Outcomes Following Biochemical or Clinical Progression in Patients with Multiple Myeloma
Authors: Goldman-Mazur Sarah , Visram Alissa , Rajkumar S Vincent , Kapoor Prashant , Dispenzieri Angela , Lacy Martha Q. , Gertz Morie A. , Buadi Francis K. , Hayman Suzanne R. , Dingli David , Kourelis Taxiarchis , Gonsalves Wilson I , Warsame Rahma M , Muchtar Eli , Leung Nelson , Kyle Robert A. , Kumar Shaji 
Published: November 2021

Abstract
Background
Multiple Myeloma (MM) remains incurable with current approaches and eventually relapses in nearly all patients. At relapse, patients may present with increasing serum and/or urine monoclonal (M) protein or with clinical features suggestive of progression. The outcomes of different progression patterns need to be better understood to provide insight about the optimal time to intervene with salvage therapy. This study aimed to describe the prevalence and outcome of biochemical (BP) versus clinical progression (CP) in a real-world setting.
Methods
We retrospectively assessed 1347 relapsed MM patients seen at Mayo Clinic between February 2001 and December 2018. CP was defined as per IMWG criteria (increase ≥50% in size or new plasmacytomas/bone lesions, hypercalcemia ≥11.5 mg/dl, decrease in hemoglobin ≥2 g/dl or to ≤10 g/dl, rise in serum creatinine ≥2g/dl, hyperviscosity), while BP was defined as increase in serum or urine M protein leading to initiation of a new line of therapy without meeting criteria for CP. Aggressive relapse was defined as new extramedullary disease (EMD), plasma cell leukemia or hyperviscosity requiring plasmapheresis. The overall survival (OS) was defined as the time from 1 st relapse to last follow-up or death. Time to next treatment (TTNT) was defined as the time between initiation of 2 nd and 3 rd line therapy.
Results
Prevalence of different patterns of relapse is presented in Table 1. The majority of progressions were BP (60.4%); among the CP (39.6%), the most common presentation was a new bone lesion.
Similar proportions of BP and CP patients were diagnosed before 2013 (70% and 73%; p=0.2). The median time from diagnosis to 1 st relapse was 22.8 months (range, 0.4-154.7) and was shorter in the CP group in comparison to BP (20.8 [range, 1.0-152.1] vs 23.7 [range, 0.4-154.7] months, p=0.001). With the exception of ISS stage, patients in the CP group had higher risk features at MM diagnosis including: high-risk (HR) FISH ([4;14], t[14;16], t[14;20], deletion 17p or p53 mutation; 29% vs 20%, p=0.01); elevated LDH (23% vs 17%, p=0.03); and EMD (19% vs 10%, p&lt;0.001). CP patients more often had non-secretory disease at baseline (6% vs 2%, p&lt;0.001).
At 1 st line, patients with eventual CP were less likely to have received novel agents (78% vs 85%, p&lt;0.001), upfront autologous stem cell transplantation (ASCT, 43% vs 51%, p=0.004), and lenalidomide-based maintenance (11% vs 16%, p=0.01). While patients in the CP group were less likely to have achieved very good partial remission (VGPR) or better to the 1 st line therapy (53% vs 60%, p=0.01), the percentage of patients who achieved CR was similar between the groups (22% vs 24%, p=0.4). Relapse while on primary treatment/maintenance was more prevalent in the CP (46% vs 40%, p=0.04). On multivariable logistic regression model male sex, plasma cell labeling index (PCLI) ≥2% and EMD at diagnosis were associated with higher risk of CP, whereas achieving VGPR or better after 1 st line treatment was associated with decreased risk of CP.
Patients with CP had shorter median TTNT from 2 nd line therapy compared to BP (9.6 vs 17.0 months, p&lt;0.001) as well as shorter median OS from 1 st relapse (26.2 vs 59.4 months, p&lt;0.001; Figure 1). Amongst patients with CP, those presenting with typical "aggressive" versus "CRAB" features at relapse had a significantly shorter median TTNT (6.0 vs 11.0 months, p&lt;0.001) and OS (17.2 vs 28.1 months, p&lt;0.001).
Using a multivariable Cox proportional hazard model, CP (vs BP) was a predictor of shorter TTNT from 2 nd line therapy (HR 1.40, 95% CI 1.20-1.62, p&lt;0.001), along with ISS stage III, HR FISH at diagnosis and relapse while on primary treatment/maintenance, whereas the use of upfront ASCT was a predictor of longer TTNT from 2 nd line therapy. CP was also a predictor of shorter OS from 1 st relapse (HR 1.53, 95% CI 1.29-1.81, p&lt;0.001) along with age &gt;65 years, male sex, ISS stage III, HR FISH at diagnosis, EMD at diagnosis and relapse while on primary treatment/maintenance.
Conclusions
Patients with clinical features at relapse have a worse prognosis after 1 st relapse than patients who relapsed solely biochemically. Approximately half of CP presented while on active treatment, which suggests that even patients monitored closely may develop CRAB features at relapse. Factors that help predict the occurrence of CP include male sex, PCLI ≥2% and EMD at diagnosis. Patients with deeper response to 1 st line treatment are less likely to develop CP.
Figure 1 Figure 1.

Disclosures
Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Dispenzieri: Sorrento Therapeutics: Consultancy; Pfizer: Research Funding; Oncopeptides: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Research Funding; Alnylam: Research Funding. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy. Dingli: Apellis: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Novartis: Research Funding; Alexion: Consultancy; Janssen: Consultancy. Kumar: Antengene: Consultancy, Honoraria; Sanofi: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Tenebio: Research Funding; Beigene: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Carsgen: Research Funding; Oncopeptides: Consultancy; Roche-Genentech: Consultancy, Research Funding; Novartis: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding.