Patients with Newly Diagnosed Multiple Myeloma and a Gain of the Long Arms of Chromosome 1 Have Inferior Outcomes, Including Early Onset Extramedullary Disease, Despite the Use of Novel Triplet Regimens
Authors: Biran Noa , Najfeld Vesna , Bagiella Emily , Jagannath Sundar , Chari Ajai 
Published: October 2019

Abstract
Abstract 4996

BACKGROUND:
In patients with newly diagnosed multiple myeloma (MM), a gain of the long arms of chromosome 1 is found in approximately 20% of patients by cytogenetics and 40% by FISH. A few studies have not found these abnormalities to be predictive of inferior progression free survival (PFS) and overall survival (OS) on multivariate analysis. The many studies that have were prior to the use of novel therapies in induction. Currently, testing for a gain or amplification of 1q21 locus is not included in the high risk genetic abnormalities by the International Myeloma Working Group (IMWG).
Recently, two groups have reported inferior outcomes with bortezomib based induction regimens followed by high dose melphalan consolidation and maintenance therapy. The gain of 1q21 was either detected by cytogenetics or gene expression profiling (GEP70) at the University of Arkansas (Waheed et al, Cancer 2011) or by FISH in CD138 selected cells by the HOVON group (Neben et al, JCO 2012).
However, the outcomes of these patients when treated with a bortezomib, lenalidomide, and dexamethasone induction regimen, which is associated with an overall response rate (ORR) of 100% and VGPR or better rate of 74% is unknown (Richardson et al. Blood 2010). Here, we describe the poor outcomes of patients with newly diagnosed MM with gain of 1q21 by FISH in unselected bone marrow aspirates despite novel agent triplet therapy.

METHODS:
The inclusion criteria for this IRB approved retrospective study were patients with symptomatic MM starting in June of 2008 who had a gain of 1q21 by FISH in 200 bone marrow interphase cells at the time of diagnosis. Patients with 1q amplification had at least 3 or more copies. PFS and OS were calculated by Kaplan-Meier analyses.

RESULTS:
23 patients met the inclusion criteria. The median age was 59. 7 (range 46–71) and twenty patients (87%) were DS III at diagnosis, 13/23(57%) were ISS Stage 3. 6/23 (26%) had hypercalcemia, 8/23 (35%) had renal insufficiency, and 19/23 (83%) had anemia. Lytic lesions were present in 17/23 (74%) of patients at diagnosis. Of note, while 4 patients had deletion 13 by cytogenetics only 2 patients had other high risk findings, one with t(4;14) and another with deletion 17.
All patients were treated with novel agent induction therapy. 19/23 (83%) were treated with triplet regimens (bortezomib, dexamethasone, and either lenalidomide or cyclophosphamide i. e. VRD or VCD). Disappointingly, primary induction failure, defined by PD or SD after 3–4 cycles, was observed in 30% of all patients.
Of the 17 patients who received upfront triplet VRD or VCD therapy (with or without HDM plus SCR) the overall response rate (ORR) was only 77% (13/17), and 47% (8/17) achieved VGPR or better. More specifically, 3/17 (18%) had CR, 5/17 (29%) had VGPR, 5/17 (29%) had PR, 1/17 (6%) had SD and 1/19 (6%) had PD. Of the 4 patients who received novel doublet therapy (VD or RD) upfront, only 1 had a VGPR, one had SD and 2 had PD.
The responses noted were not very durable, with a median PFS of 14 months. Although 3 patients have died (after 11–13 months from diagnosis), the median OS has not been reached with a median follow up of 13 months.
Plasmacytomas of the bone with soft tissue expansion were present in 48% of the patients and 3 of 23 (13%) had spinal cord compression. Extra-osseous MM within 3 months of diagnosis was observed in 5/23 (22%) patients and 4/5 did not have any other high risk cytogenetics. Three patients (13%) had CNS MM at median of 5. 3 months after diagnosis. One patient had concomitant parenchymal brain lesions, myleomatous meningitis, and intra spinal cord disease.

CONCLUSIONS:
Even in the era of novel agent induction therapies, in our series of newly diagnosed 23 patients with a gain of 1q21, the failure rate of induction was 30% with a median PFS of 14 months. Moreover, these patients had a particularly aggressive clinical course with both medullary and extramedullary plasmacytomas, suggesting that PET-CTs, rather than just skeletal surveys should be considered for initial staging and monitoring. Also, given an unusually high incidence (13%) of early onset CNS disease, prompt CSF evaluation and brain MRI should be performed on patients with neurologic symptoms or signs.
We recommend that gain or amplification of q21 identified either by FISH (even without CD138 selection – as demonstrated here) or GEP be prospectively studied in patients with newly diagnosed MM with consideration of novel therapeutic approaches.

Disclosures:
No relevant conflicts of interest to declare.