- Email: [email protected]
Recent advances in understanding multiple myeloma
Accepted Manuscript Recent Advances in Understanding Multiple Myeloma Parameswaran Hari PII: DOI: Reference:
S1658-3876(17)30041-9 http://dx.doi.org/10.1016/j.hemonc.2017.05.005 HEMONC 179
To appear in:
Hematology/Oncology and Stem Cell Therapy
Received Date: Accepted Date:
12 January 2017 30 January 2017
Please cite this article as: P. Hari, Recent Advances in Understanding Multiple Myeloma, Hematology/Oncology and Stem Cell Therapy (2017), doi: http://dx.doi.org/10.1016/j.hemonc.2017.05.005
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Recent Advances in Understanding Multiple Myeloma Parameswaran Hari * Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, USA * Corresponding author. Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. E-mail address: [email protected] (P. Hari). Running title:
Abstract There have been major recent advancements in the understanding and management of multiple myeloma which in turn has led to unprecedented survival outcomes for patients. Diagnostic and response criteria have been recently revised. Our understanding of clonal progression, evolution, and clonal tides will inform therapeutic choices and appropriate treatment for patients. Response rates to initial induction with modern triplet therapies containing proteasome inhibitors and immunomodulators have made this approach the global standard for initial treatment. Although the relevance of autologous transplantation has been questioned in the setting of modern induction therapy, we have new data suggesting its continued relevance. Recent studies performed in the context of novel agent induction suggest that autologous transplantation continues to improve response rates and progression-free survival, thus underscoring its role in transplant-eligible patients. Emerging paradigms in the treatment of multiple myeloma include immune approaches, such as adoptive cellular therapies, vaccines, or antibodybased immune manipulations, all of which seem to synergize with a transplant platform. Allogeneic transplantation is limited in scope by the concern of prohibitive toxicity and is applicable mainly to younger patients with high-risk disease. However, the allogeneic approach offers even more options of immunotherapy at relapse, including donor lymphocyte infusions, immunomodulatory drug maintenance, and withdrawal of immune suppression. Keywords
Introduction Multiple myeloma (MM) is characterized by a clonal expansion of malignant plasma cells resulting in end organ damage, including lytic bone lesions, anemia, renal failure, or hypercalcemia. Our understanding of MM biology and its management have evolved rapidly in recent years.1 Concomitant with the increasing incidence of MM in the United States to almost 30,000 patients annually, mortality has trended down in the last decade, resulting in an increased prevalence of MM.2,3 A major contributor to the decline in mortality has been the adoption of autologous hematopoietic cell transplantation (AHCT), which has been a mainstay of therapy for more than 2 decades.4 However, almost all patients relapse following AHCT, and current strategies focus on reducing progression and improving progression-free survival (PFS) using post-AHCT consolidation and/or maintenance therapies.5 Other studies have attempted to delay the use of AHCT until relapse or exclude it altogether by exploring randomized comparisons of planned upfront AHCT versus at relapse.
Does autologous transplantation still have a role in the management of MM? High-dose therapy (HDT) followed by autologous stem cell transplantation was the standard of care for transplant-eligible patients before the advent of novel targeted agents, such as immunomodulatory drugs (IMIDs) (thalidomide/ lenalidomide/ pomalidomide) and proteasome inhibitors (bortezomib/ carfilzomib). In a series of randomized trials, AHCT was uniformly associated with improved response rates and PFS, and approximately half of the studies showed an overall survival benefit and superior quality of life (41, 42). One of the studies designed to address the question of
early versus late AHCT (43), patients undergoing AHCT were found to have longer time without symptoms and treatment, and thus the patients with AHCT were found to have improved quality of life. Given the unprecedented response rates with novel agents, the role of AHCT as routine frontline therapy in all eligible patients has been questioned.6 Novel agent induction combinations have significantly improved the rate of complete response (CR), and minimal residual disease negativity, both surrogates for improved survival.7 The early versus late AHCT question in the novel agent era was investigated in a number of randomized trials,8–11 including most recently in four major international studies (Table 1). The Intergroupe Francophone du Myélome (IFM) group along with Dana-Farber Cancer Institute (DFCI) treated transplant-eligible patients with three cycles of lenalidomide/bortezomib/dexamethasone (RVD) induction followed by randomization to upfront versus delayed AHCT. In the upfront AHCT arm, AHCT was followed by two cycles of RVD consolidation and subsequently lenalidomide maintenance. Patients in the delayed AHCT arm underwent stem cell collection followed by five additional cycles of RVD consolidation and then lenalidomide maintenance. Preliminary results from the IFM group were presented in December 2015 and indicated a PFS benefit for upfront AHCT arm, although with no survival advantage. The DFCI portion of the trial uses lenalidomide maintenance until disease progression, whereas the results reported above by the IFM are limited to patients using maintenance for 1 year. A large ambitious study (EMN02- HOVON95) by the European Myeloma Network (EMN) and Hemato-Oncologie voor Volwassenen Nederland (HOVON) aimed to answer several questions regarding AHCT in MM. Results were recently reported in
