Implications and prognostic impact of mass spectrometry in patients with newly-diagnosed multiple myeloma

Abstract

Mass spectrometry (MS) is a promising tool for monitoring monoclonal protein in plasma cell dyscrasias. We included 480 transplant-eligible newly-diagnosed multiple myeloma (MM) patients from the GMMG-MM5 trial (EudraCT No. 2010-019173-16) and performed a retrospective MS analysis at baseline (480 patients) and at the pre-defined, consecutive time points after induction (444 patients), prior to maintenance (305 patients) and after one year of maintenance (227 patients). We found that MS negativity was significantly associated with improved progression-free survival (PFS) even in patients with complete response (CR) at all investigated follow-up time points. The prognostic impact was independent of established risk factors, such as the revised International Staging System. Combining MS and baseline cytogenetics improved the prediction of outcome: MS-positive patients with high-risk cytogenetics had a dismal PFS of 1.9 years (95% confidence interval [CI]: 1.6-2.3 years) from the start of maintenance. Testing the value of sequential MS prior to and after one year of maintenance, patients converting from MS positivity to negativity had an excellent PFS (median not reached) while patients converting from MS negativity to positivity progressed early (median 0.6 years, 95% CI: 0.3-not reached). Among patients with sustained MS positivity, the baseline high-risk cytogenetic status had a significant impact and defined a group with poor PFS. Combining minimal residual disease (MRD) in the bone marrow and MS allowed the identification of double negative patients with a favorable PFS (median 3.33 years, 95% CI: 3.08-not reached) and no overall survival events. Our study provides strong evidence that MS is superior to conventional response monitoring, highlighting the potential of MS to become a new standard. Our data indicate that MS should be performed sequentially and combined with baseline disease features and MRD to improve its clinical value.Clinical Trials Register: EudraCT No. 2010-019173-16.

Fig. 1. Example on longitudinal response monitoring using QIP-MS and immunofixation.

Exemplary case showing the immunofixation (IFE) results, IMWG response and QIP-MS spectra for the monoclonal intact immunoglobulin and free light chain at selected time points. In this patient, QIP-MS also identified a monoclonal IgG kappa (m/z = 11577) + free kappa (m/z = 11582) at baseline, indicating the presence of a patient-specific clone co-expressing monoclonal intact immunoglobulin and free light chain. During maintenance/observation (after 24 months) the patient achieved a complete response (CR) while remaining QIP-MS positive. * serum IFE # according to IMWG criteria [15], IFE immunofixation, IMWG International Myeloma Working Group, PR partial response, VGPR very good partial response, CR complete response.

Fig. 2. Prognostic value of mass spectrometry at defined time points.

Progression-free (PFS) and overall survival (OS) of GMMG-MM5 patients stratified by the mass spectrometry test result (negative/positive) after induction therapy (A + B), prior to maintenance therapy/observation (C + D) and after one year of maintenance treatment/observation (E + F). PFS and OS times were measured from the respective landmarks.

Fig. 3. Independent prognostic impact of mass spectrometry and its combination with established high-risk markers.

Results of a multivariable model for PFS from the start of maintenance therapy/observation (A), and after one year (±3 months) of maintenance/observation (B). PFS from start of maintenance therapy (C) and after one year of maintenance/observation (D) stratified by the combination of mass spectrometry (MS) and baseline high-risk cytogenetics. High-risk cytogenetics were defined by the presence of t(4;14), t(14;16), del(17p) and/or gain(1q21). Study arms: A1 = PAd induction therapy and lenalidomide maintenance independent on response status; A2 = VCd induction therapy and lenalidomide maintenance independent on response status; B1 = PAd induction therapy and lenalidomide maintenance if less than complete response or observation in case of complete response; B2 = VCd induction therapy and lenalidomide maintenance if less than complete response or observation in case of complete response. FISH flourescence in situ hybridization, MS mass spectrometry, rISS revised International Staging System.

Fig. 4. Prognostic Impact of mass spectrometry in patients with complete response.

A PFS landmark analysis of patients in CR from the start of maintenance therapy/observation stratified by mass spectrometry (MS). In (B) patients in CR were stratified by the combination of MS and the GMMG-MM5 treatment arm (arm A lenalidomide maintenance for a maximum of 2 years, arm B observation only, if CR).

Fig. 5. The impact of sequential mass spectrometry on PFS and the combination with the cytogenetic risk status.

A PFS landmark analysis from 1 year (±3 months) of maintenance/observation. Patients were grouped according to the combination of the two mass spectrometry (MS) test results at the start of maintenance treatment/observation and after 1 year (±3 months) of maintenance treatment/observation. Four groups were discriminated against: sustained negativity (both MS tests negative), sustained positivity (both MS tests positive) as well as conversion from positivity to negativity (MS test positive -> negative) or vice versa (MS test negative -> positive). In (B) and (C) sustained MS negative and positive patients were further stratified by the baseline FISH risk status, respectively. High-risk cytogenetics were defined by the presence of t(4;14), t(14;16), del(17p) and/or gain(1q21).

Fig. 6. Prognostic impact of the combination of minimal residual disease and mass spectrometry.

A PFS and (B) OS landmark analysis from assessment of minimal residual disease (MRD) in the bone marrow (sensitivity 10⁻⁶). Patients were grouped according to MRD and mass spectrometry (MS) status at this time point. Four groups were defined: MRD positive/MS positive, MRD negative/MS positive, MRD positive/MS negative, MRD negative/MS negative.