Abstract
We report the outcomes of 117 newly diagnosed multiple myeloma patients who received novel agents induction, had a poor response to induction and were mobilized using intravenous intermediate-dose cyclophosphamide (82%) or VD-PACE (18%) plus G-CSF and “on-demand” plerixafor. The median PFS and OS of the chemo-mobilized cohort were 21 months (95% CI 15–71) and 58 months (95% CI 47–80), respectively. We compared our cohort to a 117-patient cohort matched by the level of response at pretransplant evaluation. The matched patients were mobilized with G-CSF and “on-demand” plerixafor without chemotherapy. Patients receiving chemo-mobilization had higher stem cell yields than the growth factor only cohort (median 10.7×106 cells/kg versus median 8.77×106 cells/kg, respectively (P<0.001)). The safety profile of chemo-mobilization was favorable, and there was no difference between the two groups in length of hospitalization during ASCT (P=0.95), days to neutrophil engraftment (P=0.22), days to platelet engraftment (P=0.27), and risk of bacteremia (P=0.52). 29% of the chemo-mobilized cohort and 65% of the matched cohort required plerixafor for adequate mobilization (P<0.001). Chemo-mobilization enhances stem cell collection without adversely impacting the post-transplant clinical course.
Keywords: Mobilization, chemo-mobilization, autologous stem cell transplantation, cyclophosphamide
Introduction
Autologous stem cell transplantation (ASCT) after a triplet/quadruplet induction containing both bortezomib and lenalidomide is considered the standard of care for transplant eligible multiple myeloma (MM) patients in the US (1, 2). Mobilization is the process of forced egress of high numbers of hematopoietic stem cells from the bone marrow to the peripheral blood (3), which enables their collection by leukapheresis. This process is done by introducing agents that disrupt binding between the bone marrow microenvironment and the stem cells. High-dose granulocyte colony-stimulating factor (G-CSF) alone or in combination with myelosuppressive chemotherapy (chemo-mobilization) are two major strategies for mobilization. Plerixafor, a CXCR4 antagonist, is used “on-demand” to further augment hematopoietic stem cell yield (4), resulting in low rates of mobilization failure (5). Lenalidomide and daratumumab administered prior to ASCT may impair mobilization (6–8). Poor mobilization correlates with inferior outcomes (9), is one of the major factors effecting engraftment and might preclude ASCT since patients who undergo ASCT require a minimum of 2×106 CD34+ cells/kg. Costs of plerixafor are high (10) and may not be available globally thus it is imperative to have an alternative cost-effective strategy to optimize yield of stem cells during apheresis.
Traditionally, chemotherapy followed by granulocyte colony-stimulating factor (G-CSF) was the regimen used to collect sufficient numbers of CD34+ cells. Cyclophosphamide based mobilization was used in early large clinical trials that established the role of ASCT in MM (11–14), as well as in recently published European large randomized trials. However, many clinicians are reluctant to use cyclophosphamide due to fear of side effects, such as hemorrhagic cystitis (15) and neutropenic infection (16, 17).
In the novel agents era, refractoriness to induction is relatively rare. MM patients that are refractory to induction remain an unmet need and are often excluded from clinical trials. Consensus guidelines recommend limiting chemo-mobilization to patients who have not responded optimally to therapy (18). In the current era, chemotherapy-induced stem cell collections are used at Mayo Clinic in “poor responders” to induction, such as patients that progress prior to ASCT or patients with significant disease burden after induction (19).
We aimed to evaluate efficacy and safety of chemotherapy-induced mobilization in newly diagnosed MM patients that were “poor responders” to induction looking at endpoints including treatment toxicities, stem cell yield and engraftment.
Methods
We identified newly diagnosed multiple myeloma (NDMM) patients who underwent mobilization using chemotherapy followed by ASCT at Mayo Clinic, Rochester, Minnesota between January 2012 and September 2020. We excluded patients that underwent stem cell collection elsewhere and patients chemo-mobilized because they failed to mobilize with G-CSF and “on-demand” plerixafor. The study was approved by the Mayo Clinic Institutional Review Board (IRB).
