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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 1  |  Page : 88-93

Impact of early reduction in paraprotein on survival in transplant ineligible myeloma: Lesson from a tertiary cancer center in rural India


1 Department of Clinical Hematology and Medical Oncology, Malabar Cancer Centre, Kannur, Kerala, India
2 Division of Clinical Research and Biostatistics, Malabar Cancer Centre, Kannur, Kerala, India

Date of Submission30-May-2017
Date of Decision18-Aug-2017
Date of Acceptance25-Feb-2018
Date of Web Publication09-Apr-2018

Correspondence Address:
Chandran K Nair
Department of Clinical Hematology and Medical Oncology, Malabar Cancer Centre, Kannur, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_459_17

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 > Abstract 


Introduction: The impact of rapid reduction in paraprotein levels, with induction chemotherapy in myeloma, on treatment outcomes is less clear. There are very few studies in transplant ineligible patients treated with novel agents, correlating an early reduction in paraprotein with survival duration.
Methods: In this retrospective analysis of newly diagnosed multiple myeloma, ineligible for stem cell transplant, paraprotein levels at baseline and 3 months were noted with percentage reduction. Survival analysis was performed with Kaplan–Meier curves and Cox proportional hazard model.
Results: Among a total of 121 patients, 42 (35%), 29 (24%), and 50 (41%) had paraprotein reduction of 100%, 90%–99%, and <90%, respectively from baseline levels at 3 months. Patients with complete disappearance of paraprotein (100% reduction) when compared against those with <100% reduction at 3 months had a trend toward higher overall survival (OS) (3-year OS of 81% vs. 69%, hazard ratio [HR] = 0.54, P = 0.182). However, the progression-free survival (PFS) was significantly higher when these two groups were compared (median PFS of 51 vs. 17 months, HR = 0.33, P ≤ 0.001). When patients with ≥90% reduction were compared with <90% reduction at 3 months, there was significant improvement in both OS and PFS (3-year OS of 80% vs. 48%, HR = 0.24, P = 0.001, median PFS of 38 vs. 14 months, HR = 0.13, P < 0.001).
Conclusions: Achieving a faster and deeper reduction in paraprotein as early as 3 months could lead to significant improvement in PFS.

Keywords: Myeloma, novel agents, paraprotein, rapid, reduction, survival


How to cite this article:
Nair CK, Raghavan V, Bhattacharjee A, Kurup AR. Impact of early reduction in paraprotein on survival in transplant ineligible myeloma: Lesson from a tertiary cancer center in rural India. J Can Res Ther 2020;16:88-93

How to cite this URL:
Nair CK, Raghavan V, Bhattacharjee A, Kurup AR. Impact of early reduction in paraprotein on survival in transplant ineligible myeloma: Lesson from a tertiary cancer center in rural India. J Can Res Ther [serial online] 2020 [cited 2020 Jun 6];16:88-93. Available from: http://www.cancerjournal.net/text.asp?2020/16/1/88/229636




 > Introduction Top


The impact of rapid reduction in paraprotein levels, with induction chemotherapy in myeloma, on treatment outcomes is less clear. In the era of conventional agents (melphalan based), the multicenter phase III HOVON-16 trial had reported that median survival of patients achieving at least 50% reduction in M protein at the end of the first cycle was significantly better than those not achieving the same landmark.[1] On the contrary, in multivariate analysis of a randomized controlled trial, it was reported that patients who had initial rapid reduction in M protein had shorter progression-free survival (PFS).[2] However, the same study showed that those patients who had a lesser initial reduction in M protein had poor PFS. Both these studies included patients treated with chemotherapy alone and not consolidated with high dose melphalan/autologous stem cell transplantation.

Studies looking for a correlation between paraprotein reduction and survival in transplant-eligible patients had also reported contradictory results. Ross et al . had described (with VAD regimen) similar association between early paraprotein reduction with improved posttransplant event-free survival, even though overall survival (OS) benefit was not described.[3] On the other side, a North American retrospective study had reported that rapidity of response in patients treated with steroid-based induction therapy (without novel agents) did not translate into meaningful difference in posttransplant PFS or OS.[4] However, they had observed that patients who fail induction had worse outcome posttransplant, stressing the need for upfront intensive therapy with novel agents.

