Clinical trial NCT02394210: Post-authorisation Study of Biological Relapse in Patients With Multiple Myeloma
Official title: Post-authorisation Observational Registry to Assess the Clinical Impact of Initiating Anti-tumour Rescue Therapy in Patients With Multiple Myeloma (MM) in Asymptomatic Biological Relapse Compared to Initiating Treatment at the Time of Symptomatic Relapse.
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: Multiple Myeloma
Keywords: Multiple myeloma asymptomatic relapse symptomatic relapse
IMW Consensus Panel
anti-MM therapy
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2015-03-20
Enrollment: 415
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients with a diagnosis of MM having received first or second-line treatment who have achieved ≥PR since their last anti-MM treatment, so that patients may be included in the registry before relapse/biological progression while followed every 1 to 2 months based on routine clinical practice, as well as at the time relapse/biological progression is detected, as per the criteria of the IMW Consensus Panel 11.

Brief summary: Post-authorisation prospective follow-up study to assess the clinical impact on time to progression (TTP) from the start of anti- multiple myeloma treatment at the onset of asymptomatic relapse/biological progression versus start of treatment at the time of symptomatic relapse.

Detailed description: National, observational, prospective, post-authorisation multicentre registry.

It will include patients with a diagnosis of MM who have received no more than two lines of treatment and with at least one partial relapse (≥ PR) with their latest anti-MM treatment, duly documented in accordance with the criteria of the IMW Consensus Panel 1:

1. Patients prior to relapse/biological progression, even without being in asymptomatic relapse/biological progression are followed every one or two months at most, according to the clinical judgment of the physician investigator, and provided there is an analysis (proteinogram and/or immunofixation) in the two months (+/- 15 days) prior to inclusion in which it can be documented that the patient was not in a situation of asymptomatic relapse or progression.

Patients in first or second relapse/biological progression who initiate any of the treatments currently approved and marketed in Spain for the treatment of relapsed MM, based on the criteria of the International Myeloma Workshop (IMW) Consensus Panel 11 or patients without treatment from relapse/biological progression to clinical relapse who initiate treatment after clinical relapse, according to standard criteria for clinical practice, and according to the clinical decision of each participating physician in the study, and provided there is an analysis (proteinogram and/or immunofixation) in the two months (+/- 15 days) prior to inclusion in which it can be documented that the patient was not in a situation of relapse or asymptomatic progression.

Therefore, two groups are defined for inclusion in the registry for patients in 1st or 2nd relapse/biological progression, depending on the treatment strategy adopted according to the routine clinical practice of each site participating in the study.

Group 1: Patients in relapse/biological progression not receiving treatment until clinical relapse.

Relapse/biological progression, under the criteria of the IMW (International Myeloma Workshop) Consensus Panel 11, is understood to be an asymptomatic relapse (without CRAB symptoms) defined by a ≥25% increase over the lowest value obtained during response, in any of the following:

* Serum M-protein (absolute increase must be ≥0.5 g/dL) and/or
* Urine M-component (absolute increase must be ≥200 mg/24 hrs.) and/or
* Only for patients without measurable disease in serum and urine, a 25% increase from the lowest difference in correlated and uncorrelated FLC (absolute increase \>10 mg/dL)
* In patients with unmeasurable M-protein in serum and urine, and unmeasurable FLC levels, a 25% increase in the percentage of plasma cells in bone marrow (the absolute percentage must be ≥10%)
* In patients with asymptomatic relapse/biological progression from complete response, recurrence of M protein in serum or urine by immunofixation or electrophoresis in two consecutive samples\[1\]
* Patients in this group will be studied in two phases:

  * Phase 1 (observation phase): Patients not initially receiving anti-myeloma (anti-MM) treatment, thus patients not treated for myeloma between relapse/biological progression and clinical relapse.
  * Phase 2 (anti-MM treatment after clinical relapse): Patients receive conventional anti-myeloma treatment after clinical relapse\*.