The diagnosis and staging of MM were according to consensus criteria (20). For risk stratification, we used the international staging system (ISS) and fluorescence in situ hybridization (FISH) in CD 138 positive sorted plasma cells. High-risk FISH was defined according to IMWG risk stratification criteria (21) and included del 17p, t (4;14), t (14;16) and t (14;20). Double-hit (DH) was defined as two of the following HR genetic abnormality:17p deletion, t (4;14), t (14;16), t (14;20). The eligibility of patients for ASCT was assessed up to 30 days prior to transplant. The Mayo Clinic’s current consensus include no significant comorbidities, performance status Eastern Cooperative Oncology Group (ECOG) ≤ 2, adequate respiratory function studies (Forced expiratory volume (FEV1) ≥50%, diffusion capacity of the lungs for carbon monoxide (DLCO) ≥50%), echocardiography demonstrating ejection fraction (EF) ≥40%, adequate liver function. The stem cell collection goal of all patients under the age of 70 is 6 million CD34+ cells/kg.
Cyclophosphamide was used at a dose of 1.5 g/m2 daily for 2 consecutive days. It was administered outpatient with 1 liter of fluid prior to each dose and without mesna. G-CSF at a dose of 10 μg/kg/day was given from day +5 following cyclophosphamide and prophylactic antibiotic was given from day +5 till absolute neutrophil count was more than 500 ×106/L. CD34+ monitoring started when the WBC rose to 1000 cells /μL, approximately 11 days following cyclophosphamide. Collection began when CD34+ was over 10 cells/μL, regardless of the collection’s goal. Plerixafor at a dose of 240 μg/kg was added if WBC was >1000 cells /μL and CD34+ <10 cells/μL after 1–3 days. In patients not mobilized with cyclophosphamide receiving G-CSF only, plerixafor at a dose of 240 μg/kg was used if at day 4 of G-CSF injections peripheral CD34+ was less than 20 cells/μL. Patients with eGFR less than 50 ml/min/BSA received a reduced dose of plerixafor, 160 μg/kg. Of note, patients that received VD-PACE did not received the thalidomide since it is difficult to give thalidomide in the hospital setting due to technical issues. The G-CSF dose administered in the matched group was similar to the G-CSF dose administered in the chemo-mobilized cohort (10 μg/kg/day).
After stem cell infusion, standard supportive care was administered, which included prophylactic fluoroquinolone antibiotics, acyclovir and fluconazole. Neutrophil engraftment was defined by absolute neutrophil count (ANC) ≥ 500 cells /μl for three consecutive days and platelet engraftment by ≥ 50000/μl without transfusion support for over 7 days. The response was assessed between day 60 (high risk) to 100 (standard risk) post ASCT according to consensus criteria (22). Between 2012-July 2017 bone marrow MRD assessment was carried out using a 7-color flow with a sensitivity of 2×10−5 and since July 2017 we use an 8-color flow with a sensitivity of 2.5×10−6.
The reasons for the use of chemotherapy-induced mobilization were any of the following at pretransplant evaluation: more than 30 circulating plasma cells /150,000 events, more than 20% bone marrow plasma cells at pretransplant assessment, progressive disease and achieving less than a partial response to induction.
Transplant-related mortality (TRM) was defined as death from any cause within 100 days of stem cell infusion. OS was defined as the time from day 0 of the transplant to death or until last follow-up. PFS was defined as the time from day 0 of the transplant to progression or death or until last follow-up.
We compared our cohort to a cohort of 117 matched patients that were transplanted at Mayo Clinic over the same time period and underwent mobilization with G-CSF and “on-demand” plerixafor. We matched the cohorts by the level of response by IMWG at pretransplant evaluation.
Cox regression analysis was used to study the association between studied predictors and OS and PFS. Wilcoxon rank-sum and chi-square tests were used to analyze continuous and dichotomous variables, respectively. The two-sided P-value <0.05 was considered statistically significant. Statistical analysis was carried out using JMP 14 (SAS Institute, Cary, NC) statistical software.
