The celebration of the 50th anniversary of the founding of the American Society of Clinical Oncology provides the occasion to review the progress that has been made in the biology and treatment of multiple myeloma. With the advent of melphalan and cyclophosphamide in the early 1960s the median survival of patients with multiple myeloma more than doubled from 10 months to approximately 24 months. Throughout multiple clinical trials in the 1970s and 1980s, melphalan and prednisone remained the gold standard, with a 3-year survival of 42%. The use of high-dose melphalan with autologous hematopoietic stem cell support provided an incremental advance in the 1990s. The outlook for patients was dramatically improved in the 2000s with the introduction of thalidomide analogs and proteasome inhibitors, so that the 3-year survival of patients treated in 2008 with melphalan and prednisone had increased to 66%. The 2010s are dominated by studying the optimal combination, sequence, and duration of therapies. These clinical advances have occurred along with our evolving understanding of the molecular pathogenesis of myeloma. Myeloma can be divided into two main groups: hyperdiploid, with multiple trisomies of odd-numbered chromosomes, and nonhyperdiploid, with recurrent immunoglobulin heavy chain gene translocations. Disease progression is associated with rearrangements of MYC, the most common mutation in myeloma, present in nearly half of patients. Genomic studies have highlighted marked subclonal heterogeneity that poses one of the main challenges to successful control of the disease. This problem will be addressed in future studies in the 2020s, which will include a focus on immunologic approaches such as monoclonal antibodies, checkpoint inhibitors, engineered T-cells, and novel immunomodulators.
It is not possible in this short review to cover all of the advances that have occurred in the field of multiple myeloma in the last half-century. Instead, I will focus on a select few, providing my perspective, realizing that I am omitting many advances and other perspectives (Fig. 1). Before 1959, chemotherapists were discouraged by the failure of drugs such as urethane, stilbamidine, and antimetabolites to alter the course of the disease. Many cancer treatment centers did not encourage the referral of patients with multiple myeloma unless they had localized lytic bone lesions that could be treated with radiotherapy.1 Two important advances occurred contemporaneously in the early 1960s. One was made by Dr. Michael Potter, of the National Cancer Institute, who developed a spontaneous animal model of multiple myeloma induced by mineral oil in BALB/c mice.2 This model would prove invaluable for the studies of immunology and molecular biology, protein and DNA sequencing, and the development of hybridomas and monoclonal antibodies. The other was made by Dr. Daniel Bergsagel and colleagues in the Southwest Cancer Chemotherapy Study Group who defined response criteria and designed a rolling phase II study of different chemotherapies in patients with multiple myeloma. Given that spontaneous remission of multiple myeloma had not been reported, and no agents induced a response in more then 20% of patients, they calculated that if no responses were seen to a novel agent in 11 patients, they could conclude with a greater than 90% probability that the agent had less than a 20% response rate.3 Using a single protocol, they rapidly examined the activity of a number of drugs; the third drug they reported was melphalan.4 Given the delays associated with starting each new clinical trial, investigators today are re-examining the approach of using rolling clinical trials to examine a series of drugs in a uniform patient cohort.
Improving 5-year survival in multiple myeloma.
Five-year survival rates from the SEER 1975-2010 database are plotted, with the introduction of active drugs noted on the bottom. A dramatic increased rate of improvement was noted for patients diagnosed from 1999 to 2005. If this trend has continued, the 5-year survival for a patient diagnosed in 2014 should be approximately 66%.
The presence of serum and urine paraproteins is a unique feature of multiple myeloma. It is IgG in 52%, IgA in 21%, light chain only in 16%, IgD in 2%, biclonal in 2%, IgM in 0.5%, and without paraprotein in 6.5%. These distinctions provided the basis for the first molecular classification of multiple myeloma with clinical implications. Bergsagel et al reported in Science in 1965 that all patients with light chain kappa multiple myeloma responded to treatment with melphalan, half of patients with a heavy chain responded, and none with light chain lambda responded.5 It did not take long for others to report different results with both Dr. Burton Lee of Memorial Sloan Kettering Cancer Center and Dr. Elliott Osserman of Columbia University writing letters to Science describing several cases of light chain lambda multiple myeloma that had responded to melphalan. Dr. Osserman in particular described two patients, one incapacitated with hypercalcemia and wheelchair-bound who went to playing golf regularly (18 to 27 holes with scores in the 90s), and the other who swam 100 to 150 yards daily.6 In a sign of how times have changed, the latter patient subsequently wrote a letter to Science expressing annoyance with the underestimation of his/her athletic prowess as he/she in fact swam 500 to 550 yards daily during almost 4 years of melphalan treatment.7 It would not be for another 17 years, in 1982, that Science published another article about human myeloma, describing a human multiple myeloma cell line with a Philadelphia chromosome.8 The next Science article about human myeloma appeared 15 years later reporting the presence of Kaposi's herpes virus infection of bone marrow dendritic cells in 1997.9 As with the study from 1965, neither of these latter two studies notably advanced the field. However, after another 17 years, in 2014, Science published a study of human multiple myeloma, this time accepting a pair of back-to-back papers describing the zinc-finger transcription factors Ikaros and Aiolos as the molecular mediators of the anti-multiple myeloma activity of Thalidomide analogs.10,11 Since there were two independent papers submitted, at least this time the editors could be assured the results were reproducible.
