More on that NIH article -- cure is out there!

A kindly if mysterious email from an address ending in .fi (Finland?) attached the NIH article for me, which I reproduce here minus the tables.

There are a few big points here.   The first is that a plateau was observed after 10 years of continuous complete remission.   The second is that MEDIAN progression free survival for someone who reached complete remission through a simply induction of VAD and one or two transplants without no novel agents was over ten years.  That means more than half of the people that reached complete remission were still in remission 10 years later -- and in that group NOT ONE relapse after 10 years.

The issue is that with VAD and Melphalan (the transplant chemo) only, the CR rate was only 19%.  That's clearly not good enough.  But in Total Therapy, the CR rate of standard risk patients is 60% -- higher if one considers trace levels of M protein to be a return to a "cure with MGUS" state (although it must be said that the study I'm about to quote did not group such persons into the CR group, and so they did not have this same outcome -- albeit they also didn't have the novel agents that Total Therapy uses).

At any rate, a plateau exists in this study.  That's great news, and certainly corroborates the claim that Arkansas has made about the disease being curable.

The study itself, with apologies for ugly formatting but I do have a day job after all.  :)

Long-Term Results in Multiple Myeloma After High-Dose Melphalan and Autologous Transplantation According to Response Categories in the Era of Old Drugs
Massimo Martino,1 Maurizio Postorino,2 Giuseppe Alberto Gallo,1 Giuseppe Messina,1 Santo Neri,6 Eugenio Piro,4 Massimo Gentile,7 Tiziana Moscato,1 Renza Monteleone,1 Roberta Fedele,1 Carla Mazzone,7 Giuseppe Console,1 Giuseppa Penna,5 Caterina Alati,3 Iolanda Donatella Vincelli,3 Giuseppe Irrera,1 Caterina Musolino,5 Francesca Ronco,3 Stefano Molica,4 Fortunato Morabito7

Abstract

We investigate the prognosis of multiple myeloma in 173 patients treated with high-dose melphalan and autologous transplantation in the era of old drugs. The relapse rate is low for patients in complete remission after 10 years of follow-up with a PFS and OS values of 58% and 70%. The achievement of depth response represents the most important prognostic factor.

Background: The aim of this study was to investigate the correlation between the long-term prognosis of multiple myeloma (MM) and the quality of response to therapy in a cohort of 173 patients treated with high-dose melphalan (HDM) and autologous transplantation in the era of old drugs. 

Patients and Methods: A total of 173 patients with de novo MM who received a transplant between 1994 and 2010 were analyzed. VAD (vincristine, doxorubicin [Adria- mycin], dexamethasone) was used as front-line regimen before auto-HPCT. The conditioning was HDM 200 mg/m2. Patients were evaluated for clinical response using the criteria from the European Group for Blood and Marrow Transplantation, modified to include near complete remission (nCR) and very good partial remission (VGPR). 

Results: The response distribution after transplantation in our series was complete remission (CR) in 33 cases (19%), nearly complete remission (nCR) in 38 cases (22%), VGPR in 30 cases (17%), partial remission (PR) in 65 cases (38%), and stable disease (SD) in 7 cases (4%). Patients were followed for 48 ` 36 months. Median overall survival (OS) was not reached for the CR group. Progression-free survival (PFS) was 122 months for CR, 55 months for nCR, 56 months for VGPR, 32 months for PR, and 22 months for SD. Significant differences in PFS and OS were found between the CR and nCR groups (P 1⁄4 .003 and P 1⁄4 .001, respectively), between the CR and VGPR groups (P 1⁄4 .002 and P 1⁄4 .001, respectively), and between the CR and PR groups (P 1⁄4 .000 and P 1⁄4 .001, respectively). Responses were clustered in 3 main categories, ie, CR, nCR þ VGPR þ PR, and SD. The respective 10-year PFS and OS values were 58% and 70% for CR, 15% and 18% for nCR þ VGPR þ PR, and 0% and 0% for SD. 

Conclusion: The achievement of depth and prolonged response represents the most important prognostic factor. The relapse rate is low for patients in CR after 10 years of follow-up, possibly signifying a cure. [emphasis mine]

