Long Term Survivors (>15 years) of Multiple Myeloma: Patient Characteristics and Morbidity Burden

Background: Recent advances in Multiple Myeloma (MM) have led to improved outcomes and increased longevity for many patients, raising new questions about the consequences of multiple years of therapy on quality of life and co morbidities. The literature is sparse on this topic. Our primary objective was to define retrospectively the baseline patient and disease-related characteristics of long term (>15 year) survivors, the duration of their first progression free survival (PFS) and to describe the burden of long-term treatment or disease related morbidities.

Methods: Using an REB-approved institutional myeloma-specific database, we retrospectively identified 148 MM patients diagnosed between 1988-2008 who survived between 15-29 years after diagnosis. Baseline Charleson Comorbidity Index (CCI) was calculated retrospectively from the charts and myeloma responses were recorded according to IMWG criteria. An updated contemporaneous CCI on survivors will be presented.

Results: We identified 148 patients who survived > 15 years. Median age at diagnosis was 51.6 (32-71) years, 54% were male. Baseline CCI (from chart review) was low in these patients with 64% patients having CCI of 0-1 and only 6 (4%) had a CCI score of >4 at initial presentation. Median hemoglobin, creatinine and calcium at diagnosis were 11 (5.4-15.6) g/L, 89.0 (22-1304) umol/L and 2.4 (1.9-3.93) nmol/L respectively. Median marrow involvement was 50% (5-98). Baseline stage (available in 105 patients) was ISS I in 50%, II in 36%. Only 5% (n=7) patients had extramedullary disease and 20% (of 113 available) had elevated LDH. Paraprotein was IgG (59%) and light chain only myeloma was present in 20%. FISH or conventional cytogenetics was only available in 63 patients (42%), of those only 11% were high risk as defined by current standard definitions. Ninety one percent (n=135) of patients received high dose therapy and Autologous Stem Cell Transplant (ASCT) after induction therapy and 9% amongst these received tandem transplant for high-risk disease. 53% (n=65 of 122 with available response) of patients achieved VGPR or better (VGPR 45%, CR 8%, PR 39%, MR 2%) post ASCT.

At median follow up of 18 (15-29) years, 80 (54%) remain on follow up. Amongst these, 41 (27%) remain off therapy on observation. Median Progression Free Survival (PFS) of the cohort after first line therapy was 7 years (95% CI 7.3-10.8) thus long-term survivors declared themselves early, with 5-year and 10-year PFS of 67% and 39% respectively. Interestingly, 31 (21%) patients never relapsed after first line of therapy and depth of post ASCT response had no influence on PFS. Median number of lines of treatment was 3 (range 1-11). Only 11% (n=16) of the patients had triple-class refractory disease and as of this analysis, only five patients had received anti-BCMA CAR T-cell therapy.

With respect to cumulative morbidity, the incidence of identified secondary malignancies among these long-term survivors excluding nonmelanoma skin malignancies was 15.5% (solid tumours, n=15, therapy-related MDS/AML, n=8). The cumulative risk of an identifiable grade 3-4 infection was 20% in this cohort. The high 15-year incidence of reported cardiovascular (19%) and neurological events (12%) could be attributed to advancing age-related diseases unrelated to MM. A significant 33% of patients continued to have persistent symptomatic treatment-related peripheral neuropathy requiring pharmacotherapy. Venous thromboembolism and pulmonary embolism events occurred in 10% (n=15) and new pathological fractures were reported in 6.7% (n=10) of patients with the caveat of inconsistent bone health monitoring. Although only one patient required hemodialysis at presentation, 15-year risk of developing dialysis-dependent renal impairment was 5.4%.

Conclusions: Although our analysis is limited by its retrospective nature and frequent unavailability of baseline cytogenetics; low risk baseline features, younger age of diagnosis, use of ASCT, and a prolonged first PFS were characteristics of long-term MM survivors. Unsurprisingly, given the era and medications commonly used in myeloma treatment during the early years (steroids, adriamycin, vincristine, melphalan, cyclophosphamide, thalidomide), significant late comorbidities were frequent. With accelerating longevity, quality of life analysis and structured myeloma survivorship programs will be more relevant and helpful.

Bhella:Kite/Gilead: Consultancy, Honoraria. Chen:Eli Lilly and Company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astrazeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forus Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lancman:Pfizer: Honoraria; Johnson & Johnson: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Honoraria; Forus: Honoraria. Prica:Kite-Gilead: Honoraria; Abbvie: Honoraria; Astra-Zeneca: Honoraria. Reece:Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; ORIC: Research Funding; GSK: Honoraria; Pfizer: Honoraria; Takeda: Research Funding; Forus Therapeutics: Honoraria. Tiedemann:Janssen: Honoraria; Pfizer: Honoraria; AbbVie: Honoraria. Trudel:GSK, BMS, Roche, Genentech, Pfizer, Janssen, K36 Therapeutics: Research Funding; Princess Margaret Cancer Centre: Current Employment; GSK, BMS, Roche: Consultancy, Honoraria, Research Funding; Sanofi, GSK, Pfizer, BMS, Janssen, AstraZeneca, BMS, Forus: Honoraria. Stewart:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.