It is difficult to overestimate the importance of the BALB/c mineral oil induced plasmacytoma tumor model in modern medicine and biology, which overshadows its importance to the field of multiple myeloma. In myeloma it was used by Dr. Ernest “Bun” McCulloch in his first studies of tumor stem cells.12 And it was used as one of the first immunocompetent mouse tumor models used to develop a predictive model to test chemotherapeutic approaches.13 A major breakthrough came in 1982 when Dr. Michael Cole identified the juxtaposition of the oncogene MYC to the immunoglobulin heavy gene switch region in murine plasmacytomas.14 This stimulated interest in MYC in human multiple myeloma, but the t(8;14) translocation was only rarely identified. About 15 years later, we reported that other oncogenes (CCND1, CCND2, CCND3, MAF, MAFB, MAFA, and MMSET/FGFR3) were frequently (approximately 40%) juxtaposed to the immunoglobulin heavy gene switch region in multiple myeloma.15 And another 15 years later we reported that a promiscuous array of genetic rearrangements frequently (approximately 40%) juxtapose MYC to a variety of enhancers and super-enhancers, making this the most common mutation in multiple myeloma.16 Although obscure at first, it is now clear that both translocations into the IgH switch regions, and the dysregulation of MYC are shared features in the pathogenesis of both human and murine multiple myeloma.
The recurrent IgH chromosome translocations divide multiple myeloma into groups with slightly different clinical features, but markedly different prognosis and response to therapy. The t(11;14), and t(6;14) have a standard prognosis, the t(14;16) and t(14;20) have a poor prognosis, and the t(4;14) an intermediate prognosis. Importantly, several studies suggest that early, and possibly prolonged, use of bortezomib overcomes the early mortality associated with the t(4;14).17 Although this observation eventually formed the basis for risk-adapted therapy in multiple myeloma, it is not widely appreciated that the identification of the IgH translocations in multiple myeloma altered the therapy almost immediately. I was invited to present our work describing the IgH translocation at the International Society of Hematology meeting in 1997. Dr. Judah Folkman was the keynote speaker and presented his radical idea of inhibiting angiogenesis with interferon and thalidomide to treat blood cancers.18 Like many in the audience I was smitten with his ideas, and shortly after I returned home I received a telephone call in my laboratory from the wife of a patient with end-stage multiple myeloma seeking new treatment ideas. She had been going through a list of multiple myeloma researchers, calling them blindly looking for suggestions. I suggested she contact Dr. Folkman to enroll her husband on a clinical trial of thalidomide. With some persistence she managed to speak with Dr. Folkman, and together they convinced her husband's doctor, Dr. Bart Barlogie, to try thalidomide for the treatment of multiple myeloma, leading to the identification of its dramatic activity in the disease.19,20 Although the mechanisms of action of thalidomide in multiple myeloma have not been fully elucidated, inhibition of angiogenesis is not thought to be one of them. A major breakthrough was the identification of cereblon, part of an ubiquitin ligase complex, directly binding to thalidomide.21 And, as noted above, this year it was reported that IMiD binding to cereblon confers on the cereblon ubiquitin ligase complex the ability to ubiquitinate Ikaros and Aiolos, leading to their degradation. Subsequent studies have documented the activity of thalidomide analogs lenalidomide and pomalidomide in the treatment of multiple myeloma.22-24
Not long after the serendipitous identification of the anti-multiple myeloma activity of thalidomide, a deliberate approach to study the therapeutic anticancer effect of proteasome inhibition met with success. Dr. Marion Orlowski was one of the first scientists to describe the proteasome, and his son Robert reported in 1998, using preclinical models, that proteasome inhibition was an effective way to treat cancer, in particular curbing the growth of MYC-related tumors.25 He conducted the phase I study of bortezomib in hematologic malignancies, observing a complete response in the first multiple myeloma treated.26 The addition of bortezomib to melphalan and prednisone was shown to prolong survival compared to melphalan and prednisone, leading to the approval of bortezomib for untreated multiple myeloma.27 The identification of the proteasome as an attractive therapeutic target has led to the discovery of other proteasome inhibitors including carfilzomib,28 approved in 2012, as well as oral inhibitors currently being evaluated in clinical trials (oprozomib and ixazomib).