Results
Between January 2012 and September 2020, 1557 patients underwent ASCT at Mayo Clinic, Rochester. A total of 127 patients (8%) underwent chemo-mobilization. Ten patients were excluded: Two patients were collected elsewhere, and eight patients were chemo-mobilized due to poor mobilization using G-CSF and “on-demand” plerixafor. Overall, 117 patients were included in the analysis. Stem cell mobilization consisted of single-agent cyclophosphamide in 96 patients (82%), and VD-PACE in 21 patients (18%). Baseline characteristics for all 117 patients are listed in Table 1. The median age at ASCT was 59.5 (IQR (53.2–65.1), patients aged ≥ 70 years accounted for 9.4% of the cohort. There was a male predominance (61%). Forty-five (41%) patients had high-risk FISH and 23 patients (21%) had double hit MM (defined as two of the following HR genetic abnormality:17p deletion, t (4;14), t (14;16), t (14;20)). All patients received induction with novel agents (listed in table 1). Eleven patients (9%) received doublet induction and all others received triplet induction.
Table 1:
Baseline characteristics at diagnosis of study population
| Variable name, median (IQR) | Chemo-mobilized Cohort N=117 | Matched cohort N=117 | P value |
|---|---|---|---|
| Age at ASCT, years | 59.5 (53.2–65) | 64.2 (57–69.4) | 0.0001 |
| Male, n (%) | 71 (61) | 69 (59) | 0.9 |
| Time from diagnosis to ASCT, months | 6.9 (5.7–10.1) | 14.7 (7.25–31) | 0.0001 |
| High risk FISH, n (%) | 45 (41) | 24 (22) | 0.0026 |
| Double hit, n (%) | 23 (21) | 9 (8) | 0.01 |
| Induction Treatment, n (%) | |||
| VCd/Vd | 50 (44) | 63 (54) | |
| VRd | 65 (56) | 36 (31) | |
| KRd/KPd | 12 (10) | 12 (10) | |
| DPd/DRd/DIRd | 11 (9.4) | 8 (7) | |
| Rd/Thal-d | 24 (20) | 33 (26) | |
| VDTPACE | 22 (19) | 4 (3) | |
| Melphalan conditioning, n (%) | 0.81 | ||
| 200 mg/m2 | 99 (85) | 102 (87) | |
| 140 mg/m2 | 11 (9) | 8 (7) | |
| Others (carfilzomib and melphalan, BEAM) | 7 (6) | 7 (6) | |
| ISS, n (%) | 0.0003 | ||
| I | 16 (19) | 34 (37) | |
| II | 25 (30) | 36 (40) | |
| III | 43 (51) | 21 (23) | |
| missing | 33 | 26 | |
| % bone marrow PC at diagnosis | 70 (50–84) | 50 (25–70) | <0.0001 |
| Hemoglobin at diagnosis, g/dL | 9.45 (8–11.7) | 10.6 (9.55–12.5) | 0.0005 |
| Serum creatinine at diagnosis, mg/dL | 0.9 (0.7–1.1) | 1 (0.85–1.1) | 0.46 |
| Serum albumin at diagnosis, g/dL | 3.5 (3.2–3.7) | 3.5 (3.3–3.7) | 0.6 |
| Serum calcium at diagnosis, g/dL | 9.7 (9–11) | 9.4 (8.8–9.9) | 0.01 |
| LDH at diagnosis, U/L | 200 (141–342) | 172 (140–211) | 0.03 |
| M-spike at diagnosis. g/dL | 2.8 (0.4–4.7) | 2.4 (1.5–3.2) | 0.7 |
| Involved light chains at diagnosis, mg/dL | 136 (25–559) | 49 (12–239) | 0.017 |
| Response at ASCT, n (%) | |||
| CR/sCR | 9 (8) | 9 (8) | |
| VGPR | 14 (12) | 14 (12) | |
| PR | 36 (31) | 36 (31) | |
| SD | 31 (26) | 31 (26) | |
| PD | 27 (23) | 27 (23) | |
| MRD negative at post-transplant evaluation | 33 (28) | 36 (31) | 0.2 |
| Best response, n (%) | 0.03 | ||
| CR/sCR | 27 (23) | 48 (41) | |
| VGPR | 46 (40) | 31 (26) | |
| PR | 29 (25) | 29 (25) | |
| Pre-transplant regimens, median (IQR) | 2 (1–2) | 1 (1–2) | 0.2 |
