Clarification of the Definition of Complete Response in Multiple

Home , Antibody, Immunofixation

Letters to the Editor 2416 9 Lacy MQ, Hogan WJ, Gertz MA, Dispenzieri A, Rajkumar SV, Hayman S et al. multiple myeloma: a retrospective review from a tertiary referral center. Bone Successful treatment of scleromyxedema with autologous peripheral blood stem Marrow Transplant 2013; 48: 1302–1307. cell transplantation. Arch Dermatol 2005; 141: 1277–1282. 11 D'Souza A, Lacy M, Gertz M, Kumar S, Buadi F, Hayman S et al. Long-term 10 Dispenzieri A, Seenithamby K, Lacy MQ, Kumar SK, Buadi FK, Hayman SR et al. outcomes after autologous stem cell transplantation for patients with POEMS Patients with immunoglobulin light chain amyloidosis undergoing autologous syndrome (osteosclerotic myeloma): a single-center experience. Blood 2012; 120: stem cell transplantation have superior outcomes compared with patients with 56–62.

Clariﬁcation of the deﬁnition of complete response in multiple myeloma

Leukemia (2015) 29, 2416–2417; doi:10.1038/leu.2015.290 Table 1. Clariﬁcation of the deﬁnition of complete response in multiple myeloma

In 2006, the International Myeloma Working Group (IMWG) Response Response criteriaa 1,2 published uniform response criteria for multiple myeloma (MM). subcategory These criteria with a minor clarifications have been widely used to measure the effectiveness of myeloma therapy clinical trials.3 The Complete No evidence of initial monoclonal protein isotype(s) fi b development of effective monoclonal antibodies for the treatment response (CR) on immuno xation of the serum and urine of MM, such as elotuzumab and daratumumab have brought to our Disappearance of any soft tissue plasmacytomas ⩽ 5% plasma cells in bone marrow attention an urgent problem in which patients achieving complete response (CR) can be erroneously classified using the IMWG criteria. In some cases it is possible that the original M protein light-chain isotype is As currently written, CR in MM requires negative immunofixation for still detected on immunofixation but the accompanying heavy-chain monoclonal (M) protein in the serum and urine. The intended purpose component has disappeared; this would not be considered as a CR even of this requirement was to demonstrate that the M protein secreted by though the heavy-chain component is not detectable, since it is possible MMcellsisnolongerdetectable(Table1).Wearenowawarethatnew that the clone evolved to one that secreted only light chains. Thus, if a patient has IgA lambda myeloma, then to qualify as CR there should be no monoclonal antibodies developed for the treatment of MM (e.g., IgA detectable on serum or urine immunofixation; if free lambda is daratumumab and elotuzumab) interfere with the assay by immuno- detected without IgA, then it must be accompanied by a different heavy- fixation since they appear as M proteins on immunofixation. An chain isotype (IgG, IgM, etc). aModified from Durie et al.1bRequires two abnormal immunofixation result due to interference of the assay by a consecutive assessments to be carried out at anytime before the institution therapeutically administered M protein was not foreseen by us. of any new therapy. The purpose of this letter is to clarify that CR requires disappearance of the original M protein associated with MM on AUTHOR CONTRIBUTIONS immunofixation, and that the determination of CR is not affected by unrelated M proteins that are secondary to therapeutically BGMD, JFSM, JB and SVR reviewed the literature and wrote the administered monoclonal antibodies, biclonal gammopathy, or manuscript. All authors reviewed and approved the final manuscript. post-therapy/transplant monoclonal/oligoclonal reconstitution phenomenon. Thus, for example, if a patient with IgA kappa MM treated with a monoclonal antibody has disappearance of the CONFLICT OF INTEREST fi original M protein but has a positive immuno xation for IgG BGMD has been on the independent review committees for Onyx, Janssen and kappa, this finding will not negate the determination of CR. In this Takeda. JFSM has been on the advisory committees for Janssen, Bristol-Myers Squibb, case, the IgG kappa M protein will be considered as an artifact Sanofi, Millennium, Celgene, Novartis and Onyx. JB has received honoraria for from a therapeutically administered antibody (e.g., daratumumab lectures from Janssen and honoraria for advisory boards from Janssen and Bristol and elotuzumab are both IgG kappa monoclonal antibodies). Meyers Squibb. The remaining authors declare no conflict of interest. Therefore, in order to ensure accuracy, and to reflect the original intended meaning and definition, we have revised the BGM Durie1, JFS Miguel2, J Blade3 and SV Rajkumar4 on behalf of wording of the IMWG definition of CR (Table 1). This clarification is the International Myeloma Working Group critical to enable accurate assessment of CR in trials with 1Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA, USA; monoclonal antibodies in MM. We recognize that the clarification 2Clinica Universidad de Navarra, Centro de Investigacion Medica will still result in a modest underestimation of the true CR rate in Aplicada (CIMA), IDISNA, Pamplona, Spain; trials using monoclonal antibodies since it is impossible to 3Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i distinguish the therapeutic antibody from the patients’ M protein Sunyer (IDIBAPS), Barcelona, Spain and if they happen to be of the same heavy- and light-chain isotype. 4Division of Hematology, Mayo Clinic, Rochester, MN, USA Thus, further updates will be forthcoming once we have validated E-mail: [email protected] new assays that can distinguish the two with accuracy. In this regard, we are encouraged by data on a new daratumumab immunofixation reflex assay, in which the binding of an anti-idiotypic antibody REFERENCES to daratumumab altered its electrophoretic migration and thus 1 Durie BGM, Harousseau J-L, Miguel JS, Blade J, Barlogie B, Anderson K et al. Interna- distinguished the therapeutically administered monoclonal antibody tional uniform response criteria for multiple myeloma. Leukemia 2006; 20:1467–1473. 4 from M protein secreted by MM cells. TheroleoftheHevylite(San 2 Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K et al. Inter- Diego, CA, USA) assay (for lgA and IgG), which has a sensitivity level national uniform response criteria for multiple myeloma (corrigenda/erratum). typically seen with immunofixation, will also need to be studied. Leukemia 2007; 21: 1134.