abstract form. Initial induction therapy included bortezomib/cyclophosphamide and dexamethasone (VCD) followed by randomization to upfront AHCT or chemotherapy consolidation. The AHCT group received a single or tandem AHCT (1 or 2), whereas the consolidation group received four cycles of bortezomib, melphalan, prednisone (VMP). In addition to the single versus tandem randomization nested within the transplant cohort, there was a subsequent randomization to consolidation with VRD versus observation, following which all patients received lenalidomide maintenance. As with all modern studies of this type, PFS was superior for the transplant arm (66% at 3 years vs. 57.5%; hazard ratio [HR] = 0.73; p = .003). In conclusion, the PFS benefit from an early AHCT even after combination novel agent therapies as induction has been uniformly demonstrated across multiple large randomized studies, confirming the continued role of upfront AHCT. Longer follow-up will be necessary for overall survival results to mature. Novel agent-based triplet induction, frontline early AHCT, and maintenance therapy remains the preferred strategy for transplant-eligible patients outside of clinical trials.
After the first autotransplant: maintenance, consolidation or tandem transplant? The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0702 study randomized patients to one of the three arms: single AHCT with lenalidomide maintenance, single AHCT with RVD consolidation and lenalidomide maintenance, and tandem AHCT with lenalidomide maintenance.12 Recently reported results of this study after 3 years of follow-up indicated no differences between the three cohorts in terms of relapse risk, PFS, or overall survival. The 38-month PFS estimates were 52.2%, 56.7%,
and 56.5% for the lenalidomide maintenance, RVD consolidation, and tandem transplant groups, respectively. While these results suggest that a single AHCT followed by lenalidomide maintenance remains standard, it is notable that preliminary results from randomized subsets from the EMN02 HOVON95 study suggest that RVD consolidation and tandem AHCT were associated with superior PFS.13 In the US, the standard of care therapy after an AHCT remains lenalidomide maintenance until progression.
Autologous transplantation at relapse This should be examined in the context of two different populations: those who relapse after non-transplant-based initial therapy approaches and those who relapse after a prior AHCT. In the latter setting, the term “salvage second transplant” has been used.14 Notably, the randomized studies described in Table 1 and the previous section all predicate AHCT at relapse for the non-transplant cohort and collect autologous hematopoietic cells while the patients are in first remission with the goal of using those cells at relapse. Variable proportions (43–70%) of these patients receive AHCT at relapse indicating perhaps that the feasibility or utilization of a late AHCT is non-uniform despite the ready availability of a stored graft. A pooled analysis of two of these studies was presented by Gay et al15 and indicated that among the non-transplant cohort, those who were able to receive AHCT at relapse had superior survival (HR = 0.57; p = .037). Transplant-naïve patients who relapse following initial therapies should be offered AHCT at the time of first relapse, provided they are still eligible for transplant. One prospective and multiple retrospective studies have explored salvage AHCT in previously autotransplanted patients at relapse.14 In the only randomized phase 3 study
in this setting, Cook et al16 compared salvage AHCT with weekly cyclophosphamide following standard re-induction therapy among patients relapsing 18 months after an initial AHCT. Survival was superior in the salvage AHCT arm compared with the weekly cyclophosphamide arm (median of 67 months vs. 52 months; p = .0169). Chemotherapy sensitivity and remission duration after first AHCT are important prognostic factors for long-term disease control after the salvage AHCT. The International Myeloma Working Group (IMWG) Consensus group recommended that salvage AHCT be not relegated to a “last-ditch effort” in patients who have failed all prior therapies but should be considered an integral component of initial salvage strategies.14 The interval from first AHCT that predicts reasonable clinical benefit for patients receiving salvage AHCT is not clear. Following the IMWG consensus recommendation, I recommend that patients relapsing after 18 months beyond a first AHCT should be considered for a second transplant.