Group 2: (anti-MM treatment at the time of relapse/biological progression): Patients in this group may receive conventional anti-myeloma treatment as per routine clinical practice at the participating site:

1. Upon relapse/biological progression, defined as per the criteria of the IMW (International Myeloma Workshop) Consensus Panel Panel1, as an asymptomatic relapse (without CRAB symptoms), defined by a ≥25% increase over the lowest value obtained during remission, in any of the following:

   * Serum M-protein (absolute increase must be ≥0.5 g/dL) and/or
   * Urine M-component (absolute increase must be ≥200 mg/24 hrs.), and/or
   * Only for patients without measurable disease in serum and urine, a 25% increase over the lowest difference in correlated and uncorrelated FLC (absolute increase \>10 mg/dL)
   * In patients with unmeasurable M-protein in serum and urine, and unmeasurable FLC levels, a 25% increase in the percentage of plasma cells in bone marrow (the absolute percentage must be ≥10%)
   * In patients with asymptomatic relapse/biological progression from complete response, recurrence of M protein in serum or urine by immunofixation or electrophoresis in two consecutive samples\[1\] Or
2. Upon a significant relapse of paraprotein, defined as:

   * Duplication of M-component in two consecutive readings taken ≤2 months apart; or
   * An increase in absolute levels of serum M-protein ≥1 g/dL or M-protein in urine at ≥500 mg/24h, or
   * Increase in light chain levels ≥20 mg/dL with an abnormal ratio in two consecutive readings taken ≤2 months apart), which suggests the presence of biological progression/relapse criteria, but without including any clinical details of those involved in clinical relapse\*.

     * any change in treatment regimens, for example, discontinuation or addition of a drug (except changes in dose for any of the initial drugs) will mark the end of the anti-MM treatment phase and passing of the patient to the 36-month post-treatment follow-up phase.

In case of temporary interruptions of the study drug, under 30 days, or of any duration (except if the reason for the interruption is toxicity, the patient will continue in the anti-MM treatment phase, provided the same treatment regimen is resumed.

Patients included in the registry prior to relapse/biological progression, will be assigned to group 1 or 2 according to the strategy that the investigator decides once relapse/biological progression occurs. Furthermore, to include these patients in the phase prior to relapse/biological progression there must be an analysis (proteinogram and/or immunofixation) in the two months (+/- 15 days) prior to inclusion in which it can be documented that the patient was not in a situation of relapse or asymptomatic progression.

If patients included in the registry stage prior to relapse/biological progression relapse or progress directly with CRAB criteria they will be considered non-evaluable for the purposes of sample size, although they will be evaluated for the purposes of the secondary exploratory objective defined in section 5.2. In that case, these patients will receive anti-MM treatment/s for recurrence or progression according to clinical practice in the participating sites.

Likewise, patients who after being included in the registry receive treatment within a clinical trial will be deemed not evaluable.

From the time relapse/biological progression occurs, the investigator shall have a period of two months to decide in which observation group to include the patient.

Follow-up is established for the duration of the anti-MM treatment phase. For all patients included in the registry and whenever possible, the prospective follow-up period will be extended an additional 36 months (data collected every 6 months), starting this phase from the last dose of study medication.

Once patients have been included on the registry, they must be followed at a maximum of two month intervals, until relapse or progression of the disease, with the inclusion of data in the electronic case report form every 2 months (for patients included in the registry after relapse/biological progression), or every 4 months (for patients included in the registry prior to relapse/biological progression), in order to allow an exact calculation of TTP (primary endpoint) and the time from relapse/biological progression to clinical relapse.

To this end, the proteinogram and/or immunofixation (in case of negative protein count) must have been assessed every one or two months during or after completion of treatment prior to inclusion.

However, given the observational nature of the study, patient follow-up will take place as per routine clinical practice at each site.

Eligibility criteria: Inclusion Criteria:

1. Male or female, greater than or equal to 18 years of age patients with a diagnosis of Multiple Myeloma (MM) based on the international criteria.
2. Patients with a diagnosis of Multiple Myeloma who had not received more than two regimen therapies and who had achieved at least a Partial Response (PR) with the last anti- Multiple Myeloma treatment according the criteria of the IMW (International Myeloma Workshop) Consensus Panel 1, included before relapse/biological progression or with an asymptomatic relapse (without Calcium increase, Renal Impairment, Anemia and Bone Lesion (CRAB) symptoms) defined by a ≥25% increase on the lowest value obtained during remission, in any of the following:

   * Serum M-protein (absolute increase must be ≥05 g/dL) and/or
   * Urine M-component (absolute increase must be ≥ 200 Mg/24 hrs.), and/or
   * Only for patients without measurable components in serum and urine, a 25% increase on the lowest difference in Free light chain (FLC) ratios (absolute increase \>10 mg/dL)
   * In patients with unmeasurable M-protein in serum and urine, and unmeasurable FLC levels, a 25% increase in the percentage of plasma cells in bone marrow (the absolute percentage must be ≥10%) In any case, it is necessary to have an analysis (proteinogram and/or immunofixation) in the two months (+/- 15 days) prior to inclusion in which it can be documented that the patient was not in a situation of relapse or asymptomatic progression.

   Patients with an asymptomatic relapse/progression from a Complete Response (CR):
   * Reappearance of serum or urine M-protein by immunofixation or electrophoresis
3. Patients who consent in writing after they has clearly explained the nature and purpose of the study (consent written informed).

Exclusion Criteria:

1. Patients who are participating in an interventional clinical trial.
2. Patients that refuse to participate in the study.
3. Patients who present physical or mental incapacity to understand the information that is supplied, and/or respond to questions their doctor will perform as part of the study.
4. Clinical Relapse Criteria