Introduction

The treatment of multiple myeloma (MM) is in continuous and rapid evolution. Drugs currently used for the treatment of this disease include alkylating agents, corticosteroids, proteasome in- hibitors, immunomodulatory drugs, and anthracyclines.1 Patients who are considered potential candidates for autologous hemato- poietic progenitor cell transplantation (AHPCT) receive 2 to 4 cycles of a nonmelphalan-containing regimen and then proceed to stem cell harvest.2 For many years, VAD or pulsed high-dose dexamethasone (HDD)3 were used as frontline induction therapy, but now the strategy has changed with new agents such as immu- nomodulatory drugs and proteasome inhibitors, bortezomib in particular. Before the advent of new drugs, the complete remission (CR) rate after induction therapy was < 10%, and several trials have shown an association between depth of response to therapy and long-term outcome.4 New induction regimens offer high overall response rates, approaching levels previously noted only with AHPCT.5 Combined treatment based on novel-agent induction regimens and high-dose chemotherapy (HDC) provide further improvement in the depth of response,6,7 and for this reason, MM remains the leading indication for AHPCT worldwide,8,9 and the International Myeloma Working Group recommends that AHPCT be offered at some point during the course of treatment to a medically fit patient.10

As a contribution to the field of HDC and AHPCT in MM, we report the results of this therapeutic approach in patients coming from a regional network and treated during the era of the old drugs. We analyzed correlations between prognosis and different response categories after long-term follow-up.

Patients and Methods

A total of 173 patients with de novo MM who received AHPCT between 1994 and 2010 were analyzed. Main patient characteristics at diagnosis are summarized in Table 1. The induction chemo- therapy was performed in 6 different institutions in southern Italy. One hundred forty-six patients underwent a single transplantation and 46 patients had a tandem transplantation.
Table 1 Main Patient Characteristics at Diagnosis

VAD was used as a frontline regimen before AHPCT. The source of stem cells was peripheral blood stem cells in all cases. Stem cells were collected after cyclophosphamide mobilization at doses ranging from 3 to 4 g/m2 in association with granulocyte colony-stimulating factor 5 mg/kg. The conditioning HDC was high-dose melphalan (HDM) 200 mg/m2.

Information about response status after transplantation, evaluated simultaneously by electrophoresis (EP) and immunofixation (IF) for serum and urinary M-protein, was available for all cases. Patients were evaluated for clinical response using the criteria from the European Group for Blood and Marrow Transplantation,11 which was modified to include nearly complete remission (nCR) and very good partial remission (VGPR). Patients were divided into different groups: CR, defined as absence of a detectable M-component in serum and urine by IF in 2 measurements over 6 weeks and < 5% plasma cells in the bone marrow; nCR, defined by a negative EP result but positive detection of an M-component by IF; VGPR, defined by detection of an M-component at EP e/o IF and reduc- tion in M-component levels between 90% and 99%; partial remission (PR), defined by an M-component reduced to between 50% and 90%. The remaining patients were considered non- responders, both with progressive disease (PD) or stable disease (SD). Patients with progressive disease were excluded from analysis.

Patients were followed until death or the end of the study, and all participants were monitored by both EP and IF in serum and urine throughout follow-up. In this period, a relapse was considered a major event and it was defined as follows: in patients with CR, by recurrence of a detectable M-component on IF, even with negative EP results; in those with nCR, by a positive EP; in those with VGPR, PR, or SD by an increase of > 25% compared with the lowest M-component level previously achieved.

The evaluation of response was performed after a median time of 3.6 months (range, 3.0-6.7 months) from transplantation, and the follow-up was started at the time of response assessment and included all patients.12 Progression-free survival (PFS) was measured from the start of follow-up to the date of progression, relapse, or death; patients alive and event free were censored at the date of the last clinical control. OS was calculated from the start of follow-up to date of death or last follow-up visit.

The statistical analysis according to the different response categories was performed using SPSS software (SPSS Inc, Chicago, IL). Data are expressed as mean ` SD, survival curves were calculated according to the Kaplan-Meier method, and differences between curves were evaluated with the log-rank test. P values < .05 were considered to reflect statistical significance. Death and event rate were calculated as number of deaths (or events) per 100 patients per year.

Results

The response distribution after AHPCT in the series was 33 cases of CR (19%), 38 cases of nCR (22%), 30 cases of VGPR (17%), 65 cases of PR (38%), and 7 cases of SD (4%) (Table 2).

Patients were followed for 48 +/- 36 months. Median survival was not reached for the CR group [emphasis mine]; PFS and OS curves are reported in Figures 1 and 2, respectively. The median PFS was 122 months for patients who achieved CR [emphasis mine], 55 months for patients who achieved nCR, 56 months for patients who achieved VGPR, 32 months for patients who achieved PR,and 22 months for patients who achieved SD. The median OS decreased in parallel with PFS in the 5 response categories: 166 months (with 9% of patients deceased) for CR, 72 months (34% deceased) for nCR, 69 months (47% deceased) for VGPR, 49 months (71% deceased) for PR, and 29 months for SD.