Allogeneic transplantation for myeloma The best established immunotherapy in MM is allogeneic transplantation with a potent and often sustained graft-versus-myeloma (GVM) effect.17 A series of prospective randomized studies, summarized elsewhere,18 explored the role of a tandem AHCT and reduced-intensity conditioning allogeneic stem cell transplants from a matched sibling or unrelated donor. The results of these studies have been discordant, especially in the front line treatment of MM.19,20 Nonetheless, younger eligible patients with well-defined highrisk features should be considered for allogeneic transplant especially within a clinical trial and early in the clinical course (front line or first relapse). The risks of chronic-graftversus host disease (cGVHD) and the need for long-term immunosuppression remain
major challenges. The clinical data that suggest the benefits of adoptive immune therapy in MM include: demonstration of clinically meaningful responses (GVM effect) by donor lymphocyte infusions in patients relapsing after allogeneic transplant,21 complete remission after immunosuppression withdrawal in patients progressing after allogeneic transplant, and the correlation of cGVHD with freedom from myeloma progression after allogeneic transplant.20 Although applicable only to a minority of patients with MM, allogeneic transplant is a valuable tool for establishing long-term disease control and sometimes a cure in carefully selected high-risk patients in whom conventional therapies do not produce similar efficacy.
Immunotherapy in myeloma A variety of novel post AHCT or allogeneic transplant immunotherapeutic strategies are now being explored in MM. These include cellular approaches, such as myeloma-specific T cells (via T cell expansion), marrow infiltrating lymphocytes,22 redirected T cells with chimeric antigen receptors,23 and tumor-based vaccines to induce myeloma-specific immunity in the context of enhanced antigen presentation.24 Inhibitors of PD-1 and PDL-1 are being studied as a means of breaking down MM immune tolerance.25 Though the single agent activity of the anti-PD1 agent nivolumab was unimpressive,26 promising response rates were observed in combination with IMIDs.27 Hematopoietic transplantation provides an ideal platform for additional immune-based therapies. The recovery phase from AHCT (or other lymphodepleting therapy) represents a favorable milieu for adoptive cellular therapy. The homeostatic lymphocyte proliferation following lymphopenia is a context in which immune checkpoint blockers
may also be able to reverse MM-associated T cell exhaustion. Additionally, lymphopenia resulting from AHCT facilitates eliminating tolerogenic antigen presenting cells and induces cytokine release that generates a more favorable environment for adoptive T cell therapy. Indirect evidence suggests that the immune system can contribute to the clinical benefits of AHCT; for example, those with early lymphoid recovery after AHCT have superior long-term outcomes.
Conclusion Although MM has always been considered incurable, many investigators now believe that a significant fraction of patients currently undergoing therapy may be cured.28 The current initial therapy paradigm of induction with combination agents, autologous transplantation, and long-term maintenance can be further improved upon in all of its components. Current trials aim to improve induction and maintenance components with the addition of monoclonal antibodies or newer generation proteasome inhibitors, while transplant conditioning is also an object for further improvement. It is clear that the multi-clonal heterogeneity of MM requires multi-targeted approaches in order to effect a lasting remission or cure.
Conflicts of Interest Statement Acknowledgments
References
1.
Mahindra A, Laubach J, Raje N, Munshi N, Richardson PG, Anderson K. Latest
advances and current challenges in the treatment of multiple myeloma. Nat Rev Clin Oncol 2012;9:135–43. 2.
Turesson I, Velez R, Kristinsson SY, Landgren O. Patterns of improved survival
in patients with multiple myeloma in the twenty-first century: a population-based study. J Clin Oncol 2010;28:830–4. 3.
Ludwig H, Bolejack V, Crowley J, Bladé J, Miguel JS, Kyle RA, et al. Survival
and years of life lost in different age cohorts of patients with multiple myeloma. J Clin Oncol 2011;28:1599–605. 4.
Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, et al. A
prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 1996;335:91–7. 5.
