The most common preparative regimen for autologous transplantation (ASCT) in myeloma (MM) consists of melphalan 200 mg/m2 (MEL 200). Higher doses of melphalan 220–260 mg/m2, although relatively well tolerated, have not shown significant improvement in clinical outcomes. Several approaches have been pursued in the past to improve CR rates, including poly-chemotherapy preparative regimens, tandem ASCT, consolidation, and/or maintenance therapy. Since there is a steep dose–response effect for intravenous melphalan, we evaluated an alternative single ASCT strategy using higher-dose melphalan at 280 mg/m2 (MEL 280) with amifostine as a cytoprotectant as the maximum tolerated dose determined in an earlier phase I dose escalation trial. We report the final long-term outcomes of MM patients who underwent conditioning with MEL 280 with amifostine cytoprotection followed by ASCT. Although the complete response rate was quite high in the era pre-dating the routine use of novel therapies (proteasome inhibitors, immunomodulatory agents) (49%), the progression-free survival was a disappointing 22 months. The implications of this dichotomy between the excellent depth of ASCT response and progression-free survival are discussed.
Randomized clinical trials have established the long-term benefits of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) as part of initial therapy in patients with multiple myeloma (MM) [1,2,3,4,5]. ASCT produces more minimal residual disease (MRD) negative remissions and superior progression-free survival (PFS) and overall survival (OS) compared with chemotherapy regimens but is not curative even using current techniques . Numerous studies have demonstrated that patients achieving deeper remissions, complete, or near complete remission (CR/near CR) as well as MRD negativity after ASCT have longer PFS and OS [3,4,5,6,7]. In order to improve response rates and duration of responses by further intensifying high-dose melphalan, two planned sequential ASCTs or the tandem ASCT approach has been evaluated in several studies.The IFM 1994 trial evaluating sequential tandem melphalan-based transplants demonstrated an improved PFS and OS with tandem transplants and especially in patients who did not achieve at least a very good partial remission (VGPR), with the first transplant procedure . Other studies of tandem ASCT also show an advantage in terms of response rates, PFS, and, in some cases, OS [6,7,8,9,10]. A meta-analysis of six randomized controlled trials showed an improvement in response rates without improvement in event-free survival (EFS) or OS . A pooled analysis of long-term outcome of studies exploring various aspects of ASCT indicated a trend to superior OS with tandem transplantation  while a Cochrane analysis faulted the older randomized controlled trials for not using current “novel therapies” and study bias . In addition, approximately 25% of patients intending to perform a tandem ASCT do not complete the planned second procedure. Further, tandem procedures increase the morbidity, time for recuperation, and cost of intensive therapy.
The dose of melphalan conditioning for ASCT has ranged from 140 to 220 mg/m2, and currently 200 mg/m2 has become the universally accepted dose, except in patients aged >70 years or with renal insufficiency. A steep dose–response curve has been demonstrated for intravenous melphalan in patients with MM . Increasing the dose of melphalan in conditioning is another approach to improve the antineoplastic effect of ASCT. The use of higher doses of melphalan has been limited by extramedullary toxicities, specifically gastrointestinal and mucosal toxicity, which is often prohibitive at doses exceeding 220 mg/m2 [2, 13]. However, concomitant administration of the cytoprotective agent amifostine has been shown to ameliorate the mucosal damage of doses of melphalan up to 300 mg/m2 [2, 14]. Amifostine (WR-2721), an organic thiophosphate compound, was initially developed as a radioprotectant. It can also selectively protect normal, but not cancer, cells against the damage produced by some cytotoxic agents. Importantly, the antitumor effect is not compromised . For example, previous clinical trials have shown that amifostine can decrease the nephrotoxicity associated with cisplatin administration and the hematologic toxicity induced by cyclophosphamide .
Since higher cumulative doses of melphalan produce a better antitumor effect and based upon a previous phase 1 dose escalation trial where 300 mg/m2 was the dose-limiting toxicity, we evaluated the maximum tolerated dose of melphalan 280 mg/m2 (MEL 280) prior to a single ASCT to improve PFS, and potentially, OS. We previously reported that melphalan can safely be dose escalated to 280 mg/m2 [17, 18]. In this phase II, multi-center, nonrandomized study, escalated dose of melphalan at a dose of 280 mg/m2, preceded by two doses of amifostine, and followed by ASCT was evaluated in 57 MM patients. Herein we describe the long-term follow-up of these patients at a median follow-up of 7 years.
