Characteristics and Outcome of Multiple Myeloma Patients Presenting with Anemia Only: a Retrospective Multi-Center Study
Authors: Shragai Tamir , Gatt Moshe E. , Shaulov Adir , Katodritou Eirini , Triantafyllou Theodora , Lavi Noa , Pouli Anastasia , Sioni Anastasia , Vaxman Iuliana , Zektser Miri , Ganzel Chezi , Benyamini Noam , Trestman Svetlana , ziv Baran Tomer , Cohen Yael C , Avivi Irit 
Published: October 2019

Abstract
Background:
Multiple myeloma (MM) is defined as bone marrow monoclonal plasmocytosis combined with either specific laboratory or imaging findings (SLIM criteria) or one or more of the following myeloma defining events (MDE) including anemia, hypercalcemia, renal failure or lytic bone lesions (CRAB criteria). Patients who presents with anemia but without additional CRAB criteria are scarce, and their clinical course has not yet been characterized in the literature.
The current study was designed to evaluate the characteristics, responsiveness to treatment, progression free and overall survival in newly diagnosed MM patients presenting with anemia only.
Methods:
We retrospectively analyzed the clinical features and outcomes of MM patients that presented with anemia as the only CRAB criteria (i.e. having no evidence of skeletal involvement by PETCT, MRI or total body CT, no renal involvement and no hypercalcemia), that were diagnosed and treated in 9 Israeli and Greek centers between 2010 and 2018.
Baseline characteristics at diagnosis, ISS score, treatment regimens, depth and duration of response (by IMWG criteria), hemoglobin (HB) levels during treatment and overall survival (OS) were collected and analyzed.
Results: 63 (28 females) patients were included in the analysis. The median age was 72.2 (range 34.4-91.9) years. The median HB level at diagnosis was 9.4 g/l (IQR 6.0-12.0) and median platelets level was 172000 (IQR 59000-454000). The median percent of plasma cells (PCs) in bone marrow at diagnosis was 60% (range 20% to 99%). 11 out of 56 (19%) patients had a high-risk FISH (t 4;14, t 14;16 or del 17p). Bortezomib -based induction was administered in 83%, and upfront autologous hematopoietic stem cell transplantation (autoHCT) was employed in 32%.
ORR to 1st line was 87%. 37 (62%) achieved ≥ VGPR, 16 (25%) PR and 7 (13%) SD/PD. Significant predictors for achieving at least VGPR vs. SD or PD were higher albumin level at diagnosis (3.9±0.5 g/l vs. 3.5±0.4g/l, p<0.00), maximal HB level during treatment (13.0±1.0g/l vs. 11.5±1.2 g/l respectively, p<0.00) and maximal improvement in HB level during treatment (median 3.2 [IQR 2.2-4.5]g/l vs 2.2 [IQR 1.1-3.2]g/l, respectively, p<0.00).
Median PFS in the entire cohort was 22.1±5.82 months. Predictors for PFS duration on first-line therapy were bone marrow plasmocytosis (HR 1.012 [95% CI 1.001-1.037] p=0.03) and maximal improvement in hemoglobin level (HR 0.71 [95% CI 0.55-0.91] p< 0.00). Multivariate analysis confirmed bone marrow plasmocytosis (HR 1.03 [95% CI 1.01-1.05], p<0.00), higher HB level at diagnosis (HR 0.43 [95% CI 0.27-0.67], p<0.00) and maximal improvement in HB level during therapy (HR 0.37 [95% CI 0.25-0.56] p<0.00) to be associated with longer PFS. In multivariate analysis restricted to non-transplanted patients, factors associated with longer PFS were bone marrow plasmocytosis>60% (HR 4.6 [95% CI 1.5-14.0] p<0.00), HB level at diagnosis (HR 0.32 [95% CI 0.17-0.60], p<0.00), maximal HB improvement (HR 0.23 [95% CI 0.13-0.41] p<0.00) and older age (HR 0.92 [95% CI 0.87-0.97], p<0.00).
Within a median follow-up of 34 months, 19 (31%) patients have died; 12 due to PD. The median OS for the entire cohort was 65.93 months and the 3 years mortality rate was 17.5%.
Predictors of mortality were high risk cytogenetics (HR 3.01 [95% CI 1.02-8.88] p= 0.04), maximal HB improvement during therapy (HR 0.73, [95% CI 0.54-0.99] p=0.04), and bone marrow plasmocytosis (HR 1.04 [95% CI 1.01 to 1.07] p= 0<.00). Furthermore, median OS for patients <60% plasmocytosis was not reached, compared to 45.3 months for patients with plasmocytosis ≥60% (p=0.048) (figure 1). Only bone marrow plasmocytosis remained as significant factor for mortality in a multivariate analysis (HR 1.04 [95% CI 1.01-1.08], p=0.01).
Conclusion:
MM patients presenting with anemia only, often have a remarkable bone marrow plasmocytosis
Responsiveness to therapy, PFS and OS, depend on the degree of BM plasmocytosis and HB level at diagnosis, both reflecting disease burden. In line with that, response to therapy and long -term PFS can be accurately predicted by the degree of improvement in HB level.
In general , patients presenting with anemia only , although they do not have renal impairment or bone disease, seem to have a relatively poor OS of approximately 5 years only , suggesting that these patients may have a relatively "rapidly growing tumor", precluding the development of bone and renal disease.

Disclosures
No relevant conflicts of interest to declare.