Hari PN, McCarthy PL. Multiple myeloma: future directions in autologous
transplantation and novel agents. Biol Blood Marrow Transplant 2013;19:S20–5. 6.
Braunstein M, Niesvizky R. Deferring autologous stem cell transplantation for
consolidation of minimal residual disease in multiple myeloma. Semin Oncol 2016;43:709–11. 7.
Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, et
al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 2012;120:1801–9.
8.
Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, et al.
Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol 2015;16:1617–29. 9.
Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, et
al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 2014;371:895–905. 10.
Attal M, Lauwers-Cances V, Hulin C, Facon T, Caillot D, Escoffre M, et al.
Autologous transplantation for multiple myeloma in the era of new drugs: a phase III study of the Intergroupe Francophone du Myelome (IFM/DFCI 2009 Trial). Blood 2015;126:391. 11.
Cavo M, Beksac M, Dimopoulos MA, Pantani L, Gay F, Hájek R, et al.
Intensification therapy with bortezomib-melphalan-prednisone versus autologous stem cell transplantation for newly diagnosed multiple myeloma: An intergroup, multicenter, phase III study of the European Myeloma Network (EMN02/HO95 MM Trial). Blood 2016;128:673. 12.
Stadtmauer EA, Pasquini MC, Blackwell B, Knust K, Bashey A, Devine SM, et
al. Comparison of autologous hematopoietic cell transplant (autoHCT), bortezomib, lenalidomide (Len) and dexamethasone (RVD) consolidation with Len maintenance (ACM), tandem autohct with Len maintenance (TAM) and autohct with Len maintenance (AM) for up-front treatment of patients with multiple myeloma (MM): Primary results from the randomized phase III trial of the blood and marrow transplant clinical trials network (BMT CTN 0702-StaMINA Trial). Am Soc Hematology 2016.
13.
Sonneveld P, Beksac M, van der Holt B, Dimopoulos MA, Carella AM, Ludwig
H, et al. Consolidation followed by maintenance therapy versus maintenance alone in newly diagnosed, transplant eligible patients with multiple myeloma (MM): A randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM Trial). Am Soc Hematology 2016. 14.
Giralt S, Garderet L, Durie B, Cook G, Gahrton G, Bruno B, et al. American
society of blood and marrow transplantation, European society of blood and marrow transplantation, blood and marrow transplant clinical trials network, and international myeloma working group consensus conference on salvage hematopoietic cell transplantation in patients with relapsed multiple myeloma. Biol Blood Marrow Transplant 2015;21:2039–51. 15.
Gay F, Magarotto V, Spencer A, et al: Upfront of rescue transplant in young
patients with newly diagnosed multiple lyeloma: a pooled analysis of 529 patients. Haematologica, Ferrata Storti Foundation via Giuseppe Belli 4, 27100 Pavia, Italy, 2016, pp 3-3. 16.
Cook G, Ashcroft AJ, Cairns DA, Williams CD, Brown JM, Cavenagh JD, et al.
The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol 2016;3:e340–51. 17.
Tricot G, Vesole DH, Jagannath S, Hilton J, Munshi N, Barlogie B. Graft-versus-
myeloma effect: proof of principle. Blood 1996;87:1196–8. 18.
Dhakal B, Vesole DH, Hari PN. Allogeneic stem cell transplantation for multiple
myeloma: is there a future? Bone Marrow Transplant 2016;51:492–500.
19.
Gahrton G, Iacobelli S, Björkstrand B, Hegenbart U, Gruber A, Greinix H, et al.
Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study. Blood 2013;121:5055–63. 20.
Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E, et al.
Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol 2011;12:1195–203. 21.
Lokhorst HM, Schattenberg A, Cornelissen JJ, Van Oers MH, Fibbe W, Russell I,
et al. Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stemcell transplantation: predictive factors for response and long-term outcome. J Clin Oncol 2000;18:3031–7. 22.
Noonan KA, Huff CA, Davis J, Lemas MV, Fiorino S, Bitzan J, et al. Adoptive
transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma. Sci Transl Med 2015;7:288ra78. 23.
Garfall AL, Fraietta JA, Maus MV. Immunotherapy with chimeric antigen
receptors for multiple myeloma. Discov Med 2014;17:37–46. 24.
