Post-authorisation Study of Biological Relapse in Patients With Multiple Myeloma

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

1. 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.