All of the above-mentioned studies were done at the time of treatment with conventional (older) agents in myeloma. A number of studies looking for such correlation in the era of novel agents are scarce. Moreover, the available rare studies with novel agents were involving patients who underwent high-dose chemotherapy followed by autologous stem cell transplantation.[5] After extensive literature search for studies with the primary aim of correlation between early reduction in paraprotein with survival, we could only find a single report (published in abstract form only) involving novel agents in transplant ineligible patients.[6] With this background, we decided to analyze our cohort of transplant ineligible patients treated with novel agent-based induction chemotherapy and then to explore the treatment outcomes with respect to rapidity of response.


 > Methods Top


This is a retrospective analysis of all cases of newly diagnosed multiple myeloma, ineligible for stem cell transplant, diagnosed and treated between January 2011 and June 2016. An official approval from the Institutional Review Board was obtained before the start of the study. Baseline characteristics of all patients were documented. Paraprotein (M protein) at baseline and at 3 months were noted with percentage reduction. M protein was assessed by agarose gel electrophoresis followed by quantitation by densitometry. Response assessments were done as per the updated International Myeloma Working Group (IMWG) criteria.[7] For calculating survival duration, date of progression and date of death or date of the last follow-up of each patient were noted.

Median follow-up was calculated using Kaplan–Meier (KM) curves by reversing event and censor codes. Overall survival was calculated from the date of diagnosis to date of death or date of the last follow-up. PFS was calculated from the date of diagnosis to the date of progression or date of the last follow-up. Survival was analyzed by KM curves and Cox proportional hazards model. Univariate analyses were performed for variables such as paraprotein percentage reduction at 3 months from baseline (100% vs. <100, ≥90% vs. <90%), response at the end of the induction treatment (complete response [CR] vs. <CR, ≥very good partial response (VGPR) vs. <VGPR), international staging system (ISS), Eastern Cooperative Oncology Group performance status (ECOG PS) (<2 vs. ≥2), and age (<65 vs. ≥65). The analysis was performed with R v 3.2.2 (http://cran.r-project.org.)


 > Results Top


There were a total of 121 patients as per inclusion criteria. Reasons for transplant “ineligibility” were older age, significant comorbidities, negative attitude to transplant and financial constraints. Median age was 63 (range 44–85). Females were slightly overrepresented with male-female ratio of 0.75. Other baseline characteristics were as shown in [Table 1]. Lenalidomide, Thalidomide, and Bortezomib-based induction regimens were administered in 47 (39%), 55 (45%), and 19 (16%) patients, respectively. A median number of cycles were 8 (range, 3–12), 12 (range, 3–12), and 8 (range, 5–10) in Lenalidomide, Thalidomide, and Bortezomib-based protocols, respectively. Other treatment-related details are as shown in [Table 2]. Maintenance treatment was given in 34 (28%) of patients. There were 45 (37%) patients fitting into the criteria for renal dysfunction by IMWG. Among this, 17 patients had creatinine value of <2 mg%, but their creatinine clearance was <40. Fifty four patients (45%) had some form of comorbidities. Treatment-related adverse events were as described in [Table 3]. Among patients who died, the most common cause of death was disease progression (65%). Other common causes included infections (15%) and coronary artery disease (4%).
Table 1: Baseline characteristics of patients

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Table 2: Therapeutic strategies

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Table 3: Treatment.related adverse events

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Paraprotein reduction at 3 months

Among a total of 121 patients, 42 (35%), 29 (24%), and 50 (41%) had paraprotein reduction of 100%, 90%–99%, and <90%, respectively, from baseline levels at 3 months. Response at the end of planned treatment was as shown in [Table 1]. The overall response rate was 78%, with 17% patients achieving CR or better, and 61% patients achieving VGPR or better.

Survival

Median follow-up was 27 months (95% confidence interval [CI]: 25–34). Median overall survival (OS) was not reached for the entire cohort. Estimated 3 s OS was 71% (95% CI: 62–83) [Figure 1]. Median PFS was 24 months (95% CI: 21–36) [Figure 2].
Figure 1: Overall survival for the entire cohort

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Figure 2: Progression-free survival for entire cohort