Rosenblatt J, Vasir B, Uhl L, Blotta S, MacNamara C, Somaiya P, et al.
Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor immune responses in patients with multiple myeloma. Blood 2011;117:393– 402.
25.
Rosenblatt J, Glotzbecker B, Mills H, Vasir B, Tzachanis D, Levine JD, et al. PD-
1 blockade by CT-011, anti PD-1 antibody, enhances ex-vivo T cell responses to autologous dendritic/myeloma fusion vaccine. J Immunother 2011;34:409. 26.
Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, et al.
Preliminary results of a phase I study of nivolumab (BMS-936558) in patients with relapsed or refractory lymphoid malignancies. Blood 2014;124:291. 27.
Shah JJ, Jagannath S, Mateos MV, Palumbo A, Kher U, Marinello PM, et al.
KEYNOTE-183: A randomized, open-label phase 3 study of pembrolizumab in combination with pomalidomide and low-dose dexamethasone in refractory or relapsed and refractory multiple myeloma. J Clin Oncol 2016;34. 28.
Barlogie B, Mitchell A, van Rhee F, Epstein J, Morgan GJ, Crowley J. Curing
myeloma at last: defining criteria and providing the evidence. Blood 2014;124:3043–51.
Table 1 Recent Studies of Autotransplant versus Novel Agent Therapy Salvage Induction AHCT versus
ASCT at
Study
consolidation maintenance PFS
Palumbo et al
Rd ×4 for all patients
Median PFS: 4-y OS:
6%
GIMEMA RV-
Tandem AHCT versus
43.0 mo
81.6%
(MEL200)
2099
MPR ×6
(MEL200)
(MEL200)
versus
Re-randomized to R versus versus 22.4 no maintenance
Rd ×4 for all patients
relapse
versus 65.3% 70%
mo (MPR) (p (MPR) (p = < .001)
Gay F et al
OS
(MPR)
.02)
Median PFS: 4-y OS: 86% 21%
RV-MM-EMN- 1 or 2 AHCT versus CRD
43.3 mo
(MEL200)
(MEL200)
4418
×6
(MEL200)
versus 73%
versus
Re-randomization to R
versus 28.6
(CRD) (p =
43%
alone versus R +
mo (CRD) (p .004)
prednisone
< .001)
Attal M et al
RVD ×3 induction for all
3-y PFS:
IFM/DFCI
AHCT + RVD ×2 versus
61% (ASCT) in both arms
200910
RVD ×5
versus 48%
R for 1 y (French)
(RVD)
3-y OS 88%
(CRD)
Not Available
Cavo M et al
VCD × 3–4 for all
EMN02/HO9511 First randomization:
3-y PFS:
Not reported
66% (ASCT)
AHCT(1 versus 2) versus
versus 57.5%
VMP ×4. Second
(VMP)
Not Available
randomization: VRD ×2 versus no consolidation R for both arms until progression AHCT = autologous hematopoietic cell transplantation; ASCT = autologous stem cell transplantation; C = cyclophosphamide; D = dexamethasone; E = ;M = melphalan; mo = month; OS = overall survival; P = prednisone; PFS = progression-free survival; R = lenalidomide; Rd = ;V = bortezomib; y = year.