| Relapses pre-transplant, median (IQR) | 0 (0–1) | 0 (0–1) | 0.5 |
n=number; PI=proteasome inhibitors; Imid=immunomodulatory drugs; CR=complete response; VGPR= Very good partial response; PR= partial response; SD=stable disease; ASCT-= autologous stem cell transplantation; PC= plasma cells; VCd= bortezomib, cyclophosphamide, dexamethasone; Vd= velcade, dexamethasone; VRd=bortezomib, lenalidomide, dexamethasone; KRD=carfilzomib, lenalidomide, dexamethasone; allo=allogeneic stem cell transplantation; CAR-T=chimeric antigen receptor therapy.
The median time from diagnosis to mobilization was 6 months (IQR 5–8) and from mobilization to ASCT was 1 month (IQR 1–1). The indications for chemo-mobilization were progressive disease (36 patients), 30 circulating plasma cells /150,000 events (60 patients), more than 20% plasma cell burden in the bone marrow at pretransplant assessment (49 patients) and not achieving PR at pretransplant evaluation (28 patients). Of note, 26 patients had more than one of these criteria that led to the decision to use chemo-mobilization.
The median time from diagnosis to ASCT was 6.9 months (IQR 5.7–10.05). For peripheral blood progenitor cell collection, granulocyte colony-stimulating factors (G-CSF) were used in all patients. 34 patients (29%) of the chemo-mobilized cohort required plerixafor for adequate mobilization.
In terms of side effects (infections, neutropenic fever, fever not during neutropenia, need for transfusion, DVT), looking at the entire chemo-mobilized cohort, 23 patients (20%) had adverse events and 5 patients (4.2%) had more than one adverse event. Neutropenic fever was documented in 8 patients (7%), fever not during neutropenia in 3 patients (3%), DVT in 2 patients (2%), documented infections in 4 patients (3%) and transfusions in 3 patients (3%). Overall, 10 patients (9%) were hospitalized due to adverse events. Adverse effects due to single-agent cyclophosphamide were neutropenic fever (n=5, 5%), fever not during neutropenia (n=3, 3%), hemorrhagic cystitis (n=2, 2%, resolved within less than 48 hours with hydration and bladder irrigation), DVT (n=1, 1%), other infections (parainfluenza 1 patient, prostatitis 1 patient, cystitis caused by BK virus), and the need for blood products (n=1, 1%). Five patients (5%) were hospitalized due to adverse events. Adverse effects due to VD-PACE chemotherapy were neutropenic fever (n=3, 14%), DVT (n=1, 5%), mucositis requiring admission (n=2, 10%), and the need for packed cells transfusion (n=2, 10%). Five patients (24%) were hospitalized due to adverse events.
Reduced melphalan dose (140 mg/m2) was administered to 11 patients (9%). The median time to neutrophil engraftment was 16 days (IQR 14–19) and to platelet engraftment was 16 days (15–20). Bacteremia was confirmed in 27 patients (23%). Five patients died within 100 days of transplant, which represented a 4% 100-day mortality (TRM). Four of those patients died of rapidly relapsing MM and one had probable cerebral rhino-orbital mucormycosis and carotid artery thrombosis with acute ischemic stroke. Ninety-five patients (88%) required platelet infusions and 79 patients (75%) required RBC transfusions during ASCT.
