The median progression free survival (PFS) for younger, fitter patients with multiple myeloma is between 3 and 4 years, however some patients respond very poorly and relapse within a year of autologous transplantation. These patients then go on to receive relapse chemotherapy often with novel agents and, surprisingly, some have a longer remission with second line therapy. The prognostic factors which describe such patients are not well understood, and identifying and treating these patients remains a challenge. To characterise these patients further and describe prognostic markers, we have utilised 2 datasets (1081 patients) comprising 619 patients from the Myeloma IX trial and 462 patients from the Royal Marsden database (RMH). All patients were initially treated with high dose melphalan and peripheral blood stem cell support. Patients were then divided into two groups: early relapse (<12 months from transplant) or late relapse (>12 months after transplant or disease free at last follow up).
The Myeloma IX trial consisted of 147 patients (23.7%) in the early relapse group compared to 472 patients (76.3%) in the late relapse group, with a median PFS1 of 7.6 vs. 27.8 months (P<0.001) and OS of 28 vs. 68.8 months (P<0.001), respectively. A similar pattern was seen in the RMH database, where the early relapse group consisted of 86 patients (18.6%) compared to 376 patients (81.4%) in the late relapse group, and with a median PFS of 6.3 vs. 38.6 months (P<0.001) and OS of 31.9 vs. 117.9 months (P<0.001), respectively.
In order to describe prognostic factors for early relapse after autologous transplant, we utilized the Myeloma IX dataset, and show that a low Hb, a low platelet count, a low serum albumin, ß2M ≥5.5 mg/L, an ISS Stage III combined with adverse cytogenetics such as t(4;14) and 1q21+ at time of diagnosis predict for an early relapse (<12 months after transplant). In addition, we used Affymetrix gene expression profiling (GEP) to identify significant genes associated with early relapse. A distinct GEP signature containing 38 genes was identified as being associated with early relapse after transplantation, among which 10 genes were on chromosome X.
We then used the Royal Marsden dataset to investigate the clinical outcome for patients who relapsed early following second line treatment. To do this, we divided the early relapse group (<12 months from transplant) into two groups: patients with a longer second remission than first remission (47 patients, group A) and patients with a shorter second remission than first remission (39 patients, group B). The median PFS after second line therapy between the two groups was 11.7 vs. 1.8 months (P<0.001) and the median OS was 51.5 vs. 23.0 months (P<0.001), respectively. Univariate analysis showed that a low Hb, a low platelet count, a high ß2M and an ISS stage III at time of second line therapy and no maintenance therapy after second line treatment predicted for a shorter second remission. Failure to achieve a response at the time of first transplant or post second line therapy was highly correlated with a shorter second remission and very aggressive disease outcomes. Multivariate analysis confirmed that failure to achieve a response after second line therapy was the only significant factor correlated with a shorter second remission, and poor survival.
Taken together, our data demonstrates that approximately 20% of patients undergoing HDT will have a short remission. High ISS stage, adverse cytogenetics and failure to achieve a response to chemotherapy can be used to identify this group. In addition GEP signature can also identify such patients. About 45% of these early relapse patients will go on to have a very poor outcome, but 55% can be rescued with novel agents. Important aspects to consider in treating these patients are: careful assessment of the bone marrow reserve, the use of a non-cross reacting agent for second line treatment, an early assessment of response to therapy and incorporating novel agent maintenance therapy. Paying attention to these factors will hopefully prolong progression free survival, overall survival and in the end, quality of life in this poor prognosis group.
Davies:Celgene, Johnson & Johnson, Onyx, Novartis: Honoraria, Speakers Bureau; Merck: Speakers Bureau.
Asterisk with author names denotes non-ASH members.