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Patients with complete disappearance of paraprotein (100% reduction) when compared against those with <100% reduction at 3 months had a trend toward higher OS, even though it was not statistically significant (3-year OS of 81% vs. 69%, hazard ratio [HR] = 0.54, P = 0.182) [Figure 3]. However, the PFS was significantly higher when these two groups were compared (median PFS of 51 vs. 17 months, HR = 0.33, P ≤ 0.001)) [Figure 4]. When patients with ≥90% reduction were compared with <90% reduction at 3 months, there was significant improvement in both OS and PFS (3-year OS of 80% vs. 48%, HR = 0.24, P = 0.001, median PFS of 38 vs. 14 months, HR = 0.13, P < 0.001) [Figure 5] and [Figure 6].
Figure 3: Overall survival by 100% reduction versus <100% reduction

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Figure 4: Progression-free survival by 100% reduction versus <100% reduction

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Figure 5: Overall survival by ≥90% reduction versus <90% reduction

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Figure 6: Progression-free survival by ≥90% reduction versus <90% reduction

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Patients with CR at the end of the treatment compared against those not in CR had significant improvement in both PFS and OS (median PFS 36 vs. 22 months, HR = 0.27, P = 0.01, median OS not reached in either group, P = 0.002). Similarly, achieving VGPR or more was associated with improved PFS, although OS benefit could not be demonstrated (median PFS 35 vs. 12 months, HR = 0.19, P < 0.001, 3 years OS of 74% vs. 66%, HR = 0.53, P = 0.12)

Overall survival was significantly improved for patients with ECOG PS <2 versus ≥2 (3-year OS of 78% vs. 67%, HR = 0.37, P = 0.03). OS was not found to be significantly different for patients in different ISS category (3-year OS 78%, 74%, and 65% in stage I, II, and III respectively, P = 0.30) or for patients with age <65 years versus 65 or more (3 years OS 76% vs. 62, HR = 0.59, P = 0.21). There was no difference in PFS for patients with ECOG PS <2 versus 2 or more (median PFS of 24 months in each group, P = 0.79), for different ISS categories (median PFS of 35, 24, and 21 months in Stage I, II, and III, respectively, P = 0.382), or for patients with age <65 years versus 65 or more (median PFS 26 vs. 24 months, HR = 0.97, P = 0.91).


 > Discussion Top


The primary aim of induction chemotherapy in younger myeloma patients is symptom improvement, improvement of performance status and to prepare the patient for autologous stem cell transplant, if eligible. In older patients, achieving maximum possible response is the primary aim in addition to symptom and performance status improvements. There are enough evidence to suggest that achieving the best possible response, i.e., CR or more leads to improved PFS in myeloma treated with novel agents.[8],[9] However, there is a clear paucity of data on the impact of early reductions in paraprotein levels on survival duration in myeloma patients treated with novel agents. What we tried to address in our small group of patients (all treated with novel agents) is whether achieving best possible response at early time points does have any impact on survival duration.

In our patient cohort, complete or near complete reduction in paraprotein at 3 months resulted in significantly prolonged PFS. There were quite a few similar attempts at studying about this particular correlation in the era of conventional agents in patients treated with chemotherapy alone without intensive treatment/autologous stem cell transplant. Group from the Netherlands had previously reported a similar pattern of observation in myeloma patients treated with melphalan plus prednisolone in phase III HOVON-16 trial.[1] They had shown a significant survival advantage for patients who achieved 50% or more reduction in M protein after the end of the first cycle. In a North American randomized trial of maintenance versus no maintenance of melphalan/prednisolone in responding myeloma patients, it was found that patients with rapid reduction in M protein (as measured by the time required for M protein to reduce to 50% of the baseline value) had shorter survival.[2] However, on the positive side, they had shown that lesser reduction in M protein was associated with worse survival duration.

Similar to the above reports, conflicting results were published in studies involving patients treated with intensive therapy (autologous stem cell transplant). A study from Australian group had reported that among IgG myelomas, 50% or more reduction in paraprotein after the first cycle of VAD chemotherapy predicted better event-free survival at 3 years posttransplant even though overall survival benefit was not described.[3] MD Anderson group had reported that when patients undergoing intensive treatment (transplant) were compared against those not, nearly two-thirds of patients with rapid reduction of myeloma protein (T ½ <0.5 months) and reduction to <1 g% after primary therapy achieved CR, and achieving this landmark was associated with better long-term survival posttransplant.[10] On the contrary, a Canadian study could not demonstrate the same advantage of, rapid reduction in paraprotein, on prolonging PFS or OS in myeloma patients undergoing high-dose chemotherapy/autologous stem cell transplant.[4] However, it should be noted that all those patients in the latter study had received only steroid-based induction without novel agents and whether this made the difference is to be sorted out. Also whether undergoing an autologous stem cell transplant nullifies the effect of the early rapid response is to be answered in larger studies.

