of death as an event, regardless cause of death.

Severity of the toxicities will be graded according to the NCI CTC v.5 whenever possible. Laboratory data will be graded according to NCI CTC v.5 severity grade.

Time to next therapy will be measured from the date of randomization to the date of next anti-myeloma therapy. Death due to any cause before starting therapy will be considered an event.

MRD negativity rate and survival might significantly change in particular subgroups of patients, that are defined on prognostic factors \[ISS stage, additional cytogenetic abnormalities, previous treatment, presence of del(17p)\]. Hence, subgroup analyses will be conducted.

Fondazione EMN Italy Onlus

Lenalidomide

Proteasome Inhibitors

Carfilzomib (K):

* 20 mg/m2 IV on day 1 of cycle 1;
* 56 mg/m2 IV on days 8 and 15 in cycle 1;
* 56 mg/m2 IV on days 1, 8 and 15 in cycles 2-12;
* 56 mg/m2 on days 1 and 15 from cycle 13 and onwards.

Lenalidomide (R):

- 25 mg orally on days 1-21 of each cycle.

Dexamethasone (d):

- 40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is a 28-day cycle.

Until PD or intolerance. Only patients that achieve at least a VGPR within the first year of treatment and in sustained MRD negativity (MRD negative at least at 10-5 after 1 and 2 years of therapy) will stop carfilzomib after 2 years of treatment, and will continue with lenalidomide and dexamethasone administration.

Lenalidomide (R):

-25 mg orally on days 1-21 of each cycle.

Dexamethasone (d):

-40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is a 28-day cycles.

Until PD or intolerance.

* 20 mg/m2 IV on day 1 of cycle 1 enhanced to 56 mg/m2 on days 8, and 15 of cycle 1;
* 56 mg/m2 IV on days 1, 8 and 15 in cycles 2-12;
* 56 mg/m2 IV on days 1 and 15 from cycle 13 and onwards.

Carfilzomib

- 25 mg orally on days 1-21 of each cycle.

- 40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is to be repeated every 28 days. Patients that achieve at least a VGPR within the first year of study treatment and in sustained MRD negativity (MRD negative at least at 10-5 after 1 and 2 years of therapy) will stop carfilzomib administration after 2 years and will continue with lenalidomide and dexamethasone treatment until disease progression or intolerance to the therapy. Other patients will continue carfilzomib administration until disease progression or intolerance.

For patients \>75 years of age, the dose of dexamethasone is 20 mg/day on Days 1, 8, 15 and 22 of each treatment cycle.

Sara Bringhen

The combination of lenalidomide plus low-dose dexamethasone (Rd) is considered the new standard for elderly newly diagnosed multiple myeloma (NDMM) patients. The combination carfilzomib plus lenalidomide-dexamethasone (KRd) in relapsed-refractory MM patients improved the progression-free survival (PFS) of approximately 1 year compared to standard Rd treatment. In a small phase 2 trial (23 pts) the KRd combination in elderly NDMM pts showed a complete response (CR) rate of 79% and a PFS at 3 years of 80%. Cardiovascular adverse events are the most limiting toxicities, especially in elderly patients.

This protocol is a randomized, multicenter study designed to determine the MRD negativity and the PFS of KRd treatment regimen.

Patients will be randomized in a 1:1 ratio to receive carfilzomib-lenalidomide-dexamethasone (KRd - Arm A) or lenalidomide-dexamethasone (Rd - Arm B).

Patients will be stratified basing on international staging system (ISS) and fitness status using a web-based procedure completely concealed to study participants.

All consecutive patients ≥ 65 years with newly diagnosed MM will be enrolled in a large randomized study during a period of 24 months.

Patients will be treated until disease progression or intolerance to the therapy. The only exception is for patients enrolled in KRd arm who achieve at least a VGPR during the first year of treatment and in sustained MRD negativity (MRD negative at least at 10-5 after one and two years of therapy): these patients will stop carfilzomib administration after 2 years, whereas treatment with lenalidomide and dexamethasone will be continued.

A Trial That Compare Two Treatments in Newly Diagnosed Myeloma Patients Not Eligible for Transplant

Carfilzomib - Lenalidmide - Dexamethasone (KRd) Versus Lenalidomi - Dexamethasone (Rd) in Newly Diagnosed Myeloma Patients Not Eligible for Autologous Stem Cell Transplantation: a Randomized Phas III Trial

1. Minimal residual disease (MRD): unit of measure is not applicable, MRD is expressed as a pure number

2. Progression-free survival (PFS): unit of measure is not applicable, PFS is expressed as a pure number

Incidence of dose reduction and drug discontinuation in both treatment arms.

Benefit of proper cardiovascular baseline assessment and monitoring during treatment in both treatment arms:to mitigate major cardiovascular adverse event incidence, to prolong duration of treatment, to improve efficacy.

Safety as rate of dose reduction, drug discontinuation and toxicities

Response rate will include complete response (CR), very good partial response (VGPR) and partial response (PR) using the International Response Criteria. Responders are defined as subjects with at least a PR.

Time to progression will be measured from the date of randomization to the date of first observation of PD, or deaths related to PD.

Correlation between MRD negativity and PFS, PFS2, TTP, TNT and OS

The following outcomes will be analysed in subgroups with different prognostic factors:

* Progression-free survival (PFS),
* Time to second disease progression (PFS2),
* Time to progression (TTP),
* Time to next therapy (TNT ),
* Overall survival (OS)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Trial for Relapsed and Relapsed/Refractory Multiple Myeloma Patients	NCT04124497	Multiple Myelom... Deletion 17P Sy...	Daratumumab Pomalidomide Dexamethasone	18 Years -	Fondazione EMN Italy Onlus
A Trial That Compare Two Treatments in Newly Diagnosed Myeloma Patients Not Eligible for Transplant	NCT04096066	Multiple Myelom... New Diagnosis T...	Carfilzomib Lenalidomide Dexamethasone	65 Years -	Fondazione EMN Italy Onlus
A Trial for Relapsed and Relapsed/Refractory Multiple Myeloma Patients	NCT04124497	Multiple Myelom... Deletion 17P Sy...	Daratumumab Pomalidomide Dexamethasone	18 Years -	Fondazione EMN Italy Onlus
A Trial That Compare Two Treatments in Newly Diagnosed Myeloma Patients Not Eligible for Transplant	NCT04096066	Multiple Myelom... New Diagnosis T...	Carfilzomib Lenalidomide Dexamethasone	65 Years -	Fondazione EMN Italy Onlus

Spots Global Cancer Trial Database for immunomodulating agents