Materials and methods
Patients were treated as part of prospective phase II trial approved by the institutional review board of the involved centers and after informed consent was obtained. One common protocol was utilized by all centers with standardized response criteria and follow-up. Patients were required to have symptomatic MM requiring therapy. All patients had chemotherapy sensitive or stable disease at the time of study enrollment; patients with progressive disease were not eligible. Other eligibility criteria included age <70 years, a creatinine clearance of at least 60 mL/min, adequate organ function, and informed consent. All patients received induction therapy with high-dose dexamethasone-based regimens before stem cell mobilization. Eighteen received pulse dexamethasone, although additional therapy was administered in 4 and included thalidomide in 1, dexamethasone+thalidomide+cisplatin+doxorubicin+cyclophosphamide+etoposide (DT-PACE)  in 1, cyclophosphamide+dexamethasone+etoposide+cisplatin in 1 and vincristine+carmustine+melphalan+cyclophosphamide+prednisone followed by alpha interferon in 1. The combination of vincristine+doxorubicin+dexamethasone was administered to 35 patients, of whom 3 also received thalidomide and another DT-PACE. Dexamethasone and thalidomide was the only initial therapy utilized in 4 patients. Thalidomide was included in the induction regimen in a total of 9 individuals. The median number of different regimens before stem cell collection was 1 (range 0–6). Stem cells were mobilized according to the policies at the participating institutions and included the use of granulocyte colony-stimulating factor (G-CSF) alone in 7 patients, cyclophosphamide+granulocyte stem cell factor+/−granulocyte monocyte CSF in 22 and cyclophosphamide+etoposide+G-CSF in 29. The median number of stem cells infused was 4.06 (range 1.13–28.9)×106/kg.
Drug administration and transplant procedures
Patients received a total of two doses of 740 mg/m2 amifostine at 24 h (day −2) and again at 1 h before the dose of MEL 280 (day −1). All antihypertensive medications were held the night before amifostine and the drug was given while patients were in the recumbent position. Amifostine was administered intravenously over 5–15 min; the intravenous line was primed with normal saline before the infusion and flushed with normal saline after the infusion of amifostine. Standard premedication with dexamethasone was given as previously described, and additional dexamethasone and a 5HT-3 antagonist were given as antiemetics. Blood pressure was monitored as per the manufacturer’s recommendations. MEL 280 dose was administered intravenously over 15 min on day –1. Peripheral blood stem cells were re-infused on day 0, at least 24 h after completion of the melphalan infusion. G-CSF was administered as per institutional policy. Supportive care measures, antibiotic therapy, and transfusion support with irradiated blood products were also given according to the practices of the participating institutions.
After myeloma restaging at day 100, there was no further protocol-mandated therapy. Per physician choice, six patients received maintenance therapy, four with thalidomide, one received alpha interferon, and another subjected to the combination of thalidomide and interferon.
Regimen-related toxicity was graded according to the Seattle criteria reported by Bearman et al. . In this system, toxicity is graded on a scale of 1–4 in 7 organ systems. In general, grade 1 is mild, grade 2 is moderate but requires therapy, grade 3 is severe, and grade 4 is fatal. As this study was conducted before the Uniform International Response criteria was established, a modification of the European Group for Blood and Marrow Transplantation (EBMT)/International Bone Marrow Transplant Registry (IBMTR) criteria were used to evaluate responses at day 100 after ASCT [21, 22]. A VGPR was defined as ≥90% reduction in serum monoclonal protein and near CR (nCR) was defined as meeting all criteria for CR except for residual immunofixation positivity in the blood or urine. Progressive disease was defined by the EBMT/IBMTR criteria. OS and PFS were calculated using the method of Kaplan and Meier. Univariate analysis was performed using the log rank statistic, and multivariate analysis utilized the Cox regression method. PFS was calculated from the date of stem cell infusion, day 0, until the date of disease progression or death without progression, while OS was calculated from day 0 until death from any cause. Patients were censored at the date of last follow-up. We defined treatment-related mortality as death from any cause within the first 100 days from the transplant.
Between May 1999 and October 2003, 57 patients with MM, 52 who had not progressed following induction with conventional chemotherapy, were entered into this trial in the four participating centers: University of Kentucky Markey Cancer Center, Medical College of Wisconsin, University of Maryland Greenebaum Cancer Center, and Thomas Jefferson University Medical Center. Patient characteristics are listed in Table 1. The median age was 54 (range 35–66) years. At diagnosis, the median beta 2-microglobulin level was 3.0 (0.8–22.4) mg/L, with a median level before transplant of 1.97 (range 0.79–10.5) mg/L. Cytogenetic analyses were not performed routinely during this period; conventional karyotyping was available in only 17 patients, with 2 patients demonstrating a 13q deletion and 15 patients had normal cytogenetics. Fifty two of 57 patients (92%) had chemotherapy-sensitive disease before ASCT, defined as at least a 50% decline in the level of the monoclonal protein compared with diagnosis. The median interval from diagnosis to ASCT was 7.5 months.