We assume that the result from our study becomes interesting in the light of the rarity of the existing data looking for the correlation between early deeper reduction in paraprotein and survival in the era of novel agents. A study (published in abstract form only) had shown that early deeper response at 3 months was associated with improved PFS and OS in elderly patients treated with bortezomib/melphalan/prednisolone combination.[6] Apart from this, the available studies with novel agents, in this context, have not shown such a positive correlation as we got from our data. In a recent publication, it was shown that the mean percent reduction in M protein at 6 weeks' time point was not significantly different between patients achieving more than or equal to VGPR versus those achieving PR.[11] However, this study did not look for survival outcomes with relation to paraprotein changes. In a tandem autologous transplant trial (total therapy 3), patients had received induction therapy with a combination of bortezomib and thalidomide-based regimen and were monitored for reduction in serum-free light chain levels. Patients with 96%–100% reduction in light chains after cycle 1 had inferior survival.[5] The exactly opposite result (as compared with results from the present study) has to be interpreted with caution as it is a well-established concept that the half-life of free light chains is much shorter than that of intact immunoglobulin paraproteins.[12]

Of late, there are many upcoming and enough evidence for the relation between achieving minimal residual disease (MRD) negativity and improved progression-free and overall survival in myeloma patients.[13],[14],[15] Moreover, the many newly available agents in myeloma have been found to induce rapid and deeper response including MRD negativity.[16] We assume that a good percentage of our patients who achieved complete disappearance of paraprotein at 3 months of treatment would have been MRD negative and thus possibly explaining the improved PFS and OS. Moreover, with the background of observations from our study, we firmly believe that future prospective studies can be planned for switching the induction chemotherapy regimen for patients who achieve suboptimal response (
There are evidence from clinical and observational studies showing the benefit of achieving VGPR or more following novel agent-based induction therapy, for prolonging PFS in myeloma.[8],[9],[17] In a large retrospective analysis, involving patients ineligible for stem cell transplant, enrolled in 3 multicenter international trials with novel agents, it was shown that those who achieve CR were found to have significant improvement in PFS and OS compared to patients with VGPR. CR was found to be an independent prognostic marker for better PFS and OS in multivariate analysis also.[18] Similarly, in the phase 3 VISTA trial for transplant ineligible patients, improved PFS was shown for patients attaining CR compared to those who achieve PR, even though there was no OS benefit.[8] In the present study, we could show that achieving CR led to significant improvement in OS and PFS. Also for patients attaining VGPR or better, PFS was superior, even though there was no OS difference.


 > Conclusions Top


We could show that achieving a faster and deeper reduction in paraprotein as early as 3 months could lead to significant improvement in PFS. However, we accept our limitations in the form of being a single-center study, a retrospective one and with a relatively smaller number of patients. Furthermore, we admit that this study did not stratify patients based on cytogenetic risk stratification criteria.[19] As per the existing literature, achieving best possible response could lead to meaningful improvement in survival. Keeping this in mind and with the fortunate luxury of having (and upcoming) a number of newer drugs in the field of myeloma, one should be aiming for better early response and consequently better survival.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Schaar CG, Kluin-Nelemans JC, le Cessie S, Franck PF, te Marvelde MC, Wijermans PW, et al. Early response to therapy and survival in multiple myeloma. Br J Haematol 2004;125:162-6.  Back to cited text no. 1
    
2.
Belch A, Shelley W, Bergsagel D, Wilson K, Klimo P, White D, et al. Arandomized trial of maintenance versus no maintenance melphalan and prednisone in responding multiple myeloma patients. Br J Cancer 1988;57:94-9.  Back to cited text no. 2
    
3.
Ross DM, To LB, Horvath N. Assessment of early paraprotein response to vincristine-doxorubicin-dexamethasone chemotherapy may help guide therapy in multiple myeloma. Intern Med J 2004;34:576-8.  Back to cited text no. 3
    
4.
Prica A, Trieu Y, Xu W, Reece DE, Trudel S, Kukreti V, et al. Rapidity and quality of response to steroid-based induction therapy, without the addition of novel agents, does not affect post transplant outcomes in multiple myeloma. Clin Lymphoma Myeloma Leuk 2013;13:25-31.  Back to cited text no. 4
    