Accepted article preview online 21 October 2015; advance online publication, 13 November 2015

Leukemia (2015) 2402 – 2448 © 2015 Macmillan Publishers Limited Letters to the Editor 2417 3 Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R et al. 4 McCudden P, Axel A, Slaets D, Frans S, Bald J, Schecter JM et al. Assessing clinical Consensus recommendations for the uniform reporting of clinical trials: report response in multiple myeloma (MM) patients treated with monoclonal antibodies of the International Myeloma Workshop Consensus Panel 1. Blood 2011; 117: (mAbs): validation of a daratumumab IFE reﬂex assay to distinguish malignant 4691–4695. M-protein from therapeutic antibody. J Clin Oncol 2015; 33. (abstr 8590).

Illness and artistic creativity (on the 70th anniversary of the death of Béla Bartók, composer, ethnomusicologist and leukemia patient)

Leukemia (2015) 29, 2417–2418; doi:10.1038/leu.2015.221

The 26 September 2015 marks the 70th anniversary of the death of the Hungarian composer Béla Bartók, one of the most important composers of the 20th century, who became famous not only for his ethnomusicological studies recording the folk music of the Hungarian people, but also for his physical suffering due to several illnesses which, ultimately, caused his premature death. Béla Bartók was born in Hungary in 1881 and received first musical training on the piano from his mother. His musical talent was so remarkable that he was already composing at age 8 and he gave his first public appearance at age 10. He studied piano and composition at the Royal Academy of Music in Budapest from 1899 until 1903, and was inspired by many, but his music was genuinely Hungarian in style. Soon after leaving the academy, Béla Bartók and Zoltán Kodály, another Hungarian composer, began recording and analyzing folk Figure 1. The Hungarian composer, pianist and ethnomusicologist fi fi 1–4 Béla Bartók sitting at the piano in New York in an undated photo music, both as collectors and proli c scienti c investigators. (picture-alliance/dpa). This ethnomusicological research also heavily influenced Bartók’s own compositions. After meeting Claude Debussy, Bartók and in September for a long time. I feel the same now as I felt abandoned romanticism, adapted a more radical composing style fi ‘ ’ then. If I had stayed there, they would have molested me without and became one of the rst to write in a neo-classical manner any result until I would have got bored with it.’ In New York using some of the ancient scales from Hungarian folk music and financial hardship and disillusionment with world politics added to adopting a 12-tone scale enabling him to use various new Bartók’s state of poor health. He was no longer composing, as his harmonic combinations. spirit had been broken. On 20 June 1941 he wrote to his son: Owing to his vehement disapproval of the political change in ‘ fi I have become depressed by the frustrations I have encountered Hungary due to the nazi cation of Germany, Bartók and his wife ’ emigrated to the United States in 1940 (see Figure 1). In New York in personal and other matters . After receiving X-rays of his abdomen later that year Bartók Columbia University conferred the degree of Doctor of Music wrote: ‘... The doctor, the one who examined my ‘inwards’ in July, upon Bartók, where he transcribed and assembled Yugoslav folk songs and gave lectures, but his financial situation was insecure radiographs my left shoulder. The result is 00. But it is all the same, fi because I can play the piano, but I could do that before the X-ray and his deteriorating health was a detriment to his scienti c and ’ ’ musical activities. invasion as well . From April 1942 to February 1943 Bartók s Bartók‘s health had been poor throughout his life and had an symptoms worsened and he frequently had fevers to 39° C and ’ important part in the difficulties he faced. In 1924, when Bartók pulmonary symptoms. Eventually, the doctors diagnosed Bartók s ‘ ’ was 43 years old, there was first mention of pain in his shoulders disease as an atypical myeloid leukemia , but kept this diagnosis ‘ ’ and arms, which was likely bone pain and represented the disease, from the patient and instead called the disease a polycythemia . which ultimately led to his death—chronic myelogenous leuke- Bartók was frequently sent to Saranac Lake, NY, USA, for respite, mia. Aspirin cures improved the pain, but in 1929 the pain in his where short glimpses of improvement and hope were inter- shoulders was so severe that he was unable to play the piano, spersed with periods of deteriorating health and worsening jeopardizing his public concerts and career. In fact, one critic at symptoms. On 30 June 1943 Bartók wrote: ‘… Iamunfit for any the time wrote: ‘Bartók’s piano-playing could be enjoyed in its continuous work outside of my house. The doctors cannot find out perfect beauty because of his heroic self-control’. In 1940 the the cause of my illness; therefore, no cure and no treatment is prodrome of his disease became stronger, but it had not yet been possible, and the prospects of the future are rather gloomy…..’. diagnosed. In March 1941 he wrote from the United States: ‘I just And 2 months later: ‘….as one of them (the doctors) put it ‘it is a realize, that I haven’t written anything at all about the state of my baffling case’. But this is getting to be a rather annoying subject, shoulders. I should say that nothing changed after all. The one so I leave it.’ that was aching, is sometimes getting better, then it aches again. A marked change occurred in Bartók when Serge Koussewitzky, Of course I don’t do anything to it at all; I am convinced that the the music director of the Boston Symphony Orchestra, visited whole cure was useless, when they pulled it and so on in August Bartók in his hospital room in New York City in September 1943.

Accepted article preview online 11 August 2015; advance online publication, 4 September 2015