All of a sudden the field of multiple myeloma treatment was transformed. Finally, after more than 30 years of research it was now possible to improve on melphalan and prednisone.29 There were now four active classes of agents: DNA alkylators, glucocorticoids, IMiDs, and proteasome inhibitors. How best to combine them, sequence them, when to start them, and how long to use them are active research questions for which the answers are not yet known. Some generalizations are possible: (1) The addition of glucocorticoids to each of the other three active agents increases the response rate, but has not been shown to prolong survival. If anything one of the most important studies of the last decade showed that survival was inversely correlated with the dose of dexamethasone administered, so that so-called low-dose dexamethasone (40 mg orally weekly) has become the standard.30 (2) Proteasome inhibitors also combine well with each of the other three classes of active agents and have been shown to prolong survival.27 (3) DNA alkylators and either lenalidomide or pomalidomide have overlapping hematologic toxicity that compromises the delivery of effective doses of both agents when given in combination. For this reason three-drug over four-drug combinations are preferred.
A major focus of research has been on the prolonged use of subtherapeutic doses of an active drug in the absence of observable benefit to the patient, called “maintenance.” Maintenance with melphalan, cyclophosphamide, interferon-alpha, thalidomide, lenalidomide, and bortezomib have all been shown to be more toxic than placebo, to consistently prolong progression-free survival, but not in general overall survival. In most of the studies, only about one half of the placebo group received therapeutic doses of the novel drug at relapse, so that in effect one is comparing a group that all receive the novel drug, to one in which only half of the patients do. Given this inherent bias, it is surprising that a more consistent survival benefit is not seen, and the absence of which suggests that continuous, chronic, subtherapeutic dosing is likely inferior to intermittent therapeutic dosing. Recent genomic studies have identified a high degree of clonal heterogeneity in multiple myeloma that is dynamically modulated under sequential therapeutic pressure.31 Future therapeutic strategies will need to be designed taking this heterogeneity into account.
One way to deal with the heterogeneity is to identify additional active agents with novel mechanisms of action and nonoverlapping toxicity. Examples with single-agent activity in relapsed multiple myeloma include monoclonal antibodies to CD38 (daratumumab and SAR650984), the PIM kinase inhibitor LGH447, and the kinesin spindle inhibitor filanesib.32 Another way to deal with the heterogeneity is to harness the therapeutic power of the immune system. This can be done with checkpoint inhibitors that block the interaction between PD-1 and PD-L1.33 It can also be done with chimeric antigen receptor T or NK cells targeting multiple myeloma–specific antigens (e.g., BCMA).34 Finally, immunomodulatory drugs with novel mechanisms of action are being explored, such as LCL161, an IAP-antagonist that shifts the balance of cytokine signaling in the bone marrow microenvironment away from inflammatory cytokines (e.g., TNFa and IL6), and toward secretion of type I interferon.35
During the last 6 years for which we have data from the SEER database, the 5-year survival rate has been increasing each year by more than 2%. If we continue at this rate we will reach 100% in about 25 years. Given the new active drugs in development, and immunotherapeutic approaches on the horizon, we can be hopeful that we will reach that goal in an even shorter time, and our children will need to focus their attention on other tumors that have lagged behind the advances made in the field of multiple myeloma.
Bergsagel DE, Griffith KM, Haut A, et al. The treatment of plasma cell myeloma. Adv Cancer Res
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Osserman E, Lee B, Korngold L, et al. Melphalan and antigenic type of Bence Jones proteins in myeloma. Science
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Rettig MB, Ma HJ, Vescio RA, et al. Kaposi's sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients. Science
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Shen-Ong GL, Keath EJ, Piccoli SP, et al. Novel myc oncogene RNA from abortive immunoglobulin-gene recombination in mouse plasmacytomas. Cell
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16. Affer M, Chesi M, Chen WG, et al. Promiscuous Rearrangements of the MYC Locus Hijack Enhancers and Super-Enhancers to Dysregulate MYC Expression in Multiple Myeloma. Leukemia. Epub 2014 Feb 12.
Mikhael JR, Dingli D, Roy V, et al. Management of newly diagnosed symptomatic multiple myeloma: Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc
Perez-Atayde AR, Sallan SE, Tedrow U, et al. Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am J Pathol
Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med
Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science
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Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol
San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med
Kuhn DJ, Chen Q, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood
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Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: An open-label randomised controlled trial. Lancet Oncol
Keats JJ, Chesi M, Egan JB, et al. Clonal competition with alternating dominance in multiple myeloma. Blood
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Benson DM Jr, Bakan CE, Mishra A, et al. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: A therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood
Carpenter RO, Evbuomwan MO, Pittaluga S, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res
35. Chesi M, Garbitt V, Palmer S, et al. IAP Antagonists Are a Novel Class Of Immunomodulators That Induce Complete Response In Vk*MYC Myeloma By Stimulating Plasmacytoid Dendritic Cells To Secrete IFNa. Blood. 2013;122:128a.