5.
van Rhee F, Bolejack V, Hollmig K, Pineda-Roman M, Anaissie E, Epstein J, et al. High serum-free light chain levels and their rapid reduction in response to therapy define an aggressive multiple myeloma subtype with poor prognosis. Blood 2007;110:827-32.  Back to cited text no. 5
    
6.
Lee HS, Kim YS, Moon JH, Lee WS, Lee JH, Jo JC. Clinical impact of depth of response on 3 months after starting chemotherapy and cumulative dose of bortezomib on survival in elderly patients with multiple myeloma who treated with bortezomib combined melphalan plus prednisolone; How to improve survival rates by longer duration of treatment and early deeper response. Clin Lymphoma Myeloma Leuk 2015;15:e74.  Back to cited text no. 6
    
7.
Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International myeloma working group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15:e538-48.  Back to cited text no. 7
    
8.
Harousseau JL, Palumbo A, Richardson PG, Schlag R, Dimopoulos MA, Shpilberg O, et al. Superior outcomes associated with complete response in newly diagnosed multiple myeloma patients treated with nonintensive therapy: Analysis of the phase 3 VISTA study of bortezomib plus melphalan-prednisone versus melphalan-prednisone. Blood 2010;116:3743-50.  Back to cited text no. 8
    
9.
Mina R, Larocca A, Offidani M, Magarotto V, Caravita T, van der Holt R, et al . Impact of complete response on progression-free survival and overall survival in newly diagnosed myeloma patients treated with autologous stem cell transplantation or conventional chemotherapy: Results of a pooled analysis of 5 phase III trials. Clin Lymphoma Myeloma Leuk 2015;15 Suppl 3:e53-4.  Back to cited text no. 9
    
10.
Alexanian R, Weber D, Giralt S, Dimopoulos M, Delasalle K, Smith T, et al. Impact of complete remission with intensive therapy in patients with responsive multiple myeloma. Bone Marrow Transplant 2001;27:1037-43.  Back to cited text no. 10
    
11.
Hansen CT, Pedersen PT, Nielsen LC, Abildgaard N. Evaluation of the serum free light chain (sFLC) analysis in prediction of response in symptomatic multiple myeloma patients: Rapid profound reduction in involved FLC predicts achievement of VGPR. Eur J Haematol 2014;93:407-13.  Back to cited text no. 11
    
12.
Mead GP, Carr-Smith HD, Drayson MT, Morgan GJ, Child JA, Bradwell AR, et al. Serum free light chains for monitoring multiple myeloma. Br J Haematol 2004;126:348-54.  Back to cited text no. 12
    
13.
Anderson KC. Progress and paradigms in multiple myeloma. Clin Cancer Res 2016;22:5419-27.  Back to cited text no. 13
    
14.
Landgren O, Rajkumar SV. New developments in diagnosis, prognosis, and assessment of response in multiple myeloma. Clin Cancer Res 2016;22:5428-33.  Back to cited text no. 14
    
15.
Munshi NC, Avet-Loiseau H, Rawstron AC, Owen RG, Child JA, Thakurta A, et al. Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: A Meta-analysis. JAMA Oncol 2017;3:28-35.  Back to cited text no. 15
    
16.
Landgren O, Iskander K. Modern multiple myeloma therapy: Deep, sustained treatment response and good clinical outcomes. J Intern Med 2017;281:365-82.  Back to cited text no. 16
    
17.
Harousseau JL, Avet-Loiseau H, Attal M, Charbonnel C, Garban F, Hulin C, et al. Achievement of at least very good partial response is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dose therapy: Long-term analysis of the IFM 99-02 and 99-04 trials. J Clin Oncol 2009;27:5720-6.  Back to cited text no. 17
    
18.
Gay F, Larocca A, Wijermans P, Cavallo F, Rossi D, Schaafsma R, et al. Complete response correlates with long-term progression-free and overall survival in elderly myeloma treated with novel agents: Analysis of 1175 patients. Blood 2011;117:3025-31.  Back to cited text no. 18
    
19.
Stewart AK, Bergsagel PL, Greipp PR, Dispenzieri A, Gertz MA, Hayman SR, et al. Apractical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy. Leukemia 2007;21:529-34.  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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