All patients tolerated both amifostine infusions without interruption, although several patients received supplemental calcium gluconate infusions to treat amifostine-associated hypocalcemia. The regimen-related toxicity (graded by Bearman criteria) observed after MEL 280 and ASCT is summarized in Table 2. Of note, 25 patients (43%) experienced no mucosal toxicity, while 24 (41%) developed only grade 1 mucositis. Eight (14%) had grade 2 mucositis, with pain and/or ulceration requiring a continuous intravenous narcotic infusion, and only 1 patient (1.7%) experienced grade 3 toxicity with severe mucositis resulting in aspiration pneumonia. Other serious non-hematologic toxicities were uncommon: one patient experienced grade 3 renal insufficiency (reversible increase in creatinine greater than twice the baseline level), while the patient with grade 3 mucositis also had grade 3 pulmonary toxicity, requiring ventilator support. Grade 2 central nervous system toxicity, characterized by somnolence with confusion not explainable by other causes, was observed in three individuals; one of these also developed posterior reversible encephalopathy syndrome (PRES) with reversible cortical blindness; this syndrome has previously been reported occasionally in autologous and more commonly after allogeneic stem cell transplantation [23, 24]. This patient recovered completely and a neurologic clinical diagnosis was PRES. Grade 2 cardiac toxicity, defined as fluid retention requiring diuretic therapy, was seen in 3 patients (5%). However, four patients experienced atrial fibrillation and/or flutter requiring intervention. Only 1 patient (1.7%), the one with grade 3 mucosal and pulmonary toxicity, died of transplant-related toxicity due to multiorgan failure.
The absolute neutrophil count reached 0.5 × 109/L on a median of 12 days (range 6–40 days) post-ASCT. The median day the last platelet transfusion was administered was day 13 (range 7–32) after ASCT.
Response and survival
The day 100 response rates achieved are noted in Table 3. Of the 57 patients evaluable, 28 (49%) achieved a CR, while 4 (11%) achieved a VGPR within the first 100 days. The overall response rate at 100 days was 90%.
At a median follow-up of 7 years, 24 (43%) of the 57 patients are alive. Of these, 19 (76%) are alive after progression of MM. Of the 33 patients who died, 29 (88%) have died from progressive myeloma while 4 (12%) have succumbed from non-relapse causes, including myocardial infarction on day 1228 in 1, lung carcinoma on day 674 in 1, and graft-vs.-host disease on day 1386 following an allogeneic transplant performed for recurrent myeloma. Transplant-related mortality was 1.7% since 1 patient died on day 25 due to mucositis from melphalan resulting in aspiration pneumonia requiring ventilatory support. The patient succumbed to complications of septic shock from the pneumonia.
Figure 1a illustrates the actuarial PFS curve for the entire group of patients. The 7-year PFS was 10% with a median PFS of 22 months (95% confidence interval 1.28–2.39 years). The 7-year OS was 39%, with a median OS of 67 months (95% CI 25-53%). In multivariate analysis, higher stage disease (Durie–Salmon 3B vs. others) and elevated beta-2 microglobulin were associated with inferior PFS while thalidomide use prior to transplant resulted in superior PFS (Table 4). Similarly, higher-stage disease (Durie–Salmon 3B vs. others) and chemotherapy resistance prior to ASCT were associated with higher mortality (Table 5).
The results of this series demonstrate the feasibility and long-term safety of using MEL 280 with amifostine as a cytoprotective agent. The infusions of amifostine were not interrupted in any patient due to side effects. Of note, 84% of patients experienced grade 0–1 mucosal toxicity, including 43% with no toxicity despite the use of this high dose of melphalan. Only 14% experienced grade 2 toxicity and only 1 (1.7%) developed severe mucositis with multi-organ failure. These results are similar to the toxicity seen with melphalan at doses of 200 mg/m2 in the IFM 9502 trial comparing pretransplant intensive regimens. Moreau et al. noted severe mucositis in 30% of patients given melphalan 200 mg/m2 (MEL 200) [2, 13]. A prospective audit of oral mucositis performed by the EBMT reported that only 10% of myeloma patients treated with MEL 200 did not develop some degree of mucositis . However, since this analysis used the World Health Organization (WHO) oral toxicity grading scale, which is largely based on the ability to aliment, direct comparison of the extent of mucositis in the remaining patients with that seen in our patients is difficult. Finally, in a randomized trial, Spencer et al. reported that 11% of 47 patients treated with MEL 200 did not develop any mucositis, while 33% suffered from grade 3–4 toxicity using the WHO criteria. Among 43 patients who received a single dose of amifostine 910 mg/m2 before MEL 200, the proportion of patients who did not experience any mucosal toxicity was 21%, while the rate of severe mucositis was reduced to 12% . In contrast, Bensinger et al. completed a randomized trial of MEL 280+amifostine vs. MEL 200+amifostine . They reported a mild increase in GI toxicity in the MEL 280 vs. MEL 200 groups: gastrointestinal 11 vs. 6 patients; mucositis 7 vs. 3 patients, respectively. In addition, the MEL 280 group had slightly prolonged hospitalizations but there were no transplant-related mortality (TRM) in the 66 patients randomized to MEL 280. Therefore, amifostine was efficacious in decreasing the incidence and severity of mucositis in patients treated with MEL 200 as well as when doses of 280 mg/m2 were administered.
