A  High- Risk Genetic Signature Is Predictive For Poor Outcome In Auto-Transplant Eigible Multiple Myeloma Patients Even With Use Of Novel Agents. A Single Institution Study

Multi agent induction therapy followed by an auto transplant is currently the standard of care in fit patients up to the age of 70 in most haematology units. There is little data available on the actual real world uptake of this “standard of care” as many series have a significant selection bias. We were able to ascertain the true uptake of an auto transplant in a large, continuous series of all the patients referred to a single unit.

This study analysed the outcomes of a cohort of auto transplant eligible patients (defined as up to age  68) over a decade of treatment at one institution. Genetic analysis by karyotype (G – banding) and FISH was performed in all patients and high risk abnormalities identified. We then compared survival in the transplant and non transplant groups and performed a subset analysis according to possession of a high risk genetic signature.

The multiple myeloma database at Wellington Hospital was interrogated during the period 2002 to 2012. One hundred and forty patients were identified with an age range from 32 to 68 years. There was a male preponderance of 89 and 51 females. Conventional chromosome karyotype was done and 13q deletions were detected by this method and considered high risk. The FISH panel was comprehensive and included 13q del.,  t(4:14), t(14:16), p53 deletion. In the last five years 1Q gains, MYC and a hyper-diploid clone were  also routine.

The 140 patients were divided into 80 receiving an auto graft and 68 did not for various reasons. The reasons included refusal, co-morbid conditions such as cardiac, respiratory and significant renal impairment. Two patients who were on dialysis were auto grafted however and not excluded.

Induction treatment over the decade included VAD initially, then cyclophosphamide/ dexamethasone and then from 2008, a bortezomib based regime of Cy/Bor/D was employed. Cy/Bor/D induced patients numbered 40 or 50% of the total auto graft cohort.

There were 25% high risk abnormalities detected in the auto graft group and t(4:14) was detected in 8% and p53 del. totalled 6% (6 of 80).  The transplant related mortality in this group was 0% (no deaths within 100 days). The overall survival (OS) at three years was 62% and this compared with an OS of 30% in the non transplant group (P = 0.001). The non auto graft group also had a 25% (15 out of 60 ) bad risk signature rate which included three patients with t(4:14), six p53 del. (12%), one t(4:14) case and complex karyotypes in five. One patient had a t(4:14), a p53 deletion and a 1Q gain (triple hit). This patient subgroup had no survivors at the three year mark. The median OS of the non auto graft group was 16 months and has not been reached in the transplant group.

This group of auto grafted myeloma patients has a TMR of zero which represents some of the best results reported.  They had an excellent three year OS of 62% which is projected to be eventually greater than 75% when the more recently treated patients cross the three year mark.

The use of bortezomib in the latest auto grafted cohort currently includes only two deaths, so this drug has resulted in CR rates approaching 40% when assessed by day 100 marrows. This study illustrates real world data and clearly shows that an auto transplant confers a significant survival advantage. The possession of a bad risk signature however is the most important predictor of an adverse outcome whether or not patients receive a transplant.

No relevant conflicts of interest to declare.