S1658-3876(17)30041-9 http://dx.doi.org/10.1016/j.hemonc.2017.05.005 HEMONC 179
To appear in:
Hematology/Oncology and Stem Cell Therapy
Received Date: Accepted Date:
12 January 2017 30 January 2017
Please cite this article as: P. Hari, Recent Advances in Understanding Multiple Myeloma, Hematology/Oncology and Stem Cell Therapy (2017), doi: http://dx.doi.org/10.1016/j.hemonc.2017.05.005
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Recent Advances in Understanding Multiple Myeloma Parameswaran Hari * Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, USA * Corresponding author. Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. E-mail address: [email protected] (P. Hari). Running title:
Abstract There have been major recent advancements in the understanding and management of multiple myeloma which in turn has led to unprecedented survival outcomes for patients. Diagnostic and response criteria have been recently revised. Our understanding of clonal progression, evolution, and clonal tides will inform therapeutic choices and appropriate treatment for patients. Response rates to initial induction with modern triplet therapies containing proteasome inhibitors and immunomodulators have made this approach the global standard for initial treatment. Although the relevance of autologous transplantation has been questioned in the setting of modern induction therapy, we have new data suggesting its continued relevance. Recent studies performed in the context of novel agent induction suggest that autologous transplantation continues to improve response rates and progression-free survival, thus underscoring its role in transplant-eligible patients. Emerging paradigms in the treatment of multiple myeloma include immune approaches, such as adoptive cellular therapies, vaccines, or antibodybased immune manipulations, all of which seem to synergize with a transplant platform. Allogeneic transplantation is limited in scope by the concern of prohibitive toxicity and is applicable mainly to younger patients with high-risk disease. However, the allogeneic approach offers even more options of immunotherapy at relapse, including donor lymphocyte infusions, immunomodulatory drug maintenance, and withdrawal of immune suppression. Keywords
Introduction Multiple myeloma (MM) is characterized by a clonal expansion of malignant plasma cells resulting in end organ damage, including lytic bone lesions, anemia, renal failure, or hypercalcemia. Our understanding of MM biology and its management have evolved rapidly in recent years.1 Concomitant with the increasing incidence of MM in the United States to almost 30,000 patients annually, mortality has trended down in the last decade, resulting in an increased prevalence of MM.2,3 A major contributor to the decline in mortality has been the adoption of autologous hematopoietic cell transplantation (AHCT), which has been a mainstay of therapy for more than 2 decades.4 However, almost all patients relapse following AHCT, and current strategies focus on reducing progression and improving progression-free survival (PFS) using post-AHCT consolidation and/or maintenance therapies.5 Other studies have attempted to delay the use of AHCT until relapse or exclude it altogether by exploring randomized comparisons of planned upfront AHCT versus at relapse.
Does autologous transplantation still have a role in the management of MM? High-dose therapy (HDT) followed by autologous stem cell transplantation was the standard of care for transplant-eligible patients before the advent of novel targeted agents, such as immunomodulatory drugs (IMIDs) (thalidomide/ lenalidomide/ pomalidomide) and proteasome inhibitors (bortezomib/ carfilzomib). In a series of randomized trials, AHCT was uniformly associated with improved response rates and PFS, and approximately half of the studies showed an overall survival benefit and superior quality of life (41, 42). One of the studies designed to address the question of
early versus late AHCT (43), patients undergoing AHCT were found to have longer time without symptoms and treatment, and thus the patients with AHCT were found to have improved quality of life. Given the unprecedented response rates with novel agents, the role of AHCT as routine frontline therapy in all eligible patients has been questioned.6 Novel agent induction combinations have significantly improved the rate of complete response (CR), and minimal residual disease negativity, both surrogates for improved survival.7 The early versus late AHCT question in the novel agent era was investigated in a number of randomized trials,8–11 including most recently in four major international studies (Table 1). The Intergroupe Francophone du Myélome (IFM) group along with Dana-Farber Cancer Institute (DFCI) treated transplant-eligible patients with three cycles of lenalidomide/bortezomib/dexamethasone (RVD) induction followed by randomization to upfront versus delayed AHCT. In the upfront AHCT arm, AHCT was followed by two cycles of RVD consolidation and subsequently lenalidomide maintenance. Patients in the delayed AHCT arm underwent stem cell collection followed by five additional cycles of RVD consolidation and then lenalidomide maintenance. Preliminary results from the IFM group were presented in December 2015 and indicated a PFS benefit for upfront AHCT arm, although with no survival advantage. The DFCI portion of the trial uses lenalidomide maintenance until disease progression, whereas the results reported above by the IFM are limited to patients using maintenance for 1 year. A large ambitious study (EMN02- HOVON95) by the European Myeloma Network (EMN) and Hemato-Oncologie voor Volwassenen Nederland (HOVON) aimed to answer several questions regarding AHCT in MM. Results were recently reported in
abstract form. Initial induction therapy included bortezomib/cyclophosphamide and dexamethasone (VCD) followed by randomization to upfront AHCT or chemotherapy consolidation. The AHCT group received a single or tandem AHCT (1 or 2), whereas the consolidation group received four cycles of bortezomib, melphalan, prednisone (VMP). In addition to the single versus tandem randomization nested within the transplant cohort, there was a subsequent randomization to consolidation with VRD versus observation, following which all patients received lenalidomide maintenance. As with all modern studies of this type, PFS was superior for the transplant arm (66% at 3 years vs. 57.5%; hazard ratio [HR] = 0.73; p = .003). In conclusion, the PFS benefit from an early AHCT even after combination novel agent therapies as induction has been uniformly demonstrated across multiple large randomized studies, confirming the continued role of upfront AHCT. Longer follow-up will be necessary for overall survival results to mature. Novel agent-based triplet induction, frontline early AHCT, and maintenance therapy remains the preferred strategy for transplant-eligible patients outside of clinical trials.