The non-hematologic regimen-related toxicities observed in other organ systems were also manageable. The TRM was only 1.7%, which is again comparable to that seen in series of MM patients given MEL 200. Of note, in the study by Bensinger et al., no TRM was observed in 66 patients treated with MEL 280+amifostine. However, 5% patients developed atrial fibrillation and/or flutter. This arrhythmia has been described previously shortly after high-dose melphalan, and the temporal relationship is suggestive of a causative role [28, 29]. The other non-hematologic toxicities observed were comparable to observations by Bensinger et al. providing two studies with >110 patients treated with MEL 280 with acceptable toxicities.
Our regimen of escalated melphalan at 280 mg/m2 produced a CR rate of 49%, with a 7-year PFS of 10% and an OS of 39%. Comparing the results with the other prenovel agent era studies, it is notable that the median OS and EFS are similar to tandem ASCT  (IFM 94) from the same era. Our study was done in an era where induction therapy for MM was inadequate compared with modern novel agent based combinations in which triplets are routinely used (proteasome inhibitors, immunomodulatory agents, corticosteroids). However, the more recent MEL 280 vs. MEL 200 study by Bensinger et al. reported lower response rates: 39% ≥nCR and ≥PR 70%, possibly due to different eligibility criteria: the median number of prior therapies was 2 vs. 1 in our study . Similar to our study, genetic risk stratification of MM was not available to the majority of these patients. The successful dose escalation of melphalan conditioning to 280 mg/m2 may offer a way to avoid tandem ASCT. Even in the current era, tandem ASCT seems to offer depth of response that translates to a survival advantage as demonstrated in the HOVON65 study by Sonneveld et al. and the recent data from EMN02 study presented by Cavo et al. [10, 30]. Similarly in the novel agent era, two randomized studies have suggested superior OS for early tandem ASCT over an approach of non-transplant consolidation followed by delayed ASCT at relapse [4, 5].
Disappointingly, median PFS was approximately 22 months, whereas median OS was 67 months, perhaps reflecting the availability of novel agents at relapse for this population who did not receive them in induction. Again, similar results were reported by Bensinger et al.: the estimated 1- and 3-year PFS was 77% and 53%, respectively, for MEL 280. The risk of failure (death or progression) was similar (hazard ratio for MEL 280 vs. MEL 200 of 1.12). Of note, they did not observe a difference in OS between the two groups. Despite promising CR rates, long-term PFS and OS in our cohorts are similar to standard ASCT trials of the time. We are limited by the lack of modern risk and stage stratification tools and more modern response measures such as stringent CR (sCR) and MRD negativity. Current studies indicate that MRD negativity rates and sCR rates are more accurately correlated with PFS and OS compared with traditional CR rates [31, 32].
In summary, MEL 280 can be administered safely before ASCT and produces a high overall response rate of 90%. However, deeper responses did not result in PFS and OS outcomes superior to historical trials of tandem ASCT or even single ASCT using MEL 200. Amifostine has cytoprotectant properties and the possibility that a myeloma stem cell population was protected cannot be excluded. Notably, such a tumor-protective effect has not been noted in trials of this agent in other malignancies nor in other myeloma trials utilizing MEL 200. However, both the current trial and the Bensinger et al. trial report similar unspectacular PFS compared to historical controls, even in the setting of higher response rates, implying the potential for tumor-protective effect. Alternatively, the absence of improvement in outcomes may be a reflection of small, heterogeneous populations of myeloma patients. Based on these data, the routine use of amifostine and melphalan dose escalation beyond 200 mg/m2 cannot be recommended. Cost concerns (including the cost of amifostine) and the much-improved outcomes reported in the more modern transplant studies using MEL 200 (albeit in the context of superior induction and maintenance) suggest that conditioning should be studied again in the modern context. Recent developments such as the availability of propylene glycol-free melphalan  and development of melphalan-based combinations (such as busulfan–melphalan; busulfan–melphalan–bortezomib) [34, 35] indicate that there are many avenues to improve conditioning in myeloma in order to effect deeper responses.
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The authors declare that they have no conflict of interest.
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Hari, P., Reece, D.E., Randhawa, J. et al. Final outcomes of escalated melphalan 280 mg/m2 with amifostine cytoprotection followed autologous hematopoietic stem cell transplantation for multiple myeloma: high CR and VGPR rates do not translate into improved survival. Bone Marrow Transplant 54, 293–299 (2019). https://doi.org/10.1038/s41409-018-0261-y
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