Stem cell transplantation at our center is routinely performed as an outpatient, with patients being hospitalized when deemed clinically necessary upon physician review. Sixty (51%) patients completed the entire course of transplant without hospitalization. Among the 57 patients (49%) that required hospitalization, the median duration of hospital admission was 7 days (IQR 5–12). Reasons for hospitalization included fever or infection (35%), cardiac arrhythmia (14%), and dehydration and need for nutritional support (30%). Table 2 summarizes mobilization outcomes and Table 3 summarizes transplant outcomes. Table 4 compares outcomes of cyclophosphamide mobilization and VD-PACE mobilization. The median PFS and OS of the chemo-mobilized cohort were 21 months (95% CI 15–71) and 58 months (95% CI 47–80), respectively.
Table 2-.
Stem cell mobilization outcomes
| Variable | Chemo-mobilized Cohort N=117 | Matched cohort N=117 | P value |
|---|---|---|---|
| Apheresis collections, median (range) | 2 (1–8) | 2 (1–8) | 0.9 |
| Plexifor use, n (%) | 34 (29) | 77 (65) | <0.001 |
| Total CD34 stem cell collected, ×106 cells/kg (range) | 10.7 (7.95–13.73) | 8.77 (6.27–11.2) | <0.001 |
| CD34 stem cell dose infused, ×106 cells/kg (range) | 4.38 (1.79–14.9) | 3.89 (2.42–11.2) | 0.0008 |
| Side effects during mobilization | 23 (20%) | 0 | |
| More than one side effect during mobilization | 5 (4.2%) | 0 | |
| Admission due to adverse events during mobilization | 10 (9%) | 0 |
n=number; IQR=interquartile range.
Table 3-.
Transplant outcomes
| Variable | Chemo-mobilized Cohort N=117 | Matched cohort N=117 | P value |
|---|---|---|---|
| Days to neutrophil engraftment, median (range) | 16 (11–26) | 15 (10–29) | 0.27 |
| Days to platelets engraftment (50000), median (range) | 16 (11–64) | 16 (11–42) | 0.22 |
| Bacteremia, n (%) | 27 (23) | 22 (19) | 0.52 |
| Hospitalizations, n (%) | 57 (49) | 59 (51) | 0.9 |
| Infection | 20 (35) | 26 (41) | |
| Cardiac arrhythmia | 8 (14) | 1 (2) | |
| Dehydration | 17 (30) | 20 (32) | |
| Others | 12 (21) | 16 (25) | |
| Days in hospital of those hospitalized, median (IQR) | 7 (5–12) | 8 (5–12) | 0.95 |
| Need for RBC transfusion during ASCT, n (%) | 79 (75) | 55 (47) | <0.001 |
| Need for PLT transfusion during ASCT, n (%) | 95 (88) | 101 (86) | 0.7 |
| Neutropenic fever, n (%) | 64 (58) | 70 (60) | 0.89 |
| Mucositis, n (%) | 39 (33) | 36 (31) | 0.77 |
n=number; IQR=interquartile range.
Table 4-.