Primary outcomes:
measure: Time to progression (TTP)
timeFrame: Up to 38 months
Secondary outcomes:
measure: Race of participants at Baseline
timeFrame: Baseline visit
measure: Age of participants at Baseline
timeFrame: Baseline visit
measure: Gender of participants at Baseline
timeFrame: Baseline visit
measure: Stage of Multiple Myeloma (MM) before study entry based on the international staging system (ISS)
timeFrame: Baseline visit
measure: Time from first pathologic diagnosis
timeFrame: Baseline visit
measure: The number of Comorbidities
timeFrame: Baseline visit
measure: Concomitant treatments related to MM
timeFrame: Baseline visit
measure: ECOG performance status
timeFrame: Baseline visit
measure: Define the abnormal finding in complete blood count at base line
timeFrame: Baseline visit
measure: Define the abnormal findings within the Biochemistry panel
timeFrame: Baseline visit
measure: The time from biological progression until clinical relapse
timeFrame: Up to 38 months
measure: Overall Response rate
timeFrame: Up to 38 months
measure: Event-free survival (EFS)
timeFrame: Up to 38 months
measure: Progression-free survival (PFS)
timeFrame: Up to 38 months
measure: Overall survival (OS)
timeFrame: Up to 38 months
measure: EORTC QLQ-C30 Questionnaire
timeFrame: Up to 38 months
measure: QLQ-MY24 Questionnaire
timeFrame: Up to 38 months
measure: Cost associated with participants visit to hospital/primary health care associated with anti-myeloma therapy
timeFrame: Up to 38 months
measure: Adverse Events (AEs)
timeFrame: Up to 38 months
Other outcomes:
Locations:
city: Zaragoza
country: Spain
facility: Hospital Miguel Servet
state: Aragón
city: Zaragoza
country: Spain
facility: Hospital Royo Villanova
state: Aragón
city: Gijón
country: Spain
facility: Hospital de Cabueñes
state: Asturias
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
state: Asturias
city: Palma de Mallorca
country: Spain
facility: Hospital Son Llatzer
state: Baleares
city: La Laguna. Santa Cruz De Tenerife
country: Spain
facility: Hospital Universitario de Canarias
state: Canarias
city: Las Palmas de Gran Canaria
country: Spain
facility: Hospital de Gran Canaria, Dr. Negrín
state: Canarias
city: Santa Cruz de Tenerife
country: Spain
facility: Hospital Ntra. Sra. de la Candelaria
state: Canarias
city: Santander
country: Spain
facility: Hospital Universitario de Marqués de Valdecilla
state: Cantabria
city: Avila
country: Spain
facility: Hospital Nuestra Señora de Sonsoles Avila
state: Castilla Y León
city: Burgos
country: Spain
facility: Hospital de Burgos
state: Castilla Y León
city: León
country: Spain
facility: Hospital de León
state: Castilla Y León
city: Segovia
country: Spain
facility: Hospital de Segovia
state: Castilla Y León
city: Valladolid
country: Spain
facility: Clínico Universitario de Valladolid
state: Castilla Y León
city: Barcelona
country: Spain
facility: Hospital del Mar
state: Cataluña
city: Barcelona
country: Spain
facility: Hospital Vall d´Hebron
state: Cataluña
city: Barcelona
country: Spain
facility: Hospital Clinic I Provincial de Barcelona
state: Cataluña
city: Girona
country: Spain
facility: Hospital Universitario Josep Trueta de Girona
state: Cataluña
city: Lleida
country: Spain
facility: Hospital Arnau de Vilanova de Lleida
state: Cataluña
city: Sabadell
country: Spain
facility: Hospital de Sabadell ( Parc Taulí)
state: Cataluña
city: Catellón
country: Spain
facility: Hospital General de Castellon
state: Comunidad Valenciana
city: Valencia
country: Spain
facility: Hospital Clínico Universitario Valencia
state: Comunidad Valenciana
city: Valencia
country: Spain
facility: Hospital Arnau de Vilanova (Valencia)
state: Comunidad Valenciana
city: Valencia
country: Spain
facility: Hospital de Manises
state: Comunidad Valenciana
city: Cáceres
country: Spain
facility: Complejo Hospitalario de Cáceres (S. Pedro de Alcántara)
state: Extremadura
city: Llerena, Badajoz
country: Spain
facility: Hospital de Llerena
state: Extremadura
city: A Coruña
country: Spain
facility: Complejo Hospitalario Universitario A Coruña
state: Galicia
city: Ourense
country: Spain
facility: Complexo Hospitalario de Ourense
state: Galicia
city: Pontevedra
country: Spain
facility: Hospital Montecelo
state: Galicia
city: Vigo
country: Spain
facility: Complejo Hospitalario Universitario de Vigo
state: Galicia
city: Palma de Mallorca
country: Spain
facility: Hospital Son Espases
state: Islas Baleares
city: Alcalá de Henares
country: Spain
facility: Hospital Universitario Príncipe de Asturias
state: Madrid
city: Getafe
country: Spain
facility: Hospital Universitario de Getafe
state: Madrid
city: Pozuelo de Alarcón
country: Spain
facility: Hospital Quirón
state: Madrid
city: San Sebastián de los Reyes
country: Spain
facility: Hospital Infanta Sofía
state: Madrid
city: Cartagena
country: Spain
facility: Hospital Santa Lucía
state: Murcia
city: El Palmar, Murcia
country: Spain
facility: Hospital Virgen de Arrixaca
state: Murcia
city: Pamplona
country: Spain
facility: Hospital de Navarra
state: Navarra
city: Donostia-San Sebastián
country: Spain
facility: Hospital de Donostia
state: Pais Vasco
city: Vitoria
country: Spain
facility: Hospital Txagorritxu
state: País Vasco
city: Madrid
country: Spain
facility: Hospital Universitario de La Princesa
city: Madrid
country: Spain
facility: Hospital Infanta Leonor
city: Madrid
country: Spain
facility: Complejo Universitario de San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
Study officials:
affiliation: Celgene
name: Mireya Navarro, MD
role: STUDY_DIRECTOR
References: