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Multiple Myeloma

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Chromosome 17p Deletion

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Dexamethasone

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Daratumumab

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Dexamethasone acetate

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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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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 for Relapsed and Relapsed/Refractory Multiple Myeloma Patients	NCT04124497	Multiple Myelom... Deletion 17P Sy...	Daratumumab Pomalidomide Dexamethasone	18 Years -	Fondazione EMN Italy Onlus

Spots Global Cancer Trial Database for deletion 17p syndrome