After the first autotransplant: maintenance, consolidation or tandem transplant? The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0702 study randomized patients to one of the three arms: single AHCT with lenalidomide maintenance, single AHCT with RVD consolidation and lenalidomide maintenance, and tandem AHCT with lenalidomide maintenance.12 Recently reported results of this study after 3 years of follow-up indicated no differences between the three cohorts in terms of relapse risk, PFS, or overall survival. The 38-month PFS estimates were 52.2%, 56.7%,
and 56.5% for the lenalidomide maintenance, RVD consolidation, and tandem transplant groups, respectively. While these results suggest that a single AHCT followed by lenalidomide maintenance remains standard, it is notable that preliminary results from randomized subsets from the EMN02 HOVON95 study suggest that RVD consolidation and tandem AHCT were associated with superior PFS.13 In the US, the standard of care therapy after an AHCT remains lenalidomide maintenance until progression.
Autologous transplantation at relapse This should be examined in the context of two different populations: those who relapse after non-transplant-based initial therapy approaches and those who relapse after a prior AHCT. In the latter setting, the term “salvage second transplant” has been used.14 Notably, the randomized studies described in Table 1 and the previous section all predicate AHCT at relapse for the non-transplant cohort and collect autologous hematopoietic cells while the patients are in first remission with the goal of using those cells at relapse. Variable proportions (43–70%) of these patients receive AHCT at relapse indicating perhaps that the feasibility or utilization of a late AHCT is non-uniform despite the ready availability of a stored graft. A pooled analysis of two of these studies was presented by Gay et al15 and indicated that among the non-transplant cohort, those who were able to receive AHCT at relapse had superior survival (HR = 0.57; p = .037). Transplant-naïve patients who relapse following initial therapies should be offered AHCT at the time of first relapse, provided they are still eligible for transplant. One prospective and multiple retrospective studies have explored salvage AHCT in previously autotransplanted patients at relapse.14 In the only randomized phase 3 study
in this setting, Cook et al16 compared salvage AHCT with weekly cyclophosphamide following standard re-induction therapy among patients relapsing 18 months after an initial AHCT. Survival was superior in the salvage AHCT arm compared with the weekly cyclophosphamide arm (median of 67 months vs. 52 months; p = .0169). Chemotherapy sensitivity and remission duration after first AHCT are important prognostic factors for long-term disease control after the salvage AHCT. The International Myeloma Working Group (IMWG) Consensus group recommended that salvage AHCT be not relegated to a “last-ditch effort” in patients who have failed all prior therapies but should be considered an integral component of initial salvage strategies.14 The interval from first AHCT that predicts reasonable clinical benefit for patients receiving salvage AHCT is not clear. Following the IMWG consensus recommendation, I recommend that patients relapsing after 18 months beyond a first AHCT should be considered for a second transplant.
Allogeneic transplantation for myeloma The best established immunotherapy in MM is allogeneic transplantation with a potent and often sustained graft-versus-myeloma (GVM) effect.17 A series of prospective randomized studies, summarized elsewhere,18 explored the role of a tandem AHCT and reduced-intensity conditioning allogeneic stem cell transplants from a matched sibling or unrelated donor. The results of these studies have been discordant, especially in the front line treatment of MM.19,20 Nonetheless, younger eligible patients with well-defined highrisk features should be considered for allogeneic transplant especially within a clinical trial and early in the clinical course (front line or first relapse). The risks of chronic-graftversus host disease (cGVHD) and the need for long-term immunosuppression remain
major challenges. The clinical data that suggest the benefits of adoptive immune therapy in MM include: demonstration of clinically meaningful responses (GVM effect) by donor lymphocyte infusions in patients relapsing after allogeneic transplant,21 complete remission after immunosuppression withdrawal in patients progressing after allogeneic transplant, and the correlation of cGVHD with freedom from myeloma progression after allogeneic transplant.20 Although applicable only to a minority of patients with MM, allogeneic transplant is a valuable tool for establishing long-term disease control and sometimes a cure in carefully selected high-risk patients in whom conventional therapies do not produce similar efficacy.