Outcomes of patients mobilized with single agent cyclophosphamide versus VD-PACE
| Mobilized with cyclophosphamide | Mobilized with VD--PACE | |
|---|---|---|
| Number of patients | 96 (82%) | 21 (18%) |
| Median OS of the subgroup | 67 months (95% CI 47–80) | 41 months (95% CI 11-NR) |
| Median PFS of the subgroup | 21 months (95% CI 15–71) | 21 months (95% CI 2-NR) |
| Number of hospitalizations | 5 (5%) | 5 (24%) |
| Number of neutropenic fever events | 5 (5%) | 3 (14%) |
| Need for blood products | 1 (1%) | 2 (10%) |
| Haemorrhagic cystitis | 2 (2%) | 0 |
| Other infections | 3 (3%) | 0 |
| Mucositis requiring hospitalization | 0 | 2 (10%) |
| Deep vein thrombosis | 1 (1%) | 1 (5%) |
When comparing the chemo-mobilized cohort to the matched cohort (match by the status of the disease at pretransplant assessment), patients that where chemo-mobilized had higher stem cell yield (median 10.7 ×106 cells/kg) than patients that were mobilized with G-CSF and plerixafor (median 8.77 ×106 cells/kg) (P<0.001). 29% of the chemo-mobilized cohort and 65% of the matched cohort required plerixafor for adequate mobilization (P<0.001). Among all the patients that received plerixafor, the median CD 34 was 8.6 ×106 cells/kg (IQR 7–11.6) in the chemo-mobilized cohort and 8.64 ×106 cells/kg (IQR 6.4–11.8) in the GCSF mobilized cohort (P=0.7). Twenty-five patients received plerixafor at a reduced dose due to kidney impairment. The median number of apheresis days was two in both cohorts. There was no difference between the two groups in length of hospitalization during ASCT (P=0.9), days to neutrophil engraftment (P=0.27), days to platelet engraftment (P=0.22), rate of bacteremia (P=0.52) and the risk of neutropenic fever (P=0.89). More patients in the chemo-mobilized cohort required RBC transfusions during ASCT (P<0.001). In the GCSF and on demand plerixafor mobilization arm there were no complications prior to melphalan administration such as hospitalizations, infections, transfusions, fever >38 degrees Celsius or splenic rupture.
Thirty-eight patients in the entire cohort were older than 70 years: 27 in the G-CSF group and 11 in the chemo-mobilized group. The goal of collection in this cohort was 3 million CD34+ cells/kg, and in both the chemo-mobilized group and the matched group all patients met this goal. Among patients aged less than 70, six patients in the G-CSF group and six patients in the chemo-mobilization group did not meet the goal of 6 million CD34+ cells/kg. Over the same period (January 2012 to September 2020), 3 patients were unable to collect and proceed to ASCT. Therefore, the failure rate was 1.2%. Eight patients lacked sufficient collection with G-CSF and plerixafor and were therefore mobilized with cyclophosphamide (these patients were not included in our analysis).
The median OS of the chemo-mobilized cohort was 58 months (95% CI 47–80) while the median OS of the matched cohort was not reached (P<0.0001). The median PFS of the chemo-mobilized cohort was 21 months (95% CI 15–71) and not reached (95% CI 62-NR) in the matched cohort (P=<0.0001). Of note, the chemo-mobilized group included more patients with high-risk FISH (P=0.0026) and double hit MM (P=0.01), more patients with ISS3 (P=0.0003), higher median bone marrow plasma cells at diagnosis (P<0.0001), lower hemoglobin levels at diagnosis (P=0.0005), higher calcium levels at diagnosis (P=0.01), higher light chains at diagnosis (P=0.017) and higher LDH levels at diagnosis (0.03) (Table 1).
Discussion
Collection and cryopreservation of an adequate number of hematopoietic progenitor cells early in the disease course is an important step irrespective of whether transplantation is performed early or delayed, single or tandem. Our chemo-mobilized patients represent a refractory patient population usually characterized by poor collections, treatment adverse events and short PFS and OS. The cyclophosphamide-mobilization appeared to have a favorable safety profile with only 2 patients experiencing hemorrhagic cystitis and 5 hospital admissions. However, TRM was 4%, which is higher than typical TRM in MM patients, in large part due to the refractory state of the myeloma following induction and the high percentage of high-risk FISH genetics. When compared to a matched cohort, chemo-mobilization increased stem cell yield. Moreover, chemo-mobilization did not increase the time to engraftment or length of hospitalization during ASCT. 29% of the chemo-mobilized cohort and 65% of the matched cohort required plerixafor for adequate mobilization (P<0.0001). Of note, the matched cohort was matched based on the depth of response prior to stem cell collection. However, there are fundamental differences between the two cohorts that make the prognosis of the chemo-mobilized cohort worse such as more patients with ISS 3, more patients with high-risk FISH, higher median bone marrow plasma cells at presentation and higher LDH at presentation.
The risk-benefit ratio of chemo-mobilization versus G-CSF mobilization is a debatable issue in the literature. In a retrospective German study that included 236 patients induced with novel agents (8% received lenalidomide) and mobilized with chemotherapy (23), 29% of patients experienced side effects attributable to chemotherapy given for mobilization (including 17% neutropenic fever and 6% sepsis), out of which 8% required hospitalization. In that study, an improvement in myeloma response status attributable to mobilization was experienced by only 3% of patients. However, the benefits of chemotherapy could be underestimated in the short interval between induction and transplantation, due to a delay in response improvement or the long half-life of protein clearance. Moreover, this study did not address non-responders or patients that had significant disease burden after induction, which comprise most of our cohort. A retrospective study of 179 MM patients that achieved ≥VGPR after induction therapy showed that there is no benefit in terms of OS or PFS for chemo-mobilization and suggested a response adapted selections of mobilizations regimen (24). In most large randomized controlled studies of NDMM patients, patients with progressive disease, like the cohort reported in our study are often excluded (14). Although with modern induction therapy these patients are not as common, they still represent 5–10% of patients and are a very challenging patient population thus the value of this larger cohort presented here. To the best of our knowledge, this is the first study that addresses outcomes of chemo-mobilization in “poor responders” to induction.
In our study, the refractory chemo-mobilized patients had better stem cell yield than the matched cohort. These findings are in line with a previous phase II study (25) that compared cyclophosphamide +G-CSF to G-CSF alone after lenalidomide induction and showed that more patients achieved the primary outcome of ⩾3×106/kg CD34+ cells with 1–2 apheresis in the cyclophosphamide arm. Higher stem cell yields were also seen in a retrospective study that compared chemo-mobilization to G-CSF mobilization (26). A retrospective study of 162 MM patients (107 patients mobilized with cyclophosphamide) showed that patients mobilized with cyclophosphamide required fewer days of apheresis (27), which was not seen in our study. This difference could be attributed to the small sample size. Moreover, even though we matched the cohorts by disease status at ASCT, the chemo-mobilized cohort had more advanced disease at presentation, reflected by the significant differences in hemoglobin, calcium, LDH and bone marrow plasma cells with 52% of patients stage 3 disease. This may partially explain the reason that the OS and PFS differences between the two cohorts were not overcome by chemo-mobilization.
In a previous retrospective report from our group (28), published before plerixafor was available, patients receiving cyclophosphamide in the same regimen that was administered in our cohort, had higher stem cell yields than patients mobilized with growth factor only. However, patients mobilized with cyclophosphamide had slower engraftment of platelets and neutrophils. In the current cohort, chemo-mobilized patients did not have a longer time to platelet or neutrophil engraftment when compared to patients mobilized with G-CSF. This cohort was treated between 2000–2007 and, therefore, is different from our cohort in terms of induction regimen used (lenalidomide was included in the induction only in 4% of the patients that were mobilized with cyclophosphamide) and in the way melphalan induction was administered (100 mg/m2 on each of 2 consecutive days), which was shown to result in delayed engraftment versus melphalan 200 mg/m2 given at day −2 (29). In our cohort, engraftment was not influenced by chemo-mobilization and this is in line with a previous study of relapsed lymphoma patients that were randomized to cyclophosphamide versus G-CSF mobilization (30). Chemo-mobilization at Mayo Clinic is currently done mostly in refractory patients. VD-PACE was almost exclusive to patients in overt relapse prior to mobilization. Our cohort is a refractory cohort, with 39% of patients having more than 20% bone marrow plasma cells at pretransplant evaluation, which is known to adversely affect mobilization (31). We believe that chemo-mobilization in a population with a lower plasma cell burden would be expected to require plerixafor in fewer than 29%.