Significant differences in PFS and OS were found between the CR and nCR groups (P 1⁄4 .003 and P 1⁄4 .001, respectively), between the CR and VGPR groups (P 1⁄4 .002 and P 1⁄4 .001, respectively), between the CR and PR groups (P 1⁄4 .000 and P 1⁄4 .001, respectively), between the CR and SD groups (P 1⁄4 .000 and P 1⁄4 .001, respectively), between the nCR and PR groups (P 1⁄4 .009 and P 1⁄4 .012, respectively), and between the VGPR and PR groups (P 1⁄4 .002 and P 1⁄4 .001, respectively). A statistically significant difference in OS was found between the nCR and VGPR groups (P 1⁄4 .04), whereas no difference was demonstrated in terms

of PFS. The median survival of both PFS (Fig. 1) and OS (Fig. 2) in patients with SD was significantly shorter compared with the other response groups (Figs. 1 and 2).

Based on these results, the responses were regrouped into 3 categories (CR, nCR þ VGPR þ PR, and SD) and an additional survival analysis was performed. As expected, a statistically signifi- cant difference was found among the 3 groups in terms of both PFS and OS. We found a plateau phase in OS after 10 years [BIG emphasis mine!]; the 10-year probability of PFS and OS values were, respectively, 58% and 70% forCR,15%and18%fornCRþVGPRþPR,and0%and0% for SD (Fig. 3).

Because a different median follow-up was revealed among groups, we normalized data calculating the event and death rate, ie, the number of events or deaths per 100 patients per year. Notably, both event (5.5% cases per year) and death (1.5% cases per year) rates of patients with CR were lower compared with patients achieving less profound responses up to roughly 1 log increase in patients with SD (Table 3); however, a 3-fold increase was demonstrated in patients with nCR or VGPR, and a one-third increase was seen in patients with PR. In particular, the death rate was 1.5% for CR cases and increased up to 10-fold in patients with nCR and in those with VGPR, up to 21% and 39% in the PR and SD groups, respectively.

The HDM approach was effective in shifting in CR 23 of 163 patients (14.1%) for whom conventional chemotherapy (CC) failed to produce CR obtained this clinical result after HDM. The clinical outcome for those patients achieving CR before or after HDM did not differ significantly.

Discussion

We report in this study the long-term results in 173 patients with MM who were treated with an induction regimen containing the older drugs and HDM with AHPCT. We found a plateau phase in OS after 10 years, with 70% in the CR group alive at 10 years. The relapse rate is low for patients in CR with > 10 years of follow-up, possibly signifying a cure [again, BIG emphasis mine]. Because this is a retrospective study, many parameters are lacking and making conclusions is difficult, and the favorable results after HDM in patients who achieved CR should be considered with caution considering the potential inclusion criteria biases of a retrospective study. Despite these limitations, our data are useful for providing insight into the selection of patients who might derive maximum benefit from intensive chemotherapy.

Unfortunately, we do not have information available on the posttransplantation therapy after relapse or disease progression, which clearly has a substantial impact on OS; however, most of these patients likely received new drugs. This information would be helpful in understanding the extent to which newer agents contributed to prolonged survival. This is a limitation of the study, but it also has to be considered that at the time HDM was proposed, the new drugs were not available for induction therapy.

The rationale to proceed to HDC with AHPCT was to increase the depth of response,13 and over the past decade this approach has been considered the standard of care for younger patients with newly diagnosed MM14-16 based on an increased rate of CR, prolonged disease-free survival,17-22 and OS17,19 compared with CC in several randomized studies. However, not all the published studies have demonstrated the superiority of AHPCT,20-22 and a systematic review and meta-analysis has shown a significant benefit with single AHPCT in terms of prolonged PFS but not of OS23 In the following years, different studies evaluated the efficacy of additional therapies after AHPCT based on a second autograft with the rationale of reducing residual disease.24-26 The tandem AHPCT approach achieved improvement in OS [ANOTHER BIG EMPHASIS mine],25 even though a survival benefit was seen mainly in those patients in whom at least a VGPR was not achieved after the first transplantation.26 Recently, a Cochrane Review compared tandem AHPCT with single AHPCT as first-line treatment in patients with symptomatic MM with respect to OS, PFS, quality of life, and treatment- or transplantation-related mortality.27 They did not consider any study to be sufficiently informative for contemporary treatment decisions concerning the question of single versus tandem AHPCT in view of inherent biases. In addition, none of the trials integrated the so-called novel agents that are now considered standard treatment for MM.28 Interest in optimizing initial therapy and conditioning regimens before AHPCT remains strong. Numerous new doublet, triplet, quadruplet, and multidrug combinations are available for initial therapy in MM,1 and it is probable that incorporation of novel agents into transplantation programs results in increased rates of immunophenotypic or molecular remissions, or both,10 compared with those reported in the recent past. Moreover, we do not have data about switching induction regimens in patients who achieve only a nCR or PR before transplantation. An appropriate HDC conditioning regimen contributes to the efficacy of AHPCT mainly through the cytoreduction effect, and the development of a more effective approach may help in improving the outcome.29