Immunotherapy in myeloma A variety of novel post AHCT or allogeneic transplant immunotherapeutic strategies are now being explored in MM. These include cellular approaches, such as myeloma-specific T cells (via T cell expansion), marrow infiltrating lymphocytes,22 redirected T cells with chimeric antigen receptors,23 and tumor-based vaccines to induce myeloma-specific immunity in the context of enhanced antigen presentation.24 Inhibitors of PD-1 and PDL-1 are being studied as a means of breaking down MM immune tolerance.25 Though the single agent activity of the anti-PD1 agent nivolumab was unimpressive,26 promising response rates were observed in combination with IMIDs.27 Hematopoietic transplantation provides an ideal platform for additional immune-based therapies. The recovery phase from AHCT (or other lymphodepleting therapy) represents a favorable milieu for adoptive cellular therapy. The homeostatic lymphocyte proliferation following lymphopenia is a context in which immune checkpoint blockers
may also be able to reverse MM-associated T cell exhaustion. Additionally, lymphopenia resulting from AHCT facilitates eliminating tolerogenic antigen presenting cells and induces cytokine release that generates a more favorable environment for adoptive T cell therapy. Indirect evidence suggests that the immune system can contribute to the clinical benefits of AHCT; for example, those with early lymphoid recovery after AHCT have superior long-term outcomes.
Conclusion Although MM has always been considered incurable, many investigators now believe that a significant fraction of patients currently undergoing therapy may be cured.28 The current initial therapy paradigm of induction with combination agents, autologous transplantation, and long-term maintenance can be further improved upon in all of its components. Current trials aim to improve induction and maintenance components with the addition of monoclonal antibodies or newer generation proteasome inhibitors, while transplant conditioning is also an object for further improvement. It is clear that the multi-clonal heterogeneity of MM requires multi-targeted approaches in order to effect a lasting remission or cure.
Conflicts of Interest Statement Acknowledgments
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Table 1 Recent Studies of Autotransplant versus Novel Agent Therapy Salvage Induction AHCT versus
ASCT at
Study
consolidation maintenance PFS
Palumbo et al
Rd ×4 for all patients
Median PFS: 4-y OS:
6%
GIMEMA RV-
Tandem AHCT versus
43.0 mo
81.6%
(MEL200)
2099
MPR ×6
(MEL200)
(MEL200)
versus
Re-randomized to R versus versus 22.4 no maintenance
Rd ×4 for all patients
relapse
versus 65.3% 70%
mo (MPR) (p (MPR) (p = < .001)
Gay F et al
OS
(MPR)
.02)
Median PFS: 4-y OS: 86% 21%
RV-MM-EMN- 1 or 2 AHCT versus CRD
43.3 mo
(MEL200)
(MEL200)
4418
×6
(MEL200)
versus 73%
versus
Re-randomization to R
versus 28.6
(CRD) (p =
43%
alone versus R +
mo (CRD) (p .004)
prednisone
< .001)
Attal M et al
RVD ×3 induction for all
3-y PFS:
IFM/DFCI
AHCT + RVD ×2 versus
61% (ASCT) in both arms
200910
RVD ×5
versus 48%
R for 1 y (French)
(RVD)
3-y OS 88%
(CRD)
Not Available
Cavo M et al
VCD × 3–4 for all
EMN02/HO9511 First randomization:
3-y PFS:
Not reported
66% (ASCT)
AHCT(1 versus 2) versus
versus 57.5%
VMP ×4. Second
(VMP)
Not Available
randomization: VRD ×2 versus no consolidation R for both arms until progression AHCT = autologous hematopoietic cell transplantation; ASCT = autologous stem cell transplantation; C = cyclophosphamide; D = dexamethasone; E = ;M = melphalan; mo = month; OS = overall survival; P = prednisone; PFS = progression-free survival; R = lenalidomide; Rd = ;V = bortezomib; y = year.