Toxicity is a major concern among the refractory patient population that undergoes chemo-mobilization. No treatment-related mortality was observed before ASCT, but the transplant-related mortality (TRM) was 4%. This is a much higher number than reported in our center, but only one patient died of infection and the other 4 died of rapid disease progression, which further shows how aggressive the myeloma in this cohort is. Overall, in the chemo-mobilized cohort, 23 patients (20%) had adverse events and 5 patients (4.2%) had at least one adverse event. Ten patients (9%) were hospitalized due to adverse events of mobilization. The toxicities with chemo-mobilization included fever/infection (8%) and cytopenia requiring blood transfusion (2%). During the mobilization process, in the chemo-mobilized cohort, 7% developed neutropenic fever, 9% were hospitalized and 3% required blood product infusions. In the matched cohort there were no complications prior to melphalan administration such as hospitalizations, infections, transfusions, fever >38 degrees Celsius or splenic rupture. Only two cases of hemorrhagic cystitis were reported in patients treated with cyclophosphamide (2%) that resolved quickly with less than 48h admissions. Some patients may have been seen in different emergency rooms, so the adverse events of the chemo-mobilized cohort may have been underestimated.
Duration of hospitalization during ASCT was not prolonged in the chemo-mobilized cohort versus the matched cohort, which is in line with previous reports (28).
The matched cohort included 58 patients had sub-optimal response to induction (SD or PD). Generally, the matched cohort collected an adequate amount of stem cells to comfortably proceed to ASCT. However, the matched cohort reflects a less aggressive patient population, as shown in Table 1. Therefore, we cannot infer that mobilization with G-CSF is sufficient in a patient with a more aggressive disease. The significantly higher demand for plerixafor in the matched cohort is important since it is not available in all the countries and due to cost issues.
The cost effectivity in Italy of mobilization using G-CSF versus high dose cyclophosphamide (both with “on-demand” plerixafor) was recently reported (32). The authors reported an incremental saving of 1198.59 Euro for patients treated with G-CSF and “on-demand” plerixafor. These results may not apply to our study population. First, the cost of plerixafor is much higher in the US. Second, the population that our study reports on is a refractory population and their ability to collect stem cells is therefore reduced, potentially necessitating more plerixafor if chemotherapy is not used for mobilization, The French group recently reported the results of their cost-analysis comparison of these two strategies (33). The issue of using more plerixafor in patients suspected to be at risk of poor mobilization, like our cohort, raises the cost.
Our study has several limitations. This is a retrospective single-center study performed at a tertiary center, which could impact the generalizability of the findings. The induction regimens were not uniform and were chosen by the treating physician. We do not have data that quantifies the benefit of mobilization chemotherapy in terms of incremental improvement in myeloma response by the free light chain and intact immunoglobulin M protein levels before and after mobilization.
In summary, our data demonstrate that in MM patients eligible for ASCT that are “poor responders” to induction, chemo-mobilization with G-CSF or G-CSF and “on-demand” plerixafor is safe and is associated with high yield stem cell collection and is a valid inexpensive mobilization technique.
Funding Sources
NCI SPORE MM SPORE 5P50 CA186781-04
Footnotes
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COI:
Dr. Gertz reports: DSMB AbbVie, DSMB Celgene, Akcea Honoraria and consulting, i3Health educational materials, Prothena consulting, Research to Practice Honoraria, Alnylym consulting, Ambry Genetics honorarium, Amgen honorarium, Janssen Honorarium, Celgene Honorarium, Stock Options Aurora Bio, Ionis Advisory Board, Karyopharm Honorarium, Pfizer honorarium to institution, Sanofi honorarium
Kumar: Research funding for clinical trials to the institution: Abbvie, Amgen, BMS, Carsgen, Janssen, KITE, Merck, Astra-Zeneca, Novartis, Roche-Genentech, Takeda, Tenebio, Consulting/Advisory Board participation: (with no personal payments) Abbvie, Amgen, BMS, Janssen, Roche-Genentech, Takeda, KITE, Astra-Zeneca, and (with personal payment) Oncopeptides, Beigene, Antagene,
All authors have reviewed the manuscript, agree with its contents, and consent to its submission to BBMT.
Reference
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