However, attainment of CR after both induction therapy and AHPCT is 1 of the strongest predictors of long-term outcomes30,31 and represents a major end point of current treatment strategies.32 Moreover, sustained CR is predictive of favorable long-term out- comes,33 and continuous efforts are being made to improve the sensitivity of methods used for CR assessment, including molecular techniques34 and immunophenotyping assays.35,36 In our series HDM was effective at producing a CR in 14.1% of patients for whom CC failed to produce a CR; these patients had an outcome similar to that of patients who underwent transplantation and achieved CR.

The results from our study demonstrate a correlation between depth of posttransplantation response and outcome in the era of the old drugs, confirming previous reports. Moreover, our analysis clearly differentiated patients achieving CR (negative on IF) from those achieving nCR (positive on IF). These data are in line with a Spanish study32 in which results from a large series of uniformly treated patients demonstrated an association between quality of response after transplantation and both event-free survival (EFS) and OS. Patients achieving CR had significantly longer EFS (median, 61 vs. 40 months) and OS (medians not reached) versus patients achieving nCR, who likewise had somewhat better outcomes compared with patients achieving PR (median EFS, 34 months vs. nCR; median OS, 61 months).

In a recent study, Martinez-Lopez et al showed that achieving CR after HDC and AHPCT is the most important prognostic factor in MM, even after long-term follow-up.37 The relapse rate was low in patients who maintained a CR after > 11 years of follow-up. [My emphasis -- another corroborating study!] In this study, the median OS for the CR category was 7.6 years.

A recent meta-analysis, including 10 prospective trials38 in MM, showed that the depth of the response to treatment in this disease, particularly CR defined by an absence of the M-component and absence of plasma cells in the bone marrow, is clearly related to a better OS and PFS, but in some trials CR and nCR and VGPR were analyzed together,17,25,39 whereas our and other authors’ data33 indicate that these posttransplantation response categories are different regarding their impact on long-term disease outcome.

The prevailing opinion is still that myeloma is an incurable disease. Nevertheless, in our cohorts, none of the patients main- taining a CR 10 years after HDC and AHPCT experienced a relapse of disease, thus suggesting that a small fraction of patients with a long-term CR can be cured. [HUGE EMPHASIS MINE].  This emphasizes the importance of response stability over time in MM33,40,41 and reinforces the idea of using maintenance treatments to avoid recurrence of the disease and to increase the response rate. However, this does not mean that additional treatment that drives more patients into CR also gives them a better prognosis. Neither is the correlation of CR-longer survival an argument for maintenance therapy. The benefit of these additional approaches has to be proved by randomized trials.
Another concern is that IF, used to assess response status after transplantation, has well-known limitations, and it is a subjective and sometimes difficult to interpret method. The introduction of more objective and sensitive methods,34,36 including imaging techniques42 to assay response, will not replace IF but could lead to a deeper evaluation of the response to treatment.

In conclusion, the achievement of depth and prolonged response after AHPCT represents the most important prognostic factor, supporting the concept that a small cure rate could also be achieved in patients treated with old drug combinations as induction and consolidated with an AHPCT. 

Author Contributions
Study concepts: MM, MP, and FM
Study design: MM, MP, and FM
Data acquisition: MM, MP, GAG, GM, SN, EP, TM, RF, GC,
GI, CA, IDV, CM, FR, SM, and FM
Quality control of data and algorithms: MM, MP, GAG,
and FM
Data analysis and interpretation: MM, MP, and FM Statistical analysis: MM and MP
Manuscript preparation: MM, MP, and FM Manuscript editing: MM, MP, and FM
Manuscript review: MM, MP, GAG, and FM

Acknowledgments
We wish to thank all the centers in southern Italy that gathered all relevant information to locate eligible patients and performed data management: Hematology and Bone Marrow Transplant Unit, Reggio Calabria (Pasquale Iacopino, Elisabetta Massara); Hema- tology Unit, Reggio Calabria (Francesco Nobile, Vincenzo Callea, Caterina Stelitano); Hematology Unit, Caserta (Antonio Abba- dessa); Hematology Unit, Papardo, Messina (Maura Brugiatelli); Hematology and Oncology Unit, Catanzaro (Maria Grazia Kropp, Rosanna Mirabelli); Hematology Unit, Catanzaro University (Francesco Tassone, Marco Rossi); Hematology Unit, Cosenza (Ernesto Vigna); and Oncology Unit, Rossano Calabro (Francesco Iuliano).

Disclosure
The authors have stated that they have no conflicts of interest. 

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